This document summarizes recent trends in colorectal cancer incidence among young adults in the United States. It finds that rates of colorectal cancer among those under 50 have been rising about 2-3% annually since the early 1990s. This is concerning as colorectal cancer typically affects older adults. Risk factors like obesity, lack of physical activity, and unhealthy diets may be contributing to earlier onset of the disease. More research is still needed to understand the full causes of the increasing trends in young adults. The document recommends awareness of family history to guide early screening when appropriate.
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Early age onset_colorectal_cancer_2015
1.
2.
3.
4.
5. Increase in incidence of colorectal cancer
among young adults in the US
Rebecca Siegel, MPH
Surveillance & Health Services Research Program
March 21, 2015
6. Among <50 years: 13,000 cases and 3,000 deaths
Estimated numbers of new cases & deaths in 2015
7. Top 5 cancers, ages 20-49 years
Lung (18%)
Colorectum (12%)
Brain (8%)
Leukemia (7%)
Pancreas (5%)
Breast (26%)
Lung (15%)
Colorectum (8%)
Cervix uteri (7%)
Ovary (5%)
Colorectum (10%)
Testis (9%)
Prostate (9%)
Melanoma (8%)
NHL (7%)
Incidence Mortality
Breast (36%)
Thyroid (12%)
Melanoma (7%)
Colorectum (5%)
Cervix uteri (5%)
Men Women Men Women
8. Anatomy of the colorectum
(right-sided colon)
(left-sided colon)
9. Subsite distribution by age at diagnosis
0-49 years 50+ years
Proximal 25% 43%
Distal 27% 23%
Rectum 41% 28%
Other 8% 6%
Right side
Left side
11. 0
10
20
30
40
50
60
70
1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011
Rateper100,000
Year of diagnosis
Colorectum, 3% per year
Colon, 3% per year
Rectum, 2% per year
Incidence trends overall, 1975-2011
Source: SEER 9 registries, 1975-2011.
Declines during 2002-2011:
12. The American Surgeon, Oct
2003
SEER 9, 5,383 patients 20-39 yrs
1973-1999
Cancer Epidemiol, Biomarkers, &
Prevention, June 2009
SEER 13, 20,646 patients 20-49 yrs
1992-2005
The American Surgeon, Sept
1998
LSU Medical Ctr, 37 patients < 40
1976-1997
Awareness of the increase in early-onset disease
13. Incidence trends by age: 50+ versus 20-49
Source: SEER 9 registries, 1975-2011; 2-yr moving average.
0
2
4
6
8
10
12
14
1975-
76
1980-
81
1985-
86
1990-
91
1995-
96
2000-
01
2005-
06
2010-
11
Rateper100,000
Men
Women
45%
2% per year
Since 1993-1994
0
50
100
150
200
250
300
1975-
76
1980-
81
1985-
86
1990-
91
1995-
96
2000-
01
2005-
06
2010-
11
Rateper100,000
Men
Women
Ages 50+ Ages 20-49
15. Incidence trends by stage at diagnosis, ages 20-49 years
Source: SEER 9 registries, 1975-2011; 2-year moving average.
0
0.5
1
1.5
2
2.5
3
1975-76 1980-81 1985-86 1990-91 1995-96 2000-01 2005-06 2010-11
Colon
Localized
Regional
Distant
0
0.5
1
1.5
2
2.5
3
1975-76 1980-81 1985-86 1990-91 1995-96 2000-01 2005-06 2010-11
Rectum
Localized
Regional
Distant
Rateper100,000
3.6% per year from
2002-2011
2.9% per year
from 2002-2011
16. Trends by histologic subtype, 20-49 years
Mucinous
Signet-ring cell
Adenocarcinoma, NOS
Source: SEER 9 registries and Joinpoint Regression Program.
17. Incidence trends by 10-year age group
40-49
2% per year
30-39
2% per year
20-29
3% per year
0
5
10
15
20
25
30
1975-
76
1980-
81
1985-
86
1990-
91
1995-
96
2000-
01
2005-
06
2010-
11
Rateper100,000people
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
20-29 years
Source: SEER 9 registries, 1975-2011; 2-year moving average.
20-29 years
5%
30-39 years
20%
40-49 years
75%
Increase during 2002-2011:
22. Mortality trends in ages 20-49 years
0
0.5
1
1.5
2
2.5
3
3.5
4
Deathsper100,000
20-49 years
Source: National Center for Health Statistics, National Vital Statistics System.
0
20
40
60
80
100
120
50+ years
23. Factors that influence population cancer trends
Detection/imaging
practices
Risk factors
Screening behaviors MortalityIncidence
Treatment
Increase in: Incidence Mortality
Risk factor ↑ ↑
Screening ↑ ↓
Detection/imaging practice ↑ Possible artifactual ↑
Effective treatment No effect ↓
24. Colorectal cancer risk factors: medical and family history
Relative risk
Family history
1 first-degree relative 2.2
More than 1 relative 4.0
Relative with diagnosis
before age 45
3.9
Medical history
Inflammatory bowel disease
Crohn disease 2.6
Ulcerative colitis
Colon 2.8
Rectum 1.9
Diabetes 1.2
26. Trends in obesity and diabetes
0
5
10
15
20
25
1971-74 1976-80 1988-94 1999-02 2003-06 2007-08 2009-10 2011-12
Percent
Ages 6-11
Ages 12-19
6%
Obesity prevalence
6
16
0
2
4
6
8
10
12
14
16
18
20
1980
1982
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
2004
2006
2008
2010
Rateper1,000
167%
Diabetes, ages 0-44 years
21%
Source: National Health and Nutrition Examination Survey. Source: National Health Interview Survey.
27. Obesity and colorectal cancer: pooled relative risk
Ning et al. A quantitative analysis of body mass index and colorectal cancer: findings from 56 observational studies. Obesity
Reviews 2010.
Relative risk (95% CI)
BMI
<23.0
BMI > 30
Subsite Colon 1.0 1.49 (1.35,
1.63)
Rectum 1.0 1.26 (1.17,
1.37)
Sex Men 1.0 1.53 (1.44,
1.62)
Women 1.0 1.25 (1.14,
30. Trends in beverage consumption
Nielsen et al. Changes in beverage intake between 1977 and 2001. Am J Prev Med 2004.
0
2
4
6
8
10
12
14
2-18 yrs 19-39 yrs 2-18 yrs 19-39 yrs
Sweetened beverages Milk
Percentoftotaldailycalorieintake
1977-78
1989-91
1994-96
1999-01
31. State patterns in obesity and CRC incidence rates
Obesity prevalence, ages 18-49, 2001 CRC incidence rates, ages 20-49, 2007-2011
Pearson’s r = 0.57
Source: Behavioral and Risk Factors Surveillance System Source: US Cancer Statistics, WONDER Online Database
32. Most colorectal cancers are due to unknown risk factors
Source: The Cancer Atlas, 2nd Edition
Up to 87% of colorectal cancers worldwide are
due to unknown risk factors.
33. Strategies for reducing colorectal cancer risk
Maintain a healthy weight
Be physically active
Consume a healthy diet
Limit alcohol consumption
Consume recommended levels of calcium
Avoid tobacco products
Screening at 50, OR earlier with a family history of
adenomas or CRC
34. Who should begin screening before 50?
High risk Age to begin
Familial adenomatous polyposis (FAP) 10-12 years
Lynch syndrome 20-25 years*
Inflammatory bowel disease
(ulcerative colitis or Crohn disease)
Varies depending on
age at onset
*Or 10 years before youngest case in immediate family
35. Who else should begin screening before 50?
Increased risk Age to begin
Cancer/adenomas in a first-degree
relative
40 years OR
10 years before
youngest case
Cancer in > 2 second-degree relatives 40 years
36. Conclusions
• CRC incidence rates continue to increase in young adults
• Know when to begin screening based on your family history
• Increase awareness to hasten follow-up of symptomatic young adults
1. Rectal bleeding
2. Abdominal pain
3. Change in bowel habits
• Critical need for further research to elucidate the cause of this trend
39. American Cancer Society CRC screening guidelines
• Increase unestablished during previous evidence review
• In beginning stages of guideline review; independent, systematic review of
the literature, including harms & benefits of screening
• Current evidence may justify earlier screening
• Benefits must outweigh harms at the population level
rare before 50 (0.3%)
3 serious adverse events (perforation, adverse reaction to sedation) per 1,000
colonoscopies
cost
40. Percentage of individuals who develop CRC by specific age
0.00%
0.50%
1.00%
1.50%
2.00%
2.50%
3.00%
3.50%
4.00%
4.50%
5.00%
15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 95+
Age (years)
41. Harms & limitations of colonoscopy screening
• 33% of patients report at least 1 GI symptom following the
procedure
• Serious adverse event rate: 2.8 per 1,000
• Adverse reaction to the sedative
• Bleeding if a polyp or tissue sample is taken
• Perforation of the colon wall
• Screening won’t detect all cancers
46. Defining Body Mass Index (BMI)
Weight
(kg)
Height
(m)2
BMI =
For children & adolescents, obesity is
defined as a BMI > the 95th percentile
based on age/sex-specific growth
charts developed by CDC
49. What is a colon adenomatous polyp?
Polyps begin in the cells of glandular
structures lining the colon. Most polyps are
benign, but one kind is the cause of greater
concern–the colon adenomatous polyp
(adenoma). This growth is associated with
DNA changes in the lining of the colon. Polyps
can become cancerous if undetected or
ignored.
51. ACS screening guidelines – average risk
Men and women, ages 50+ Frequency
Fecal occult blood test (FOBT)
with at least 50% test
sensitivity for cancer, or fecal
immunochemical test (FIT) with
at least 50% test sensitivity for
cancer
Annual
Stool DNA test Every 3 years
Flexible sigmoidoscopy Every 5 years
Double contrast barium enema Every 5 years
Colonoscopy Every 10 years
CT colonography Every 5 years
52. Trends in the use of screening tests (ages 50-75)
0
10
20
30
40
50
60
70
80
2000 2003 2005 2008 2010 2013
Percentage
Any exam
Colonoscopy (10 yrs)
FOBT (past year)
Sigmoidoscopy (5 yrs)
54. THE CLINICAL CHALLENGES OF EAO-
CRC :
REDUCING LATE STAGE DIAGNOSIS;
IMPROVING SURVIVAL
Y. Nancy You, MD, MHsc
Assistant Professor
Department Of Surgical Oncology
Medical Director
Familial High-risk Gastrointestinal Cancer Clinic
University Of Texas MD Anderson Cancer Center
March 21, 2015
55. • Persistently increasing incidence
• Majority between ages of 40-49
• Predominately located in distal colon and rectum
• Advanced-stage disease at presentation
CLINICAL CHALLENGES OF EAO-CRC
UNIQUE FEATURES OF EAO-CRC: SUMMARY
56. 39 year-old dental hygienist
Single mother; estranged family
Grandmother, colon cancer in
60’s
Intermittent rectal bleeding > 1
year
ER visit x 3, no work-up
CLINICAL CHALLENGES OF EAO-CRC
AN ILLUSTRATION
57. COLORECTAL CANCER TRENDS
39 YEAR-OLD, STAGE IV RECTAL CANCER
5/year 0
Chemo
10-12/year0
Liver
surgery
#1
Liver
surgery
#2
Chemo +
Radiation
5/year 1 11/year 1
Rectal
surgery
#1
Chemo
Rectal
surgery #2;
Liver
surgery #3
8/year 3 –
3/year 4
Chemo Chemo
Hospice
2/year 2
58. CLINICAL CHALLENGES OF EAO-CRC
OUTLINE
• What are the clinical challenges ?
• How can we improve ?
59. CLINICAL CHALLENGES OF EAO-CRC
WHAT ARE THE CHALLENGES
Interrupts adulthood
Stresses support network
Hereditary? Genetic?
Delay in self referral
Variable access to care
Late-stage at diagnosis
39 year-old dental hygienist
Single mother; estranged
family
Grandmother, colon cancer in
60’s
Intermittent rectal bleeding >
1 year
ER visit x 3, no work-up
60. CLINICAL CHALLENGES OF EAO-CRC
WHAT ARE THE CHALLENGES
Multiple treatments
Many modalities
Long time
Treatment-related
toxicities/adverse effects
Variable survival outcome
Quality of survival
5/year 0
Chemo
10-12/year0
Liver
surgery
#1
Liver
surgery
#2
Chemo +
Radiation
5/year 1 11/year 1
Rectal
surgery
#1
Chemo
Rectal
surgery #2;
Liver
surgery #3
8/year 3 –
3/year 4
Chemo Chemo
Hospice
2/year 2
61. CLINICAL CHALLENGES OF EAO-CRC
OUTLINE
• What are the clinical challenges ?
• Focusing on Survival
• How can we improve ?
62. Bleyer et al. Nature Reviews Oncology. 2007.
CLINICAL CHALLENGES OF EAO-CRC
SURVIVAL : SEER 1993-1998
63. CLINICAL CHALLENGES OF EAO-CRC
OUTLINE
• What are the clinical challenges ?
Focusing on Survival
• What influences survival and how can we improve ?
Stage of disease
Treatment
Quality of life
64. You et al. Arch Int Med.
CLINICAL CHALLENGES OF EAO-CRC
NCDB, 1998-2007
Age 18-49 Years (N=64,068) vs. Age 50+ Years (N=524,801)
65. Age-adjusted CRC death
rate has declined between
1975-2005
Factors thought to contribute to the
decline in death rate:
CLINICAL CHALLENGES OF EAO-CRC
AGE-ADJUSTED DEATH RATE: DECLINED 1975-2005
66. All CRC
~ 5%
“Hereditary”
Burt et al. Gastroenterology 2000.
CLINICAL CHALLENGES OF EAO-CRC
SUBGROUPS OF CRC & SCREENING GUIDELINES
3-5%
67. All CRC
~ 5%
“Hereditary”
CLINICAL CHALLENGES OF EAO-CRC
SUBGROUPS OF CRC & SCREENING GUIDELINES
Start Frequency
High Risk
(“Heredita
ry”)
Hereditary
syndromes;
Inflammatory
bowel
syndrome etc
Teen-25;
8 years of
disease
Every 1-2
years
Increased
Risk
(“Familial
”)
Family history;
Prior polyp or
cancer
Age 40, or 10
years before the
youngest case in
the immediate
family,
Every 3-5
years
Average
Risk
(“Sporadi
Age 50 Every 7-10
years
American Cancer Society
68. You et al. ASCRS Annual Meeting 2013.
• 223 CRC patients aged 18-50
• Stratify by Tumor mismatch repair (MMR) status & Family history
CLINICAL CHALLENGES OF EAO-CRC
APPLYING TO EAO-CRC SUBGROUPS
69. All CRC
~ 5%
“Hereditary”
CLINICAL CHALLENGES OF EAO-CRC
SUBGROUPS OF CRC & SCREENING GUIDELINES
Goal
High Risk
(“Hereditary”)
Defined and effective
prevention, surveillance
strategies exist
Make the diagnosis
• Clinical suspicion
• Proband and family
diagnosis /Registry
73. All CRC
~ 5%
“Hereditary”
CLINICAL CHALLENGES OF EAO-CRC
SUBGROUPS OF CRC & SCREENING GUIDELINES
Goal
High Risk
(“Hereditary”)
Defined and effective
prevention, surveillance
strategies exist
Make the diagnosis
• Clinical suspicion
• Proband and family
diagnosis /Registry
Increased
Risk
(“Familial”)
Guidelines for
screening younger
than age 50 exist
Know family history
Engage in screening
Average Risk
(“Sporadic”)
Symptom to diagnosis
time
74. CLINICAL CHALLENGES OF EAO-CRC
OUTLINE
• What are the clinical challenges ?
• What influences survival and how can we improve ?
Stage of disease
Treatment
Quality of life
75. THE IMPACT OF YOUNG AGE ON SURVIVAL IN
PATIENTS WITH METASTATIC COLORECTAL
CANCER: ANALYSIS FROM THE ARCAD
CLINICAL TRIALS PROGRAM
CHRISTOPHER H. LIEU, LINDSAY RENFRO, AIMERY DE
GRAMONT, TIMOTHY S. MAUGHAN, MATTHEW T.
SEYMOUR, LEONARD SALTZ, RICHARD M. GOLDBERG,
DAN SARGENT, S. GAIL ECKHARDT, CATHY ENG
75
Courtesy of Dr Cathy Eng
CLINICAL CHALLENGES OF EAO-CRC
SAME TREATMENT, WORSE OUTCOME ?
Lieu et al. JCO 2014
76. Overall Survival
Age in Years
RelativeHazard
1.0
1.2
1.4
1.6
1.8
20 40 60 80
p < 0.0001
Progression-Free Survival
Age in Years
RelativeHazard
1.0
1.1
1.2
1.3
1.4
20 40 60 80
20,000 patients enrolled to 22 first-line phase III trials
ARCAD Foundation Colorectal Database
OS 1-year: 28% increased risk
of death (REF: age 57)
p < 0.0001
PFS 1-year: 28% increased risk
of progression (REF: age 61)
Lieu et al. JCO 2014
77. You et al. In Press JAMA Surgery
NCDB,
2003 to 2005
OR for
Chemo
(95% CI)
OR for Multi-
agent
regimen
(95% CI)
5-year
Adjusted
Relative
Survival (No
chemo)
5-year
Adjusted
Relative
Survival
(Chemo)
Stage I
Aged 65-75
(n=8,991)
1 1 96.8 --
Aged18-49
(n=1,926)
2.88
(2.21-3.77)
1.38
(0.71-2.68)
98.4 --
Stage II low risk
Aged 65-75
(n=4822)
1 1 89.2 95.4
Aged18-49
(n=1636)
4.22
(3.70-4.81)
1.67
(1.34-2.09)
93.3 95.2
CLINICAL CHALLENGES OF EAO-CRC
OVER-TREATMENT, NO BETTER OUTCOME ?
78. NCDB,
2003 to
2005
OR for
Chemo
(95% CI)
OR for Multi-
agent
regimen
(95% CI)
5-year Adjusted
Relative
Survival (No
chemo)
5-year
Adjusted
Relative
Survival
(Chemo)
Stage II high risk
Aged 65-75
(n=6189)
1 1 74.6 85.8
Aged18-49
(n=1447)
3.69
(3.23-4.20)
1.77
(1.46-2.14)
78.9 87.7
Stage III
Aged 65-75
(n=11202)
1 1 39.1 71.0
Aged18-49
(n=4780)
2.42
(2.18-2.68)
1.75
(1.58-1.93)
54.7
0.64(0.57-0.71)
73.7
0.84(0.79-0.9)
CLINICAL CHALLENGES OF EAO-CRC
OVER-TREATMENT, NO BETTER OUTCOME ?
You et al. In Press JAMA Surgery
79. CLINICAL CHALLENGES OF EAO-CRC
OUTLINE
• What are the clinical challenges ?
• What influences survival and how can we improve ?
Stage of disease
Treatment
Quality of life
80. 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0%
Benefits
Positive feelings
Family distress
Recurrence distress
Appearance concerns
Financial problems
Sexual dysfunction
Sexual disinterest
Social avoidance
Fatigue
Physical pain
Cognitive problems
Negative feelings
QUALITY OF LIFE IN ADULT CANCER SURVIVORS (QLACS)
% of Scores ≥ 4 per Domain
YS LS
• 830 (68%) survivors responded
• 282 Young-onset (43.4 ± 6.1 years)
• 548 Later-onset (62.6 ± 7.5 years)
• Mean years from diagnosis: 10.8 years*
*
*
*
*
*
*
*
81. EORTC CR-29 (SCORE > 3)
*P<0.05
34.2
19.5
57.3
23.0
20.5
13.4
40.2
16.4
0 10 20 30 40 50 60 70
* Anxiety
* Body image
* Male sexual function
* Female sexual function
Percent of Respondents Reporting Score > 3
Young-Onset Survivors Late-Onset Survivors
CLINICAL CHALLENGES OF EAO-CRC
FUNCTIONAL OUTCOMES & CANCER SURVIVORSHIP
82. CLINICAL CHALLENGES OF EAO-CRC
SUMMARY
• Key challenge : improve survival
• Factors that influence survival
Stage of disease :
Reduce late-stage diagnosis
Treatment :
Optimize benefit (response) vs. risk
(toxicity)
Quality of life :
Maximize quality
84. Hereditary Colorectal Cancer
Syndromes and the Contribution
to Early Age Onset Colorectal
Cancer
Fay Kastrinos MD, MPH
Columbia University Medical Center
Herbert Irving Comprehensive Cancer Center
Hereditary GI Cancer Risk and Prevention Program, Director
87. Genes Associated with a
High Risk of Colorectal Cancer
Gene Syndrome Hereditary Pattern Predominant Cancer
Tumor suppressor genes
APC FAP/ Attenuated
polyposis
Dominant Colon, intestine, etc.
STK11 Peutz-Jeghers Dominant Multiple (including intestine)
PTEN Cowden Dominant Multiple (including intestine)
BMPR1A Juvenile polyposis Dominant Gastrointestinal
SMAD4 (DPC4) Juvenile polyposis Dominant Gastrointestinal
Repair/Stability genes
hMLH1, hMSH2, hMSH6,
PMS2
Lynch Dominant Multiple (including colon, uterus, and
others)
MYH (MutYH) Attenuated polyposis Recessive Colon
88. How common is CRC in adults
younger than 50?
• ~10% of CRCs arise in men and women <50
yrs
140,000 new cases, 2014
• Incidence in US is 7 per 100,000 people/year
(<50) vs 130 per 100,000 people/year (≥50)
14,000
10% <50 years
89. How common are inherited CRC
syndromes in EAO-CRC?
• ~10% of EAO-CRC is attributed to known
inherited CRC syndromes
– 14,000 ~1,400 total cases
• Likely underestimated
– This has not been comprehensively studied
• What about the pool of “at-risk” individuals?
10%
90.
91. Lynch Syndrome
Most prevalent hereditary CRC syndrome
5% of all CRC
Defective DNA Mismatch Repair
Mutations in MLH1, MSH2, MSH6, PMS2
Lifetime risk of CRC ~60%; endometrial cancer ~40-
60%
Risk is markedly lower if colonoscopies begin early
92. Lynch Syndrome Results
From Failure of Mismatch
Repair (MMR) Genes
Base pair
mismatch
Normal
DNA repair
Defective DNA
repair (MMR+)
T CTA C
A G C T G
T C G A C
A G C T G
T CTA C
A G C T G A G A T G
T C T A C
93. Mismatch Repair Failure Leads
to Microsatellite Instability (MSI)
Normal
Microsatellite
instability Addition of
nucleotide repeats
94. Lynch Syndrome Clinical
Features
Striking family history affecting
multiple generations
Early (but variable) age at CRC
diagnosis (mean 45 years)
Multiple primary cancers
Extracolonic cancers:
Endometrium
Ovary
Urinary tract
Stomach
small bowel
sebaceous carcinomas of skin
95. Lynch Syndrome
• Sine qua non is identification of a germline mutation
• Families originally identified based
on Amsterdam Criteria (AC-I)
• ≥ 3 cases of CRC
• ≥ 2 generations affected
• at least one CRC< 50 years
• no evidence of FAP
• 50% of AC-I families do not have a MMR mutation
• Testing only those who meet AC fails to detect 50%
96. Clinical Criteria for the Identification of
Lynch Syndrome
• Revised Bethesda Guidelines
– Incorporates MSI testing, extracolonic cancers
– Cumbersome criteria to apply regularly which makes
uptake low
– Testing those who meet any of the Bethesda criteria would
fail to detect 30% of gene mutations carriers
97. Lynch syndrome and EAO-CRC
• Lynch syndrome accounts for 3-4% of ALL
CRCs, regardless of ages
• What % of EAO-CRC is due to Lynch
syndrome?
• Few studies have examined random samples
of the prevalence among CRC patients <50
years
98. Lynch syndrome and EAO-CRC
• US study examining the prevalence of Lynch
syndrome
– Unselected, population-based sample
– Young-onset CRC cases diagnosed <50 years
– Identified through the CCFR
• Results: 195 eligible subjects
– Mean age of diagnosis: 43 years
– 5.6% (11/195) had MMR gene associated with
Lynch syndrome
Limburg PJ et al. Clin Gastroenterol Hepatol. 2011;9(6):497-502
99. Lynch syndrome and EAO-CRC
• Spanish study examining the prevalence of
Lynch syndrome
– Unselected, population-based sample
– Young-onset CRC cases diagnosed <50 years
– Identified through 2 surgical centers in Spain
• Results: 140 eligible subjects
– Mean age of diagnosis: 44.1 years
– 7.8 (11/140) had MMR gene associated with
Lynch syndrome
Giraldez MD et al. Clin Cancer Res. 2010; 16: 5402-5413.
100. Summary of Lynch syndrome and
contribution on EAO-CRC
• 3-4 % of all CRCs, regardless of age, are due
to Lynch syndrome
• 6-8% of EAO-CRC are due to Lynch syndrome
• Largest impact for at-risk individuals
– Early identification of mutation carriers prevents
cancer
101. Hereditary GI Cancer Syndromes:
How good are we at identifying
families with germline mutations?
Proband
HEREDITARY GI CANCER SYNDROME
Germline Testing
Pedigree
Clinical Criteria
+/- tumor testing
+
?
102. Hereditary GI cancer syndromes:
What have we learned from
clinical genetic testing?
• Ability to define new conditions from
existing ones
• Familial Colorectal Cancer Type X
• Identification of new gene mutations
• MYH associated polyposis
103. Original Contribution. JAMA. 2005;293(16):1979-1985.
Lower Cancer Incidence in Amsterdam-I Criteria Families Without Mismatch
Repair Deficiency: Familial Colorectal Cancer Type X
Noralane M. Lindor, MD; Kari Rabe, MS; Gloria M. Petersen, PhD; Robert Haile, PhD; Graham Casey,
PhD; John Baron, MD; Steve Gallinger, MD; Bharati Bapat, PhD; Melyssa Aronson, MSc, CGC; John
Hopper, PhD; Jeremy Jass, MD; Loic LeMarchand, MD, PhD; John Grove, PhD; John Potter, MD, PhD;
Polly Newcomb, PhD; Jonathan P. Terdiman, MD; Peggy Conrad, MS; Gabriella Moslein, MD; Richard
Goldberg, MD; Argyrios Ziogas, PhD; Hoda Anton-Culver, PhD; Mariza de Andrade, PhD; Kim Siegmund,
PhD; Stephen N. Thibodeau, PhD; Lisa A. Boardman, MD; Daniela Seminara, PhD, MPH
Ability to define new conditions from
existing ones
104. • Families fulfill AC-I criteria
– Suspected Lynch syndrome but no mutation
• Lower CRC incidence than Lynch syndrome
– SIR 2.3 (1.7-3.0) vs SIR 6.1 (5.2-7.2)
• Incidence may be lower for other cancers
• Families should not be described or counseled
as having Lynch syndrome
• Lynch Syndrome ≠ Familial CRC Type X
Familial Colorectal Cancer Type X
105. • Genetic etiology is largely unknown
– Has a monogenic component
• likely caused by high-penetrance mutations
– ?Polygenic component: Is there an interaction of
multiple low-penetrance genetic variants
• Clinical characteristics such as lower risk of CRC and
fewer associated extracolonic cancers suggest this
• More similar to sporadic CRC?
• Represents a novel form of familial CRC and
families are resource for research
Familial Colorectal Cancer Type X
106. HOWEVER….
• Phenotype varies from “classic” to “attenuated”
• 30% are de novo cases: no family history
• Classic FAP easy to recognize
• Penetrance for adenomas and
cancer near 100% in APC+
gene mutation carriers
Familial Adenomatous Polyposis
107. Variations of classic phenotypes are
common: Attenuated FAP
• Attenuated polyposis is a phenotypically distinct variant of FAP
• Arises from mutations in proximal or distal portions of APC gene
Characteristics
• Mean age at CRC diagnosis: 54 years
• Cumulative risk of CRC by the age of 80 yr is ~69%
• Proximal>>distal colon polyps and 75% of tumors occur in the
proximal colon
*The prevalence of APC mutations is likely similar in
EAO-CRC*
108. • Polyp phenotype more so “attenuated”
• Autosomal recessive pattern of inheritance
• Biallelic mutation carriers: 53 fold excess risk of CRC
• Up to 80% increased risk of CRC in lifetime
• Monoallelic mutation carriers: OR 1.15
• Mutational hotspots:
–White, Northern Europeans : Y165C
G382D
–Indian/Pakistani: E466X
MYH associated polyposis (MAP):
A newer entity in inherited CRC risk
account for 80%
of all mutations
Jenkins MA, et al. Cancer Epidemiol Biomarkers Prev 2006; 15:312-4
Win AK, et al. Fam Cancer 2011; 10:1-9
109. MYH associated polyposis
• ~3% of EAO-CRC is due to MYH mutations
– Compared to <1% of all CRC cases, regardless of
age
• ~30% of biallelic MYH carriers develop CRC
without polyps
– According to population-based studies
• Recommendation that all early-onset CRC
should be tested for MUTYH mutations
Riegert-Johnson DL et al. Genet Test. 2007;11:361–365.
Giraldez MD et al. Clin Cancer Res. 2010; 16: 5402-5413.
110. Germline Testing
Proband
HEREDITARY GI CANCER SYNDROME
Pedigree
Clinical Criteria
+/- tumor testing
+
Stepwise Approach for Inherited CRC Syndromes
• Requires recognition of cancer syndromes by providers
–Diagnosis may be missed
–Additional genes with other cancer syndromes increase
CRC risk
• Time consuming process, multiple decisions
–Test and re-test
–Complex decision-making for patients
111. Germline p53 Mutations and
Early Age Onset Cancers
• Li-Fraumeni syndrome
– caused by p53 mutations
• Lifetime risk of cancer is ~70-100%
• Carriers develop early onset cancers
– Leukemias, brain tumors, sarcomas, breast cancer,
adenocortical cancers
– Reports of gastric and CRC
112. • 457 patients with CRC ≤40 years old
• 1.3% carried a p53 gene mutation
– Comparable to the prevalence of APC gene
mutations associated with FAP
• None of the patients met clinical criteria for
Li-Fraumeni Syndrome
113. Advances in Genetic Testing for
Inherited CRC
• Next Generation Sequencing (NGS) allows for simultaneous
assessment of many cancer susceptibility genes with multi-
gene panel testing:
– Breast, colon, ovarian, pancreas….
• The role of NGS panel testing and its yield over traditional
genetic testing strategies are unclear
• Will change the conventional approach to genetic evaluation
118. Pilot study
• To determine the frequency and clinical phenotype
of patients undergoing genetic testing for Lynch
syndrome using a 25- gene hereditary cancer panel
• 343 non-consecutive subjects with banked blood
samples
• Validation study ongoing
MLH1 APC BRCA1 PTEN RAD51C
MSH2 MYH BRCA2 TP53 RAD51D
MSH6 BMPR1A PALB2 CDH1 BRIP1
PMS2 SMAD4 CHEK2 CDKN2A BARD1
EPCAM STK11 ATM CDK4 NBN
Yurgelun M et al. J Clin Oncol 32, 2014 (suppl 15s; abstr 1509)
119. Overall Panel Testing Results
Total cohort 343 patients
No mutation found 277 (81%)
All mutation carriers 66 (19%)
Lynch mutation 48 (14%)
Any non-Lynch mutation 19 (6%)
Non-Lynch CRC* mutation 3
BRCA1/2 mutation 10
Other† mutation 9
Rows not mutually exclusive due to 4 subjects having ≥1 pathogenic mutation
* APC, biallelic MYH, BMPR1A
† ATM, BARD1, BRIP1, CHEK2, NBN
120. Summary & Future Directions
• 85 % of EAO-CRC are not explained by known inherited CRC
syndromes
• NGS Panel testing will redefine the contribution of known cancer-
related genes in EAO-CRC
• Continued research efforts are necessary in affected individuals
and family members
– Gene discovery
– Screening and surveillance recommendations
124. Zane Cohen Center for Digestive Diseases
Research Treatment Education Support
Gastrointestinal Cancers
Research Groups
Familial Gastrointestinal Cancer Registry
(FGICR)
Ontario Pancreas Cancer Study (OPCS)
Ontario Familial Colorectal Cancer Registry (OFCCR)
Soft Tissue Sarcoma Research Program (STSRP)
Diseases
Lynch Syndrome (LS)
Familial Adenomatous Polyposis (FAP)
MYH - Associated Polyposis (MAP)
Peutz-Jeghers Syndrome (PJS)
Juvenile Polyposis (JP)
Hereditary Hemorrhagic Telangiectasia (HHT)
Hereditary Diffuse Gastric Cancer Syndrome (HDGC)
Pancreatic Cancer
126. age-standardized incidence rate per 100,000 43.7
age-standardized mortality rate per 100,000 15.9
estimated new cases in 2014 136,830
% of all new cancer cases 8.2%
estimated deaths in 2014 50,310
% of all cancer deaths 8.6%
CRC incidence and mortality in the US
● third leading cause of cancer incidence in both males and females
● second leading cause of cancer mortality in both males and females
SEER 9 Incidence & U.S. Mortality 1975-2011, All Races, Both Sexes.
127. EAO-CRC incidence and mortality in the US
● approximately 10% of colorectal cancers have early-onset
NEW CASES DEATHS
Male Female Male Female
Age (yrs) Count % Count % Count % Count %
0-49 7,270 10 6,250 10 1,840 7 1,450 6
50-64 22,890 32 16,570 25 6,780 26 4,590 19
65-79 27,950 39 23,050 35 10,100 38 7,710 32
80+ 13,720 19 19,130 29 7,550 29 10,290 43
Estimated Numbers of New Colorectal Cancer Cases and Deaths by Age and Sex, United States, 2014
Siegel, R., DeSantis, C. and Jemal, A. (2014), Colorectal cancer statistics, 2014. CA: A Cancer Journal for Clinicians, 64: 104–117.
doi: 10.3322/caac.21220
128. CRC incidence and mortality in Canada
● incidence and mortality rates are higher in Canada than in the US
● second leading cause of cancer incidence and mortality in males
● third leading cause of cancer incidence and mortality in females
age-standardized incidence rate per 100,000 48.9
age-standardized mortality rate per 100,000 17.9
estimated new cases in 2014 24,400
% of all new cancer cases 12.8%
estimated deaths in 2014 9,300
% of all cancer deaths 11.5%
Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2014. Toronto, ON: Canadian Cancer Society; 2014.
129. EAO-CRC incidence and mortality in Canada
● approximately 6% of colorectal cancers have early-onset
NEW CASES DEATHS
Male Female Male Female
Age (yrs) Count % Count % Count % Count %
0-29 45 <1% 45 <1% 10 <1% 5 <1%
30-49 720 5 660 6 175 3.5 145 3.5
50-59 2,100 15 1,550 14 580 11.5 390 10
60-69 4,000 29.5 2,500 23 1,250 25 700 18
70-79 4,000 29.5 2,800 26 1,500 30 1,000 25.5
80+ 2,800 20.5 3,300 30.5 1,450 29 1,650 42
Estimated Numbers of New Colorectal Cancer Cases and Deaths by Age and Sex, Canada, 2011
Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2014. Toronto, ON: Canadian Cancer Society; 2014.
130. CRC incidence trends in the US
● CRC ASIR have been decreasing on average 3.1% per year since 2002
SEER 9 Incidence & U.S. Mortality 1975-2011, All Races, Both Sexes. Rates are Age-Adjusted.
131. CRC incidence is increasing in young adults
Age (y) 1973
Incidence
1999
Incidence
EAPC
Colon 20-40 1.8 2.1 0.75**
60+ 179 204.4 0.26
Rectum 20-40 0.8 1.4 3.15**
60+ 86 72.1 -0.73**
Race/ethnicity n APC
All races M 10,913 1.5**
F 9,733 1.6**
Non-Hispanic White M 6,748 2.0**
F 5,626 2.2**
Non-Hispanic Black M 1,409 −0.2
F 1,456 −0.6
Hispanic M 1,307 2.7**
F 1,250 1.1
Asian American/ Pacific Islander M 1,284 1.2
F 1,239 0.6
Subsite APC
Rectum 2.6**
Sigmoid 0.4
Descending colon -1.8**
Colon excluding rectum -0.2
• O’Connell et al.
Young adults 20-40y, SEER 1973-1999
• Meyer et al.
Young adults <40y, SEER 1973-2005
• Seigel et al.
Young adults 20-49y, SEER 1992-2005
132. CRC incidence trends among young non-hispanic white adults (20-49yrs)
by age and anatomic subsite,1992 to 2005
Age n APC
M 20-29 249 5.2*
30-39 1,419 3*
40-49 5,080 1.5*
F 20-29 240 5.6*
30-39 1,125 2*
40-49 4,261 2.1*
Subsite n APC
M Proximal 2,054 0
Distal 1,609 1.5*
Rectum 2,609 3.5*
F Proximal 1,548 0.8
Distal 1,619 2.3*
Rectum 2,065 2.9*
CRC incidence is increasing in young adults
Seigel et al.
• O’Connell et al.
Young adults 20-40y, SEER 1973-1999
• Meyer et al.
Young adults <40y, SEER 1973-2005
133. CRC incidence and mortality trends in Canada
● CRC ASIR has been decreasing on average 0.8% per year in males, 2001-2010
● CRC ASIR has been decreasing on average 0.6% per year in females, 2001-2010
Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2014. Toronto, ON: Canadian Cancer Society; 2014.
134. CRC incidence is increasing in young adults
Cancer Care Ontario. Colorectal cancer incidence increasing among adolescents and young adults. August 2009. Available at https://www.cancercare.on.ca/cancerfacts.
135. Hereditary CRC risk
• familial cases comprise approximately 30% of all CRC
• mutations in highly penetrant CRC susceptibility genes account for 5-10% of all CRC
• etiology of remaining 20-25% of inherited CRC is not completely understood
136. Hereditary CRC syndromes
POLYPOSIS
adenomatous polyposis syndromes
Familial Adenomatous polyposis (FAP) – AD, mutation in APC
Attenuated FAP (AFAP) - AD, APC mutations at 5’ or 3’ ends of gene or in certain locations of exon 9
MUTYH-associated polyposis (MAP) – AR, biallelic mutations in MUTYH
Polymerase-proofreading associated polyposis – AD, mutation in POLE or POLD1
hamartomatous polyposis
Peutz-Jeghers syndrome (PJS) - AD, mutations in STK11
Juvenile Polyposis syndrome (JPS) - AD, mutation in SMAD4 or BMPR1A
Cowden syndrome (PTEN hamartoma tumor syndrome) - AD, germline mutation in PTEN
hyperplastic/serrated polyposis
Serrated polyposis syndrome – uncertain genetic etiology; unclear hereditary predisposition
Hereditary mixed polyposis syndrome
NONPOLYPOSIS
Lynch syndrome (LS) – AD, mutation in DNA mismatch repair (MMR) gene (MLH1, MSH2, MSH6, PMS2) or EPCAM
Biallelic Mismatch Repair deficiency
Other (Li-Fraumeni, Bloom syndrome)
137. POLYPOSIS
adenomatous polyposis syndromes
Familial Adenomatous polyposis (FAP) – AD, germline mutation in APC
Attenuated FAP (AFAP) - AD, germline APC mutations at 5’ or 3’ ends of gene or in certain locations of exon 9
10 to 99 synchronous adenomas
emergence of adenomas and CRC development delayed 10 to 20 years
CRC risk 70% by age 80
100s to 1000s of synchronous adenomas beginning in adolescence
CRC risk >95% by age 50 if untreated
MUTYH-associated polyposis (MAP) - AR, biallelic mutations in MUTYH
variable phenotype, most commonly 20 to 99 polyps but may present with <10 or >500
CRC risk >40% by age 60
Polymerase-proofreading associated polyposis (PPAS) – AD, mutation in POLE or POLD1
10 to 100 adenomas, may present with other polyp histology
CRC risk undefined
138. POLYPOSIS
hamartomatous polyposis
Peutz-Jeghers syndrome (PJS) - AD, germline mutations in STK11
GI polyps in 90-100% of cases
mucocutaneous pigmentation in >95% of cases most commonly perioral and buccal mucosa
lifetime CRC risk 40%
elevated risk for gastric, small bowel , breast, lung, pancreatic, and gynecologic cancers
Juvenile Polyposis syndrome (JPS) - AD, mutation in SMAD4 or BMPR1A
multiple juvenile polyps in colon, small bowel, and stomach
CRC risk 20% by age 35 and up to 70% by age 60
Cowden syndrome (PTEN hamartoma tumor syndrome) - AD, germline mutation in PTEN
range of phenotypes, colon polyps present in up to 95%, <10 to 100s of polyps, various histology
lifetime CRC risk may be up to 15%
143. Br J Surg. 2013 Dec;100(13):1719-31. doi: 10.1002/bjs.9316.
Systematic review of the impact of registration and screening on colorectal cancer
incidence and mortality in familial adenomatous polyposis and Lynch syndrome.
Barrow P1, Khan M, Lalloo F, Evans DG, Hill J.
METHODS
• English-language studies describing CRC incidence and/or mortality in patients with FAP or LS
• comparison of : screened and unscreened patients OR time periods before and after establishment of the registry
RESULTS
FAP – 33/33 studies report reduction of CRC incidence and mortality with registration and screening
LS – 9/10 studies report reduction of CRC incidence and mortality with registration and screening
144. J Exp Clin Cancer Res. 2014 Jan 2;33:1. doi: 10.1186/1756-9966-33-1.
Early-onset colorectal cancer patients without family history
are "at very low risk" for lynch syndrome.
Stigliano V1, Sanchez-Mete L, Martayan A, Diodoro M, Casini B, Sperduti I, Anti M.
145. Clinicopathologic features of non-familial EAO-CRC
Early-onset (≤40
years) colorectal
adenocarcinoma
(%) (N=55)
Control (>40 years of
age) colorectal
adenocarcinoma (%)
(N=73)
P value
Tumor
location
Right colon 11 (20) 31 (42) 0.007
Left colon
and rectum
44 (80) 42 (58)
Sigmoid 24 (44) 33 (45)
Rectum 20 (36) 9 (12)
Tumor stage
I 6 (11) 14 (19) 0.21
II 14 (26) 21 (29)
III 20 (36) 28 (38)
IV 15 (27) 10 (14)
Tumor grade
Low 40 (73) 63 (86) 0.06
High 15 (27) 10 (14)
Perineural
invasion
16 (29) 8 (11) 0.009
Venous
invasion
12 (22) 4 (6) 0.006
Mucinous histology
present 42 (76) 11 (15) 0.22
absent 13 (24) 62 (85)
Signet ring histology
present 7 (13) 1 (1) 0.021
absent 48 (87) 72 (99)
● more frequent location in distal colon
and rectum
● later stage at presentation
● more frequent aggressive histologic features
venous invasion
perineural invasion
mucinous histology
signet ring histology
Chang DT, Pai RK, Rybicki LA, et al. Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma:
an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features. Mod Pathol 2012 Aug;25(8):1128–1139
146. PLoS One. 2014 Aug 1;9(8):e103159.
Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a
morphological, molecular and genetics study.
Kirzin S1, Marisa L2, Guimbaud R3, De Reynies A2, Legrain M4, Laurent-Puig P5, Cordelier P6, Pradère B7, Bonnet D8, Meggetto F6, Portier G7,
Brousset P9, Selves J9.
METHODS
• surgical patients at university hospital in France 1999-2005
▪ 39 MSS tumor <45y cases
▪ 9 MSI tumor <45y cases
▪ 36 MSS tumor >60y cases
▪ 14 MSI tumor >60y cases
RESULTS
• absence of BRAF mutations
and methylator phenotype in EAO-CRC
• 49 signaling pathways upregulated in EAO-CRC
CONCLUSIONS
EAO-CRC is distinct clinico-molecular entity
MSS
young
MSS old MSI
young
MSI old
KRAS mut 14 (37%) 16 (44%) 3 (33%) 4 (29%)
WT 24 (63%) 20 (56%) 6 (67%) 10 (71%)
BRAF
V600E
mut 0 (0%) 5 (14%) 0 (0%) 5 (36%)
WT 39 (100%) 31
(86%)
9 (100%) 9 (64%)
TP 53 mut 17 (44%) 17 (47%) 0 (0%) 5 (36%)
WT 22 (56%) 19 (53%) 9 (100%) 9 (64%)
PIK-
3CA
mut 5 (21%) 2 (6%) 4 (80%) 3 (27%)
WT 19 (79%) 32 (94%) 1 (20%) 8 (73%)
CIMP unmethylated 38 (100%) 29
(81%)
9 (100%) 5 (38%)
methylated 0 (0%) 7 (19%) 0 (0%) 8 (62%)
147. Am J Surg Pathol. 2009 Apr;33(4):572-82. doi: 10.1097/PAS.0b013e31818afd6b.
Clinical, pathologic, and molecular features of early-onset colorectal carcinoma.
Yantiss RK1, Goodarzi M, Zhou XK, Rennert H, Pirog EC, Banner BF, Chen YT.
METHODS
• surgical patients UMass Memorial Healthcare and
Weill Cornell Medical College 2000-2007
24 patients <40y
15 patients 40-40y
30 patients >50y
RESULTS
• more frequent AMACR expression in patients <40y
• 4 micro-RNA species significantly overexpressed in patients <40y
(miR-21, miR-20a, miR-181b, mi-203)
CONCLUSIONS
posttranscriptional regulation of mRNA may be particularly important for
the development of CRC in young patients
150. Whole genome sequencing
vs
Exome sequencing
Whole genome
expensive
IT issues
complete sequence
Exome
cheaper
more manageable
coding regions
incomplete sequence
151. Nat Genet. 2011 May; 43(5): 442–446.
Exome sequencing identifies GRIN2A as frequently mutated in
melanoma
Xiaomu Wei,1 Vijay Walia,1,12 Jimmy C Lin,2,12 Jamie K Teer,3 Todd D Prickett,1 Jared Gartner,1 Sean Davis,4 NISC Comparative Sequencing Program,5 Katherine Stemke-
Hale,6 Michael A Davies,6,7 Jeffrey E Gershenwald,8,9 William Robinson,10 Steven Robinson,10 Steven A Rosenberg,11 and Yardena Samuels1
Science. 2009 Apr 10;324(5924):217
Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene.
Jones S1, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigiani G, Kern SE, Velculescu VE, Kinzler KW,
Vogelstein B, Eshleman JR, Goggins M, Klein AP.
Nat Genet. 2011 Jun 19;43(7):663-7.
Exome sequencing identifies MAX mutations as a cause of hereditary
pheochromocytoma.
Comino-Méndez I1, Gracia-Aznárez FJ, Schiavi F, Landa I, Leandro-García LJ, Letón R, Honrado E, Ramos-Medina R, Caronia D, Pita G, Gómez-Graña A, de Cubas AA, Inglada-Pérez L, Maliszewska A, Taschin E, Bobisse
S, Pica G, Loli P, Hernández-Lavado R, Díaz JA, Gómez-Morales M, González-Neira A, Roncador G, Rodríguez-Antona C, Benítez J, Mannelli M, Opocher G, Robledo M, Cascón A.
Nature. 2011 Jan 27; 469(7331): 539–542.
Exome sequencing identifies frequent mutation of the SWI/SNF complex
gene PBRM1 in renal carcinoma
Ignacio Varela,1 Patrick Tarpey,1 Keiran Raine,1 Dachuan Huang,2 Choon Kiat Ong,2 Philip Stephens,1 Helen Davies,1 David Jones,1 Meng-Lay Lin,1 Jon
Teague,1 Graham Bignell,1 Adam Butler,1 Juok Cho,1 Gillian L. Dalgliesh,1 Danushka Galappaththige,1 Chris Greenman,1 Claire Hardy,1 Mingming Jia,1 Calli
Latimer,1 King Wai Lau,1 John Marshall,1 Stuart McLaren,1 Andrew Menzies,1 Laura Mudie,1 Lucy Stebbings,1 David A. Largaespada,3 L.F.A. Wessels,4
Stephane Richard,5,6 Richard J Kahnoski,7 John Anema,7 David A. Tuveson,8 Pedro A. Perez-Mancera,8 Ville Mustonen,8 Andrej Fischer,9,10 David J.
Adams,11 Alistair Rust,11 Waraporn Chan-on,2 Chutima Subimerb,2 Karl Dykema,12 Kyle Furge,12 Peter J. Campbell,1 Bin Tean Teh,2,14 Michael R.
Stratton,1,15 and P. Andrew Futreal1
Exome sequencing and cancer genetics
152. Nat Genet. 2013 Feb;45(2):136-44.
Germline mutations affecting the proofreading domains of POLE and POLD1
predispose to colorectal adenomas and carcinomas.
Palles C1, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, Kemp Z, Spain SL, Guarino E, Salguero I, Sherborne A, Chubb D, Carvajal-Carmona LG, Ma Y, Kaur K, Dobbins S, Barclay E, Gorman M,
Martin L, Kovac MB, Humphray S; CORGI Consortium; WGS500 Consortium, Lucassen A, Holmes CC, Bentley D, Donnelly P, Taylor J, Petridis C, Roylance R, Sawyer EJ, Kerr DJ, Clark S, Grimes J, Kearsey
SE, Thomas HJ, McVean G, Houlston RS, Tomlinson I.
• whole genome sequencing and linkage analysis
• COloreRectal Gene Identification (CORGI) study; recruits from UK Clinical Genetics Departments
• 20 discovery phase samples:
15 unrelated probands diagnosed with ≥10 colorectal adenomas before age 60
relative with >5 colorectal adenomas for 3 probands, and 2 affected relatives for 1 proband
• 3,805 white UK validation phase samples enriched for family history of CRC and early-onset
• 6,721 white UK control samples without personal history of CRC
153. POLE L424V variant
• pedigree SM2702, only variant shared by all 3 affected individuals
• present in 12 additional unrelated cases from validation phase and no controls
• additional genotyping in 12 families showed all carriers developed colorectal tumors
POLD1 S478N variant
• pedigree SM1645, shared by both of the 2 affected individuals
• present in additional proband plus additional unrelated case from validation phase and no controls
• additional genotyping in SM1645 and proband family showed all carriers developed colorectal tumors
dominantly-inherited high penetrance susceptibility for colorectal adenoma and carcinoma
mutations map to proof-reading (exonuclease) domain of DNA polymerases ε and δ;
predicted to impair correction of mispaired bases inserted during DNA replication
154. Hum Mutat. 2013 Jul;34(7):1026-34. doi: 10.1002/humu.22333. Epub 2013 May 20.
Exome resequencing identifies potential tumor-suppressor
genes that predispose to colorectal cancer.
Smith CG1, Naven M, Harris R, Colley J, West H, Li N, Liu Y, Adams R, Maughan TS, Nichols L, Kaplan R, Wagner MJ, McLeod HL, Cheadle JP.
METHODS
• exome sequencing of 50 germline DNA samples
• unrelated sporadic CRC patients from UK national multicenter
randomized controlled trials COIN and COIN-B
155. analysis strategy 1
search for protein-truncating variants in subset of 1,138 genes from pathways implicated in CRC
oncogenes excluded
search for LOH by Sanger sequencing of matched tumor DNA when available
32 variants in 31 genes
5 variants with somatic biallelic inactivation
FANCM, LAMB4, PTCHD3, LAMC3, TREX2
analysis strategy 2
search for protein-truncating variants in all genes
initially limited search to 18 EAO-CRC cases in sample set
expanded to include all cases
173 variants in 159 genes in EAO-CRC
additional 331 variants in additional 305 genes in remainder
156. Cancer Genetics 208 (2015) 35-40
Systematic search for rare variants in Finnish
early-onset colorectal cancer patients
Tomas Tanskanen a, Alexandra E. Gylfe a, Riku Katainen a, Minna Taipale b,e, Laura Renkonen-Sinisalo a,c, Heikki J€arvinen c, Jukka-Pekka Mecklin d,
Jan B€ohm d, Outi Kilpivaara a, Esa Pitk€anen a, Kimmo Palin a, Pia Vahteristo a, Sari Tuupanen a, Lauri A. Aaltonen a,*
METHODS
• exome sequencing
• unselected surgical patients from 9 Finnish hospitals 1994-1998
• discovery set of 22 non-familial EAO-CRC cases <40y
• validation set of 95 familial CRC cases
157. RESULTS
no genes with rare loss-of-function (LoF) variants present in more than one EOA-CRC patient
ADAMTS4, CYTL1, SYNE1 LoF variants in one EAO-CRC patient and familial CRC cases
ACSL5 p.Pro71Leu, INTS5 p.Pro922Leu missense variants in 2 EAO-CRC patients and no familial CRC cases
MCTP2, ARHGAP12, ATM, DONSON, ROS1 each with homozygous variants in one EOA-CRC patient
no compound heterozygous LoF variants
CONCLUSIONS
results suggest genetic heterogeneity in unexplained EAO-CRC
158. The Toronto EAO-CRC cohort
FGICR
Undefined conditions n=122
• 97 complete testing
• 5 partial testing
• 20 no testing
• complete testing
• no polyposis
• no significant family history:
▪ pedigree does not meet Amsterdam
or Revised Bethesda criteria
▪ no relative with EAO-CRC (≤35y)
▪ no first degree relative with CRC
• germline and tumor DNA available
30 EAO-CRC germline and tumor exomes
159. rare variant hypothesis
▪ undiscovered moderately penetrant genetic variants
cause increased CRC risk
perhaps not one single variant but unique combinations ;
OR the interaction of certain variant(s) with environmental exposures
and/or epigenetic alterations, etc….
160. References
Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available
from: http://globocan.iarc.fr, accessed November 15, 2014.
American Cancer Society. Colorectal Cancer Facts and Figures 2014-2016. Atlanta: American Cancer Society; 2014.
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Siegel R, Desantis C, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014 Mar-Apr 64(2):104-17.
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Cheng L, Eng C, Neiman LX, Kapadia AS, Du XL. Trends in colorectal cancer incidence by anatomic site and disease stage in the United States from 1976-2005. Am J Clin Oncol. 2011 Dec;34(6):573-80
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Bailey CE, Hu CY, You YN, et al. Increasing Disparities in the Age-Related Incidences of Colon and Rectal Cancers in the United States, 1975-2010. JAMA Surg. 2014 Nov 5:1-6.
Siegel RL, Jemal A, Ward EM. Increase in incidence of colorectal cancer among young men and women in the United States. Cancer Epidemiol Biomarkers Prev. 2009 Jun;18(6):1695-8.
You YN, Xing Y, Feig BW, Chang GJ, Cormier JN. Young-onset colorectal cancer: is it time to pay attention? Arch Intern Med. 2012 Feb 13;172(3):287-9.
Pignone M, Rich M, Teutsch SM, et al. Screening for colorectal cancer in adults at average risk: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med. 2002 Jul 16;137(2):132-41.
Whitlock EP, Lin JS, Liles E, Beil TL, Fu R. Screening for colorectal cancer: a targeted, updated systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2008 Nov 4;149(9):638-58.
Myers EA, Feingold DL, Forde KA, et al. Colorectal cancer in patients under 50 years of age: A retrospective analysis of two institutions' experience. World J Gastroenterol. 2013 Sep 14;19(34):5651-7.
Kirzin S, Marisa L, Guimbaud R, et al. Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a morphological, molecular and genetics study. PLoS One. 2014 Aug 1;9(8):e103159.
Chang DT, Pai RK, Rybicki LA, et al. Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid
involvement, and adverse morphologic features. Mod Pathol 2012 Aug;25(8):1128–1139
Yantiss RK, Goodarzi M, Zhou XK, et al. Clinical, pathologic, and molecular features of early-onset colorectal carcinoma. Am J Surg Pathol 2009 Apr;33(4):572–582
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Minardi AJ, Sittig KM, Zibari GB, McDonald JC. Colorectal cancer in the young patient. Am Surg. 1998;64:849–853.
Domergue J, Ismail M, Astre C, et al. Colorectal carcinoma in patients younger than 40 years of age. Montpellier Cancer Institute experience with 78 patients. Cancer. 1988;61:835–840.
Palmer ML, Herrera L, Petrelli NJ. Colorectal adenocarcinoma in patients less than 40 years of age. Dis Colon Rectum. 1991;34:343–346.
Chiang JM, Chen MC, Changchien CR, et al. Favorable influence of age on tumor characteristics of sporadic colorectal adenocarcinoma: patients 30 years of age or younger may be a distinct patient group. Dis Colon Rectum.
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Berg M, Danielsen SA, Ahlquist T, Merok MA, Agesen TH, et al. (2010) DNA sequence profiles of the colorectal cancer critical gene set KRAS-BRAF-PIK3CA-PTEN-TP53 related to age at disease onset. PLoS One. 2010 Nov
12;5(11):e13978.
Alsop K, Mead L, Smith LD, Royce SG, Tesoriero AA, et al. (2006) Low somatic K-ras mutation frequency in colorectal cancer diagnosed under the age of 45 years. Eur J Cancer 42: 1357–1361
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Reich DE, Lander ES. On the allelic spectrum of human disease. Trends Genet. 2001;17:502–10.
Wang WY, Barratt BJ, Clayton DG, Todd JA. Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet. 2005;6:109–118.
Bodmer W1, Bonilla C. Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet. 2008 Jun;40(6):695-701. doi: 10.1038/ng.f.136.
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9;101(45):15992–7.
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Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013
Feb;45(2):136-44.
Smith CG, Naven M, Harris R, Colley J, West H, Li N, et al. Exome resequencing identifies potential tumor-suppressor genes that predispose to colorectal cancer. Hum Mutat. 2013 Jul;34(7):1026-34.
Newcomb PA, Baron J, Cotterchio M, Gallinger S, Grove J, Haile R, et al. Colon Cancer Family Registry: an international resource for studies of the genetic epidemiology of colon cancer. Cancer Epidemiol Biomarkers Prev. 2007
Nov;16(11):2331-43.
162. Jiyoung Ahn, PhD, RD
Associate Professor
Dept. of Population Health
NYU School of Medicine
Early Age Onset Colorectal Cancer Summit, March 2005
Gut Microbiome, Fiber Intake,
and Risk of Colorectal Cancer
163. 16
3
Human microbiome
• Human microbiome, totality of human microbiota.
• Our understanding of microbiome has been limited.
• Bacterial DNA sequencing opened new possibility
to study microbiome comprehensively and accurately.
Ahn et al, Cancer Cause and Control, 2012
164. 16
4
World Health Organization
Group 1 infectious agents that cause cancer
Bacteria
Helicobacter pylori (H. pylori)
Viruses
Epstein-Barr Virus (EBV)
Hepatitis B Virus (HBV)
Hepatitis C Virus (HCV)
Human Herpesvirus 8 (HHV-8)
Human Immunodeficiency Virus (HIV)
Human Papillomavirus (HPV)
Human T-Cell Lymphotrophic/Leukemia Virus Type 1
(HTLV-1)
165. 16
5
• Recently completed study of microbiome and
colorectal cancer
- published in Journal of National Cancer Institute
• Large scale on-going effort on
- NYU Human Microbiome Study Cohort
Overview of talk
166. 16
6
Gut microbiome and CRC
• Gut microbiome plays key roles in inflammation and in the
breakdown of otherwise indigestible food compounds,
such as fiber.
• Animal studies (Infect Immun 1998, mBio 2013)
- mice develops fewer colon tumors under germ-free conditions
- fecal transplant from CRC mice results in tumor formation
• Systematic epidemiologic surveys of gut microbiome with
cases and controls are lacking.
• We tested the hypothesis that altered gut microbiome is
associated with risk of CRC.
167. 16
7
• Hospital based case-control study
- 47 CRC cases and 94 non-cancer controls
- recruited 3 hospitals in Washington DC area
- matched by age, gender, and BMI
• Diet and demographic questionnaires
• In-home 2 day fecal collection
• 16s rRNA gene sequencing microbiome assay
Study Design
168. 16
8
Microbiome Assay and Data Analysis
- Compared overall gut microbiome diversity and microbial taxa
abundances in CRC cases and controls
170. 17
0
Gut microbiome diversity in CRC and controls
500 1000 1500 2000 2500 3000
6
7
8
9
Shannon Index in Colorectal Cancer Cases and Controls
Sequences Per Sample
ShannonIndex
Controls
Cases
Less diverse in cases than in controls
Ahn et al, JNCI, 2013
P = 0.02
172. 17
2
Fusobacterium increases CRC risk
• Multivariate OR=3.74, p=0.0035.
• Fusobacterium is gram negative
inflammatory bacteria.
• Consistent with our result, two studies
reported that Fusobacterium is enriched in
human colorectal cancer tissue compared to
adjacent normal tissue
(Genome Research 2012 and Science 2013).
Ahn et al, JNCI, 2013
173. 17
3
Clostridia decreases in CRC patients
• Clostridia depleted in CRC cases
(Multivariate OR = 0.8, P=0.005).
• Clostridia ferment dietary fiber
to short chain fatty acid (butyrate),
anti-carcinogenic components.
Ahn et al, JNCI, 2013
175. 17
5
Low Fiber Intake
High fiber intake and high clostridia
High Fiber Intake
High fiber intake - for high vs. low Clostridia:
multivariate OR=1.24 (p=0.009)
Domminiani et al, PLOS ONE, 2015
Clostridia
Overall diversity Genera (unsupervised clustering)
176. 17
6
Summary
• CRC risk was associated
- with decreased gut microbiome diversity;
- increased presence of Fusobacterium;
- depletion of fiber–fermenting Clostridia.
• High fiber intake Clostridia CRC.
177. 17
7
NYU Human Microbiome Cohort:
Human Microbiome and Colorectal Tumor (HMAC) Study
(supported by Dept. Population Health, NYU Cancer Institute, and NCI)
Ongoing Recruitment (~ 500 recruited, 3000 planned)
- GI clinic and colonoscopy centers at NYULMC and other 3 sites in US.
- Fecal/oral/tissue sample collection
- Comprehensive diet/demographic questionnaires
- Detailed clinical and pathology information
Follow up for future tumor assessment
- Annual follow up questionnaire and medical chart verification
178. 17
8
Implications
• Learn about the causes of CRC.
• Identifying people at high risk for CRC.
• Possible prevention of CRC by tailored bacterial
and diet modifications.
179. 17
9
Research Team
• NYU: Richard Hayes, Mitchell Bernstein, George Miller, Zhiheng Pei
• My group: Christine Domminiani, Xiaozhou Fan, Jing Wu, Ryan Shanly, Elong Zhang
• NCI: Mark Purdue, Rashimi Sinha, Jim Goedert, Neal Freedman
• ACS: Susan Gapstur, Eric Jacobs
• CDC: Jean Shapirio
Grant Support
• NIH R01 CA 164964 (PI. Ahn): Microbiome-pancreas cancer
• NIH U01 CA182370 (MPI. Ahn/Pei): Microbiome-esophagus cancer
• NIH R03 CA159414 & NIH R21 CA183887 (PI. Ahn): Microbiome-CRC
• NIH R01 CA 164964 (PIs. Hayes/Pei): Microbiome-HNC
• NYU Abu Dhabi (PI. Ahn): Microbiome - CVD
• NIH R21 ES021194 (PI. Ahn) & NIH R21 ES021242 (PI. Ahn): Diet studies
www.NYUMGEL.org
(Ahn – Diet, microbiome and genetic epidemiology lab)
182. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Thomas K Weber, MD FACS
Professor of Surgery
State University of New York
Health Sciences Center
Brooklyn, New York
183.
184. Incidence trends by age: 50+ versus 20-49
Source: SEER 9 registries, 1975-2011; 2-yr moving average.
0
2
4
6
8
10
12
14
1975-76
1977-78
1979-80
1981-82
1983-84
1985-86
1987-88
1989-90
1991-92
1993-94
1995-96
1997-98
1999-00
2001-02
2003-04
2005-06
2007-08
2009-10
Rateper100,000
Men
Women
45%
2% per year
Since 1993-1994
0
50
100
150
200
250
300
1975-76
1977-78
1979-80
1981-82
1983-84
1985-86
1987-88
1989-90
1991-92
1993-94
1995-96
1997-98
1999-00
2001-02
2003-04
2005-06
2007-08
2009-10
Rateper100,000
Men
Women
Ages 50+ Ages 20-49
185. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• We have a major cancer control /
epidemiologic challenge
• The “seismic” nature of this challenge are
illustrated by very simple “30,000 feet”
observations.
186. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• “A study of initial presentation of young
onset CRC patients without established risk
factors found that 86% were symptomatic
at the time of diagnosis” *
• Siegel et al Can Epi Biomark 18(6) 1695-8
187. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
188. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
189. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• For almost a quarter of a century our
collective “conditioned reflexes” have been
wired to think “genetic hereditary
syndrome” when we see a young (under
50) solid tumor patient in general and
especially with breast and colorectal
cancer.
• However…………..
190. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
191. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• However…………..
• At least 75% of EAO-CRC patients DO NOT
report positive family history of the
disease
• Dr Kastrinos shared Dr Limburg’s Colorectal
CFR data indicating less than 6% of < 50
patients carried a Lynch Syndrome gene
mutation.
192. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• So…………..
• We are facing a new problem…
• A Fresh Challenge…....
• A novel opportunity to advance our
understanding of the basic biology of the
pathophysiology of solid tumor malignancy
in the young.
193. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• I have no links whatsoever to this man…
195. HOWEVER……
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• A Potentially Useful Construct:
• “There are known knowns. These are things
we know that we know.
• There are known unknowns. That is to say,
there are things that we know we don't
know.
• But there are also unknown unknowns.
There are things we don't know we don't
know.”
196. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Known Knowns……The Basics
• Health Insurance: what are the dimensions of
this problem? What specific strategies could
address this? Do related pre-existing issues
impact it”
• No Primary Care Physician: again – the
dimensions?
• Remember – in NYC > 80% unscreened had
insurance AND a primary care physician
197. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Known Knowns……The Basics
• A POSITIVE family history for CRC and or
Lynch related malignancies
• A positive history for Inflammatory Bowel
Disease - IBD
198. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Unknown Knowns……What is the true risk –
in YOUNG ADULTS?
199. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Unknown Knowns……What is the true risk –
especially in the young?
• Exercise vs. Sedentary Lifestyle??
• Obesity?
• Red Meat?
• Milk?
• Fast Foods?
• That’s NOT ME!
200. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Unknown Knowns……What is the true risk –
especially in the young?
• Diabetes
• Sleep Patterns?
• Sitting Position?
• Alcohol?
• Tobacco?
• Recreational Drugs ?
201. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Unknown Knowns……What is the true risk –
especially in the young?
• Microbiome?
• Periodontal Disease?
• Our Environment?
• The Exposome?
202. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
What DO we know about the
Unknown Knowns……?
• Any Data?
203. COloRECtal Transdisciplinary Study NCI
GAME-ON Consortium
• •Global study n= 52,649
• •OncoArray consortium n= 45,000
• •Diverse populations
• •Harmonizing epidemiologic data
• •Developing integrated risk prediction model
209. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Unknown Knowns……What is the true risk –
especially in the young?
• Genetics……………………………..
• “Known Syndromes?
• Unknown Genetic Elements and
Syndromes
• Unknown Unknowns?
210.
211.
212. GWAS, SNPS,THE “EXPOSOME” and
Colorectal Cancer
• GWAS SNP studies have been…..disappointing
• If 21,000 is “underpowered” then ….?
• GWAS / SNP approach has not focused on
EAO-CRC (“enriched”)
• The GWAS SNP approach contrasts with the
whole exome / whole genome work discussed
by Drs McNamara and Kastrinos.
213. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• “But there are also unknown unknowns.
There are things we don't know we don't
know.”
• ?
• ?
• ?
• ?
214. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• “But there are also unknown unknowns.
There are things we don't know we don't
know.”
• Changing patterns of: Antibiotic Usage
• Aspirin Use?
• Attention Deficit Meds
• In Utero Exposures – “Exposome”
• Statins?
215. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• How Can We Move Forward?
216. • No Health Insurance
• No Primary Physician
• INEFFECTIVE PRIMARY CARE & OTHER
PHYSICIANS
• Positive Family History
• Inflammatory Bowel Disease
• Diabetes
• High Calorie / Red Meat Containing / Processed
Foods
219. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Unknown Knowns……What is the true risk –
especially in the young?
• Diabetes
• Sleep Patterns?
• Sitting Position?
• Alcohol?
• Tobacco?
• Recreational Drugs ?
220. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Unknown Knowns……What is the true risk –
especially in the young?
• Microbiome?
• Periodontal Disease?
• Our Environment?
• The Exposome?
222. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• “There are also unknown unknowns.
There are things we don't know we don't
know.”
• ?
• ?
• ?
• ?
223. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• “There are also unknown unknowns.
There are things we don't know we don't
know.”
• Changing Patterns of: Antibiotic usage?
• Aspirin?
• Puberty and Menarche?
• Attention Deficit Meds?
• In-Utero Exposures?
226. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
And How Do We Advance Knowledge About
Young Adult CRC Unknowns?
• Little or none of what we have reviewed
has been directed to EAO-CRC
• Our NCI / CDC Cancer Registries do NOT
collect family history or other basic risk
factor data
227. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
And How Do We Advance Knowledge About
Young Adult CRC Unknowns?
• Little or none of what we have reviewed
has been directed to YOUNG ADULTS!
• Our NCI / CDC Cancer Registries do NOT
collect family history or other basic risk
factor data.
228.
229.
230. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
And How Do We Advance Knowledge About
Young Adult CRC Unknowns?
• As Discussed at Yesterday’s Never Too
Young Coalition Meeting:
• An IRB guided, HIPAA Compliant, State of
the Art Epidemiologic SURVEY of Young
Adult Survivors – (and Families?)
• MSKCC & MD Anderson – Genetic Alliance
231. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
One Thing We All SHOULD Know:
• If you are symptomatic – or have positive
“physical signs”
• You Need / Your Patient Needs……..
• A DIAGNOSTIC EVALUATION!
• Rectal Bleeding, Abdominal Pain, Change in
Bowel Habit
232. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
SUMMARY?
233. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
“You Never Know…”
234. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• We know a great deal
• There are clear opportunities to use
that knowledge to inform patient
choice and provider response / action.
• Knowledge of RISK FACTORS can be
immediately deployed to RISK
REDUCTION strategies.
235. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• Known RISK FACTORS need to be
validated in YOUNG ADULTS.
• Tackling UNKOWNS – requires
resourcing our national / international
cancer registries to address the
problem
• EAO-CRC Survivor Survey Project
236. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
RISK
• Identification
• Clarification
• Mitigation / Reduction
237. Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
THANK YOU!
238. Martha Raymond, MA, CPN
Early Age Onset Colorectal Cancer Summit
March 21, 2015
Memorial Sloan Kettering Cancer Center
New York, New York
The Patient Perspective:
Exploring the ‘New Normal’ of the Young
Colon Cancer Patient
239. Quality of Life After an EAO-CRC
Diagnosis:
Knowledge Gaps and
Opportunities
Susan K. Peterson, PhD, MPH
Professor, Behavioral Science
1st Early Age Onset Colorectal Cancer Summit
New York, NY
March 21, 2015
240. Cancer Survivorship
• Cancer survivorship = the state or process
of living after a diagnosis of cancer
• Encompasses not only the physical but also
the social, psychological, and
spiritual/existential impact of cancer on one’s
life and for the remainder of one’s life.
241. Measuring Quality of Life
• Physical functioning
• Health status
• Sexuality and fertility
• Emotional adjustment
• Psychological and
behavioral functioning
• Spiritual/existential
domains
• Future outlook
• Independence
• School performance
• Work performance
• Social relationships
• Family relationships
242. • Establish autonomy and independence
– Achieve emotional independence from adults
– Self-esteem and identity development
– Acquire a set of values and an ethical system as a
guide to behavior
• Social and intimate relationships
– More mature relations with peers
– Prepare for marriage and family
• Establish financial independence
– Completion of school
– Prepare for a career.
Crucial Developmental
Milestones in Young
Adulthood
243. The Impact of an Illness
• Changes in mobility and physical functioning
• Changes in physical appearance
• Separation from peers and usual activities
• Increased dependence on parents at a
time they would usually be practicing
independence
245. N=523 young survivors, age 15-39
• Compared to peers, YCS had lower physical and
social functioning; psychosocial, emotional, and
work/school functioning were similar to peers
• Worse HRQOL associated with: < high school, no
insurance, Hispanic ethnicity, active treatment (esp.
chemo), younger age, greater symptom burden
• Demands of normal physical, hormonal, cognitive
changes + other normal developmental changes
may contribute to lower levels of physical functioning
and fatigue
Smith, JCO, 2013
Health-related QOL in Young Cancer
Survivors
246. N=8375 survivors, diagnosed age 15-39
• Compared to peers, 30% of those age 40-64 report
poor/fair health vs. controls
• > 1 diagnosis associated with poorer QOL
• 45% of female CRC survivors report fair/poor health
– Long-term issues with infertility, bowel function
• Earlier age of diagnosis associated with more days
of poor mental health compared with older age at
diagnosis
– Gap in psychological support for youngest survivors
• Young age at diagnosis may have long-term QOL
impact across lifespan
Kirchhoff, JAYAO, 2014
Health-related QOL in Young Cancer
Survivors
247. • About half or fewer may achieve
recommended levels of physical activity (PA)
(ages 20-44)
• About half may be overweight or obese
• More physically active compared to older
survivors, less compared to age-related
peers
• Benefits of PA include improved QOL, symptom
reduction, and improved survival/reduced
recurrence risk in some cancers
• Tobacco use may be higher compared to older
survivors
Health Behaviors in Young Adult Cancer
Survivors
248. 20
32
39 39
12
29
18
21
9
0
1
0
2
0
3
0
5
0
4
0
0 1 2 3
Number of Risk Factors
4
Percent Affected Unaffected
Prevalence of Risk Behaviors* for Colorectal Cancer
Among Persons at Risk for Lynch Syndrome
(n=429)
Risk Behavior Index Score (M), Cancer-affected vs. unaffected
1.4 vs. 1.7 (p<0.01)
*Smoking, alcohol use, dietary factors Burton, 2011
249. Unmet need rated by
70% or more
- Sexuality/intimacy-related
counseling
- Adoption services
- Retreats, camps
N=879 young cancer survivors
Needs were greater for younger
survivors and those diagnosed at
younger ages
Unmet need rated by
50% or more
- Diet, nutrition, exercise
- Family counseling
- Substance abuse
counseling
- Assistance with
transportation, child care
Unmet Information and Service Needs
of Young Cancer Survivors
250. • Medical care
– Perceived excellence in care after diagnosis
– Dissatisfaction with initial diagnosis delay
• Patient factors - still-maturing cognitive function,
reliance on peers for information
• Provider factors – not attributing symptoms to
cancer, poor provider-patient communication
– Side effects and symptoms
• Fatigue, depression, nausea, weight gain/loss, bowel function,
sexuality/fertility, changes in eating, decreased energy, body
image concerns
Zebrack, Psychosoc Onc, 2014
QOL Domains for Young Cancer Survivors
251. • Practical
– Financial
• Inadequate or gaps in health insurance
• Difficulty navigating health insurance coverage
• Work interruptions
• Acquiring early debt & limited financial resources
– School/ work disruption
• Treatment takes precedence over work, school
QOL Domains for Young Cancer Survivors
252. • Psychological and Spiritual
– Managing distress & emotions related to cancer,
treatment, and fear of recurrence
– Social functioning and isolation
• Disclosure and communication
– Maintain/re-establish normalcy
– Loss: job/school, appearance change,
relationship changes
***Positive attitudes, beliefs, feelings emerge from
cancer experience
QOL Domains for Young Cancer Survivors
253. Cancer Can Promote Psychological
Growth: Resilience Concept
• Some people can transform their lives by
responding to an illness in ways that
enhance the quality and meaning of their
lives
• Resilience = process for identifying and
developing resources or strengths to manage
stressors in order to gain positive outcome
from the experience
• Positive growth: greater maturity, appreciation
for life than population norms
254. • Racial/ethnic minority and medically underserved cancer
survivors have greater disparities in cancer outcomes
and access to survivorship care
– AfricanAmericans: higher mortality for CRC
– Uninsured or underinsured persons → more likely to
be diagnosed with advanced cancer → less likely to
receive standard care and survive → less likely to
adhere to surveillance and survivorship care
regimens
• Uninsured/underinsured = predominantly Hispanic,
recent immigrants, and the working poor
– Lifestyle behaviors (e.g., obesity, low physical activity,
tobacco use) related to cancer recurrence or mortality
are more prevalent among racial/ethnic minority, lower
resourced, and less educated survivors
CDC, 2011; American Cancer Society, 2012
Health disparities in U.S. cancer survivors
255. Including “Previvors” in the Discussion
About EAO-CRC
• Previvors = at increased risk of hereditary CRC, no CRC diagnosis
• Bowel function and QOL in children with FAP who underwent colectomy
at age < 14 y
• n=28, 56% female, mean colectomy age=12 y, current age=24 y
• Reported more night incontinence, nighttime stools (p<0.05); daytime
incontinence not different from adult sample
• 60% reported feeling embarassed “always or sometimes” due to bowel
concerns
• 20% reported restrictions at school or work, 30% restrictions in sports
due to bowel concerns
• 36% worried ‘at least some’ about post-surgery cancer risk; greater
in younger patients had greater worry
• Younger patients reported more FAP surgery-related distress
– Number of FAP-affected family members associated with higher distress
• Body image and self-esteem scores in normal ranges
Durno, Dis Colon Rectum (2012)
256. 72% seek health information online
-Used phone: 31% cell phone, 52%
smartphone
- 19% smartphone owners
download Pew Internet Research Project, 2012; 2014
Social and mobile media to
reach EAO-CRC survivors
257. Computer and mobile technology use in the U.S.
Pew Internet Research Project, 2014
259. • In general, young adult cancer survivors not well-
represented in QOL studies of survivors
– Especially EAO-CRC
• QOL needs for young adult survivors are specific and
differ from older survivors
e.g., social functioning, financial stress, sexuality,
health information
→ Need better understanding of QOL in EAO-CRC
→ QOL measures specific to EAO-CRC
→ Resources targeted toward specific QOL support
in EAO-CRC
Gaps and Opportunities
260. • Subgroups of young adult cancer survivors
have specific needs
– Those diagnosed at youngest ages
– Underserved
– Fertility, sexuality considerations
– Pre-vivors
→ Need better understanding of life-stage specific
QOL in EAO- CRC
→ Resources targeted toward specific QOL
support in EAO-CRC
Gaps and Opportunities
261. • Health care system may not be responsive to needs
of EAO-CRC
– Cancer treatment settings may reflect pediatric vs. older
adult divisions in care
– Delay in initial diagnosis and treatment, despite
persistent symptoms & health concerns
• Delays in diagnosis → skepticism, mistrust → poor
adherence to treatment, failure to seek future care
→ Resources needed for EAO-CRC that are
appropriate for varied stages of life, development
→ Support for providers who care for EAO-CRC
e.g., Focus Under Forty (ASCO, Livestrong), EAO-
targeted survivorship care plans and services
Gaps and Opportunities
262. National Cancer Institute, National Institutes of Health, 1R42 CA126453,
1R41-CA126453-01
Seed Money Grant, Duncan Family Institute for Cancer Risk Assessment
and Prevention
Cancer Center Support Grant (CA016672, PI: R. DePinho)
National Cancer Institute, National Institutes of Health
MarthaAskins, PhD
Associate Professor and Pediatric Psychologist Psychosocial
Director,Adolescent and Young Adult Program
The Children’s Cancer Hospital at MD Anderson Cancer Center
Acknowledgements
263.
264. *
• Cancer survivorship = the state or process
of living after a diagnosis of cancer
• Encompasses not only the physical but also
the social, psychological, and
spiritual/existential impact of cancer on one’s
life and for the remainder of one’s life.
265. *
• Physical functioning
• Health status
• Sexuality and fertility
• Emotional adjustment
• Psychological and
*behavioral functioning
• Spiritual/existential
*domains
• Future outlook
• Independence
• School performance
• Work performance
• Social relationships
• Family relationships
266. • Establish autonomy and independence
– Achieve emotional independence from adults
– Self-esteem and identity development
– Acquire a set of values and an ethical system as a
guide to behavior
• Social and intimate relationships
– More mature relations with peers
– Prepare for marriage and family
• Establish financial independence
– Completion of school
– Prepare for a career.
*
267. *
• Changes in mobility and physical functioning
• Changes in physical appearance
• Separation from peers and usual activities
• Increased dependence on parents at a
time they would usually be practicing
independence
269. N=523 young survivors, age 15-39
• Compared to peers, YCS had lower physical and
social functioning; psychosocial, emotional, and
work/school functioning were similar to peers
• Worse HRQOL associated with: < high school, no
insurance, Hispanic ethnicity, active treatment (esp.
chemo), younger age, greater symptom burden
• Demands of normal physical, hormonal, cognitive
changes + other normal developmental changes
may contribute to lower levels of physical functioning
and fatigue
Smith, JCO, 2013
*
270. N=8375 survivors, diagnosed age 15-39
• Compared to peers, 30% of those age 40-64 report
poor/fair health vs. controls
• > 1 diagnosis associated with poorer QOL
• 45% of female CRC survivors report fair/poor health
– Long-term issues with infertility, bowel function
• Earlier age of diagnosis associated with more days
of poor mental health compared with older age at
diagnosis
– Gap in psychological support for youngest survivors
• Young age at diagnosis may have long-term QOL
impact across lifespan
Kirchhoff, JAYAO, 2014
*
271. • About half or fewer may achieve
recommended levels of physical activity (PA)
(ages 20-44)
• About half may be overweight or obese
• More physically active compared to older
survivors, less compared to age-related
peers
• Benefits of PA include improved QOL,
symptom reduction, and improved
survival/reduced recurrence risk in some
cancers
• Tobacco use may be higher compared to
*
273. Unmet need rated by
70% or more
- Sexuality/intimacy-related
counseling
- Adoption services
- Retreats, camps
N=879 young cancer survivors
Needs were greater for younger
survivors and those diagnosed at
younger ages
Unmet need rated by
50% or more
- Diet, nutrition, exercise
- Family counseling
- Substance abuse
counseling
- Assistance with
transportation, child care
*
274. • Medical care
– Perceived excellence in care after diagnosis
– Dissatisfaction with initial diagnosis delay
• Patient factors - still-maturing cognitive function,
reliance on peers for information
• Provider factors – not attributing symptoms to
cancer, poor provider-patient communication
– Side effects and symptoms
• Fatigue, depression, nausea, weight gain/loss, bowel function,
sexuality/fertility, changes in eating, decreased energy, body
image concerns
Zebrack, Psychosoc Onc, 2014
*
275. • Practical
– Financial
• Inadequate or gaps in health insurance
• Difficulty navigating health insurance coverage
• Work interruptions
• Acquiring early debt & limited financial resources
– School/ work disruption
• Treatment takes precedence over work, school
*
276. • Psychological and Spiritual
– Managing distress & emotions related to cancer,
treatment, and fear of recurrence
– Social functioning and isolation
• Disclosure and communication
– Maintain/re-establish normalcy
– Loss: job/school, appearance change,
relationship changes
***Positive attitudes, beliefs, feelings emerge from
cancer experience
*
277. *
• Some people can transform their lives by
responding to an illness in ways that
enhance the quality and meaning of their
lives
• Resilience = process for identifying and
developing resources or strengths to manage
stressors in order to gain positive outcome
from the experience
• Positive growth: greater maturity, appreciation
for life than population norms
278. • Racial/ethnic minority and medically underserved cancer
survivors have greater disparities in cancer outcomes
and access to survivorship care
– African Americans: higher mortality for CRC
– Uninsured or underinsured persons → more likely to
be diagnosed with advanced cancer → less likely to
receive standard care and survive → less likely to
adhere to surveillance and survivorship care
regimens
• Uninsured/underinsured = predominantly Hispanic,
recent immigrants, and the working poor
– Lifestyle behaviors (e.g., obesity, low physical activity,
tobacco use) related to cancer recurrence or mortality
are more prevalent among racial/ethnic minority,
lower resourced, and less educated survivors
CDC, 2011; American Cancer Society, 2012
*
279. *
• Previvors = at increased risk of hereditary CRC, no CRC diagnosis
• Bowel function and QOL in children with FAP who underwent colectomy
at age < 14 y
• n=28, 56% female, mean colectomy age=12 y, current age=24 y
• Reported more night incontinence, nighttime stools (p<0.05); daytime
incontinence not different from adult sample
• 60% reported feeling embarassed “always or sometimes” due to bowel
concerns
• 20% reported restrictions at school or work, 30% restrictions in sports
due to bowel concerns
• 36% worried ‘at least some’ about post-surgery cancer risk; greater
in younger patients had greater worry
• Younger patients reported more FAP surgery-related distress
– Number of FAP-affected family members associated with higher distress
• Body image and self-esteem scores in normal ranges
Durno, Dis Colon Rectum (2012)
280. 72% seek health information online
-Used phone: 31% cell phone, 52%
smartphone
- 19% smartphone owners
download Pew Internet Research Project, 2012; 2014
* Social and mobile media
to reach EAO-CRC
survivors
281. * Computer and mobile technology
use in the U.S.
Pew Internet Research Project,
2014