Family First: What you need to know about family history, genetic testing, and colorectal cancer.

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Family First:
What you need to know about genetic testing,
family history& colorectal cancer
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Speaker
Heather Hampel, MS, CGC
Ohio State University
Comprehensive Cancer Center
Twitter: @hhampel1

Family First: What you need
to know about genetic
testing, family history &
colorectal cancer
Heather Hampel, MS, CGC
Professor, Division of Human Genetics
November 5, 2011

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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Most cancers are not inherited
5-10% hereditary10-15% familial
75-85% sporadic

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Who is at high risk for cancer?
History is the key…

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Family History
An important first step in risk
assessment for genetic diseases
and other hereditary health
conditions

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Genetic Family History –
My Family Health Portrait
• “The family tree has become the most
important genetic test of all…”
• To help focus attention on the importance of family
health history, U.S. Surgeon General in cooperation
with other agencies within the U.S. Department of
Health and Human Services (HHS) has launched a
national public health campaign, called the U.S.
Surgeon General's Family History Initiative, to
encourage all American families to learn more about
their family health history. http://www.hhs.gov/familyhistory/

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• Americans know that family history is
important to health. A recent survey
found that 96 percent of Americans
believe that knowing their family history
is important. Yet, the same survey found
that only one-third of Americans have
ever tried to gather and write down their
family's health history.
http://www.hhs.gov/familyhistory/

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• Because family health history is such a
powerful screening tool, the Surgeon
General has created a new
computerized tool to help make it fun
and easy for anyone to create a
sophisticated portrait of their family's
health. http://www.hhs.gov/familyhistory/

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National Family History Day
• Thanksgiving is an annual National
Family History Day. Thanksgiving is the
traditional start of the holiday season for
most Americans.
• Whenever families gather, the Surgeon
General encourages them to talk about,
and to write down, the health problems
that seem to run in their family. Learning
about their family's health history may
help ensure a longer future together.
• http://www.hhs.gov/familyhistory/

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Family history is a risk factor for
diseases throughout all stages of life
infants
children
adolescents
adults
older
adults
birth defects
blood
disorders
Alzheimer’s
disease
osteoporosis
cancer
heart
disease
diabetes
depression
asthma
autism

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Taking a Family History
 Obtain at least a three-generation
pedigree
 Ask about all individuals in the family
and record:
 Age at any diagnosis, age at and
cause of death
 Any corrective surgeries
 Associated congenital abnormalities
 Record ethnicity and religious
background
 Some cancer syndromes are more common
in individuals from certain ethnic groups

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Three-Generation Pedigree
Colon cancer
dx 40
62
35
German/Polish English/Irish
Endometrial Cancer
dx 49
d. 72
d. 80
67 5565 Diabetes, dx
45 59
52
30
d. 70 d. 85

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Family History Questionnaires
Name
Davis, John
Jones, Mary
Date of
Birth
2/1/40
4/9/42
Age at dx/
Type of
Cancer
CRC dx 48
Endometrial
dx 52
Date
of
Death
4/3/87
N/A
Hospital
U. Minn.
Franklin
Medical
center

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Information to Obtain About
Affected Relatives
 Current age
 Age at and date of diagnosis/death
 Type and number of colon polyps
 Type and location of cancer
 Primary cancer location vs. metastatic
cancer site
 Hospital where treated
 Environmental exposures (eg, sun)

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Information to Obtain About
Unaffected Relatives
 Current age
 Health status and history of significant
illnesses
 Presence of other physical findings
associated with syndromes
 If deceased, cause of and age at death

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“Female” cancer
 Ask about the presenting features
 Detected by Pap smear – likely cervical cancer
 Diagnosed due to heavy bleeding – likely
uterine/endometrial cancer
 Bloated (looked 6 months pregnant) – likely ovarian
cancer
 Ask about the treatment
 Hysterectomy but ovaries left behind – probably not
ovarian cancer
 No chemotherapy – probably NOT ovarian cancer
 LEEP procedure or colposcopy – probably cervical
dysplasia or cancer

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Unknown type of cancer
 Request copies of medical records (pathology
reports are the key) from the hospital where the
relative was treated
 If a family member makes the request, there will be a
charge for the records
 If you physician or genetic counselor makes the
request, there will not be a charge for the records
 Request death certificates
 Can be obtained from the state department of health
relatively inexpensively
 Can be obtained at www,vitalchek.com from any state
– arrive quickly, slightly more expensive

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High Risk Clues:
 Cancer in 2 or more close relatives
(on same side of family)
 Multiple generations affected
 Early age at diagnosis
 Multiple rare cancers (sebaceous skin cancer)
 Multiple primary tumors (colon and uterus;
more than one colon cancer)
 Multiple colon polyps (>10)
 Patients with certain pathology findings
 Abnormal IHC or MSI+ testing

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CAUTION

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Family History can be unreliable
 Many people do not know the details of their family
history.
 Specific sites of tumors unknown
 Ages of onset unknown
 Historical information needs to be verified in order to
accurately assess risk.
 Family size is getting smaller – can “hide”
susceptibility
 Increased use of effective screening/prevention
options (i.e. colonoscopy) can prevent cancers that
would have occurred otherwise

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Initial pedigree After review of records
Stomach
Ca
Prostate
problems
Bone Ca
d. 48
Breast Ca
dx 45
d. 48
Ovarian Ca
dx 43, d. 49
Prostate Ca
dx 50

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Histories are dynamic
 With the passage of time, additional diagnoses may
have been made.
 These changes in diagnosis may affect the likelihood
of a hereditary cancer syndrome.

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Initial History 2 years later
Colon Ca, 50
Colon Ca, 50
Endometrial
Ca, 44
Colon polyps, 48

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Flowchart for Hereditary Colon Cancer
Differential Diagnosis
Presence of
>10 polyps
Type of polyps
Lynch syndrome
Familial Colorectal Cancer
syndrome type X
MUTYH-Associated Polyposis
Peutz-Jeghers syndrome
Juvenile Polyposis
Serrated Polyposis syndrome
Familial Adenomatous Polyposis
Attenuated FAP
MUTYH-Associated Polyposis
NoYes
AdenomatousHamartomatous

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Hereditary Cancer Syndromes: Lynch
Syndrome & FAP
MLH1
PMS2
MSH2 MSH6 APC

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Sporadic Inherited
• Later age at onset (60s or 70s)
• Little or no family history of cancer
• Single or unilateral tumors
•Early age at onset (<50)
•Multiple generations with
cancer
•Clustering of certain cancers
(i.e. breast/ovarian)
Normal gene
Somatic
mutation
Somatic
mutation
Germline
mutation
Somatic
mutation

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Autosomal Dominant Inheritance
Carrier Parent Non-carrier Parent
Aa aa
Aa Aa aa aa
Carrier Carrier Non-carrier Non-carrier
1/2 1/2

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Lynch Syndrome
 Early but variable age
at CRC diagnosis
(~45 years)
 Tumor site in
proximal colon
predominates
 Extracolonic cancers:
endometrium, ovary,
stomach, urinary
tract, small bowel,
bile ducts, sebaceous
skin tumors

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Amsterdam II criteria
• 3 or more relatives with verified HNPCC-
associated cancer in family
• Two or more generations
• One case a first-degree relative of the
other two
• One CRC dx <50
• FAP excluded
Vasen HFA et al. Gastroenterology. 116:1453, 1999
Does not include
ovarian, gastric, brain,
biliary tract or
pancreatic cancer

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Bethesda Guidelines
 Individual with CRC dx <50
 Individual with synchronous or metachronous
CRC, or other HNPCC-associated tumors
regardless of age
 Individual with CRC with MSI-H histology dx <60
 Individual with CRC with >1 FDR with an
HNPCC-associated tumor, with one cancer dx
<50
 Individual with CRC with >2 FDRs or SDRs with
an HNPCC-associated tumor, regardless of age
Umar A, et al. JNCI. 2004;96(4):261-268.

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Lynch Syndrome Cancer Risks (to 70)
Cancer Lynch syndrome General Public
Colon cancer 56-85% 5%
Endometrial cancer 35-60% 2%
Gastric cancer 13% 1%
Ovarian cancer 12% 1.5%
Small bowel, bladder,
ureter, renal pelvis, brain
<4% each <1% each

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Lynch syndrome Surveillance Options
Lindor N et al. JAMA 2006;296:1507-17. & Vasen HFA et al. J Med Genet 2007;44:353-62.
Intervention Recommendation
Colonoscopy Every 1-2 y beginning at age 20-25 (MLH1 &
MSH2), or 30 (MSH6 & PMS2)
Endometrial sampling Every 1 y beginning at age 30-35
Transvaginal U/S Every 1 y beginning at age 30-35
Urinalysis with cytology Every 1-2 y beginning at age 30-35
History & Exam w/
review of systems
Every 1 y beginning at age 21

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Case 1

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Case 2

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Clinical Features of FAP
 Estimated penetrance
for adenomas >90%
 Risk of extracolonic
tumors (upper GI,
desmoid, osteoma,
thyroid, brain, other)
 CHRPE may be present
 Untreated polyposis
leads to 100% risk of
cancer

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Attenuated FAP
l Later onset (CRC ~age 50)
l Few colonic adenomas
l Not associated with CHRPE
l UGI lesions
l Associated with mutations at
5' and 3' ends of APC gene

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MUTYH-Associated Polyposis (MAP)
 Recessive inheritance – carrier frequency high
 Biallelic MYH mutations are found in:
 96/1457 (6.6%) patients with >100 adenomas
 233/3253 (7%) patients with 20-99 adenomas
 37/970 (4%) patients with 10-19 adenomas
 19/1147 (2%) patients with <10 adenomas
 Y165C & G382D common in W.E. Caucasians
 E466X in Eastern Indian families
Grover S et al. JAMA 2012;308:485-92.

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MUTYH-Associated Polyposis (MAP)
 MYH mutations in CRC dx <50
 8/1116 (0.7%) +
 12/1238 (1%) +
 4/64 (6.3%) +
 Heterozygote risk
 14/259 heterozygotes had adenomas vs 2/107
controls
 2/50 obligate carrier parents had CRC – Expected
 If there is a cancer risk for heterozygotes – LOW
Wang L et al. Gastroenterology 2004;127:9-16;
Croitoru S et al. J Natl Cancer Inst 2004;96:1631-4.
Balaguer et al. Clin Gastroenterol Hepatol 2007;5:379-87

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MAP Management
 Colonoscopy every 2-3 y begin at 25-30 if negative
for polyps
 Once polyps are found, colonoscopy and
polypectomy every 1-2 y
 Subtotal colectomy or proctocolectomy depending
on adenoma density and distribution
 Consider UGI endoscopy and side viewing
duodenoscopy begin at 30-35 and repeat depending
on findings
 Annual physical examination
NCCN Guidelines for Colorectal Cancer Screening 2.2014

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Who to test for FAP & MAP?
 APC testing criteria
 Personal history of >10 adenomas
 Personal history of a desmoid tumor
 Known APC mutation in family
 MUTYH testing criteria
 Personal history of >10 adenomas
 Individual meeting SPS criteria with some adenomas
 Known MUTYH mutations in family
 Start testing with affected relative if possible
 If affected relative is deceased, can test at-risk
relative but negative result is uninformative
 Can test minors because cancer screening starts in
childhood
NCCN Guidelines for Colorectal Cancer Screening 2.2014

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Moderate Risk Families
 1-2 cases of a cancer in the family
 Do not need referral for genetic counseling
 Do need increased cancer surveillance
 Generally the first degree relatives of a person with a
cancer are about twice as likely to develop that
same cancer than someone without that family
history

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Familial Colorectal Cancer Risks
Taylor, DP, Gastroenterology 2010;138:877-886.

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Familial Colorectal Cancer Screening
Recommendations
 FDR diagnosed <50 or 2 FDR dx at any age
 Colonoscopy every 3-5 years beginning at age 40 (or 10
years before earliest dx of CRC
 FDR diagnosed >50
 Colonoscopy every 5 years beginning at age 50 (or 10
years before earliest dx of CRC
 SDR diagnosed <50
 Colonoscopy beginning at age 50 repeat depending on
findings
 FDR with advanced adenoma(s)
 Colonoscopy beginning at age 50 or age of onset repeat
depending on findings
 Otherwise follow Average Risk recommendations
 Colonoscopy every 10 years beginning at age 50

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Family Healthlink
 Interactive web tool that estimates risk by
reviewing patterns of cancer and heart disease
and related conditions in a family
 10-15 min depending on the size of the family
 No pedigree to view; no updating
 Personalized risk assessment (pdf) to share with
healthcare providers
https://familyhealthlink.osumc.edu

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Genetic Counseling

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Genetic Counseling:
Purpose
 Appreciate the way heredity contributes to
cancer
 Understand an individual’s risk of
developing cancer
 Understand the options for dealing with an
increased risk for cancer
 Choose a course of action for managing
cancer risk that seems personally
appropriate (genetic testing, screening or
long-term follow up)

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Genetic Counseling:
What happens
 Collection of personal and family history
 3 generation pedigree
 Education and risk assessment
 Options for genetic testing and medical
management
 Discussion of risks, benefits and limitations
 Screening/Chemoprevention/Prophylaxis
 Follow-up
 Provide psychosocial support
 Family members

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Genetic Testing:
Purpose
 If the exact gene mutation can be identified in a
family, it can:
 Diagnose the family with a specific cancer syndrome
 Determine for which cancers the family is at risk
 Determine a cancer surveillance & prevention plan
 Allow at-risk family members to be tested
inexpensively and reliably
 Relatives who inherit the mutation need to follow the
increased cancer surveillance & prevention plan
 Relatives who do NOT inherit the mutation can follow
the American Cancer Society guidelines for cancer
screening in the general population
 50 colonoscopies versus 3 colonoscopies

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Genetic Testing:
What happens
 Testing is most accurate when you begin by testing
a family member who has had cancer (or polyps)
 If they test positive, the family has a diagnosis and a
known mutation for follow-up testing
 If they test negative, the family history may or may not
still be hereditary but there is no known mutation for
follow-up testing
 Many sites will start Lynch syndrome testing with a
screening test on the colon or endometrial tumor
 Stored in a wax block at the hospital where you had
surgery
 Genetic Testing is done using either a blood sample
or a saliva/mouthwash sample

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Genetic Testing:
What happens
 Costs:
 Tumor screening tests $500-$1500
 Genetic testing $1500/gene or $1500-4500/all genes
 Known mutation testing $200 - $500
 Results:
 Can take anywhere from 2-12 weeks
 May be given by telephone or in the setting of post-
test genetic counseling depending on center

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Genetic Testing:
Informed Consent
 Benefits
 Know reason for cancers in family
 Ability to determine who is and who is not at risk
 Ability to be screened appropriately
 Limitations
 Variants of Uncertain Significance
 Genes that have not been discovered yet
 Risks
 Bruise from blood draw
 Psychological risks (guilt from passing gene onto
children, adjustment to testing positive, survival guilt
when testing negative)
 Insurance discrimination

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GINA
 Prevents health insurers from denying coverage,
adjusting premiums, or otherwise discriminating on the
basis of genetic information.
 Group and self-insured policies
 Insurers may not request that an individual undergo a
genetic test.
 Employers cannot use genetic information to make
hiring, firing, compensation, or promotion decisions.
 Sharply limits a health insurer's or employer's right to
request, require, or purchase someone's genetic
information.

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Refer to an cancer genetic counselor near you
 Find a Local Counselor from the NSGC
http://nsgc.org/p/cm/ld/fid=164
 Find a Local Cancer Genetics expert from the NCI
http://www.cancer.gov/cancertopics/genetics/directory
Refer to a national telecounseling service
 Informed DNA at http://www.InformedDNA.com
 1-800-975-4819
How to find a genetic counselor near you
Heather Hampel

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Resources
 Heather Hampel
 614-293-7240
 Heather.Hampel@osumc.edu
 Family HealthLink
 https://familyhealthlink.osumc
.edu
 Free, on-line tool that
assesses family history of
cancer and cardiovascular
disease

Family First: What you need to know about family history, genetic testing, and colorectal cancer.

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Family First: What you need to know about family history, genetic testing, and colorectal cancer.