Audio and slides for this presentation are available on YouTube: http://youtu.be/e_KVYJX2GTs Have you ever wondered about your genetic predisposition to cancer? How cancer evolves in families? Or how cancer cells differ from normal cells in your body? Join Judy Garber, MD, MPH, director of the Center for Cancer Genetics and Prevention at Dana-Farber Cancer Institute, as she explores the basics of cancer genetics, DNA mutations, genetic screening, management, and more.

1. Cancer Genetics
Judy E. Garber, MD MPH
Director, Cancer Genetics and Prevention
Dana-Farber Cancer Institute

3. Cancer is a Genetic Disease
Normal cells and Cancer cells contain the same 30,000 genes
what distinguishes them is which of the genes
are turned on and off
Normal Cancer
Which genes are activated in cancer?

4. Chromosomes, DNA, and Genes
Gene
Nucleus
Cell Chromosomes
Protein
Adapted from Understanding Gene Testing, NIH, 1995

5. The DNA Double Helix
Sugar
phosphate Base pair
backbone Bases
Adenine (A) Cytosine (C)
Thymine (T) Guanine (G)

6. Normal Male Karyotype
p
Centromere
q
Chromosome 5

7. Genetic Code
A codon is made of 3 base pairs
64 codons total
1 codon (AUG) encodes 61 codons encode 3 codons stop
methionine and starts 20 amino acids protein
translation of all proteins (redundant code) translation
A U G G C A U A A
Met Ala

8. Disease-Associated Mutations
Alter Protein Function
Functional protein Nonfunctional or
missing protein

9. Autosomal Dominant Inheritance
 Each child has 50%
chance of inheriting the
mutation
 No “skipped generations”
 Equally transmitted by
men and women
Unaffected
Affected

10. The Two-Hit Hypothesis
First hit
First hit in
Second hit
germline
(tumor)

11. Tumor Suppressor Genes
Normal genes
(prevent cancer)
1st mutation
(susceptible carrier)
2nd mutation or loss
(leads to cancer)

12. Oncogenes
Normal genes
(regulate cell
growth)
1st mutation
(leads to
accelerated cell
division)
1 mutation sufficient for role in cancer development

13. Normal (male) chromosomes and
BRCA1-deficient cancer cells with
gross chromosomal abnormalities

15. More Subtle Pedigrees
PR 60 CO 61?
55* OV 59
BR 32 BR 34
*TAH/BSO at 40

16. Genetic Testing 2012
• Genetic testing requires a DNA sample from
blood, saliva or other tissue
• Testing costs are usually covered by health
insurance, at least partially
• Laws to prevent discrimination in health
insurance exist (GINA)
• Testing is often offered at the time of cancer
diagnosis, because the information can affect
management decisions
• Autonomy and Access are still important

17. +

18. Once the mutation is
found in one person
in the family after full
price testing, the rest
of the family can be
tested to see whether
they do or do NOT
share the mutation.
The “single site”
testing is usually
about $500.

19. BR/OV Cancer Risk Management
Options for BRCA Mutation Carriers
Surveillance (does not  risk)
• Mammogram, MRI, Exam, +/- US
• (TransVaginal Ultrasound, CA125)
Chemoprevention
• Tamoxifen/ Raloxifene?
Exemestane? Other?
• Birth Control Pills  Ov ca risk
Prophylactic Surgery
• 90% Bilateral mastectomy
• Removal ovaries & fallopian tubes:
90% Ov ca risk; if done
premenopausal, ~50%  BrCa risk

20. I’M OUT OF
ESTROGEN
AND I AM
NOT HAPPY
ABOUT IT

21. Risk of Colorectal Cancer (CRC)
General population 5%
Personal history of
colorectal neoplasia 15%–20%
Inflammatory 15%–40%
bowel disease
HNPCC mutation 70%–80%
FAP >95%
0 20 40 60 80 100
Lifetime risk (%)

22. Hereditary Non-Polyposis Colorectal
Cancer (HNPCC, Lynch Syndrome)
• Colon, Uterine and
other cancers
• In HNPCC, the tumor
CO 45 UT 38
tissue stored in a
CO 40 pathology department
_ + can be studied for
evidence that the
CO 28 Cecum 35 syndrome is present, so
ST 32
even a deceased relative
can be informative
4

23. A Li - F raum eni S yndrom e K indred
C R C , 72 Lung, 48 80
O S , 14
Laryn x, 56 B reast, 26
B reast, 22, 27
S T S , 33*
S tom ach, 32
B reast, 32 ACC, 5
O S , 14
S T S , 26*
* tum or in R T field of prior m alig na ncy

25. FDG-PET/CT Screening in LFS Results
Fused PET/CT
CT

26. Survival of TP53 Mutation Carriers in
Surveillance and Non-Surveillance Groups
Villani A et al. Lancet Oncol 2011;12:559-567

27. Decisions Potentially Influenced by
BRCA1/2 Status in Breast Cancer Patients
• Management of newly diagnosed patients
– Primary Therapy: Surgical Options
– Chemotherapy
– Hormonal therapy
• Management of breast cancer survivors
– Additional primary breast cancer risk
– Ovarian cancer risk
– Treatment of metastatic disease
• Implications for Relatives

28. Breast Cancer Subtypes are Associated
with Different Germline Mutations
ER+ PR+/HER2-
BRCA2, TP53
ER+ or ER-/HER2+
TP53
ER-, PR-, HER2-
BRCA1

29. Kaplan-Meier estimates of recurrence-free survival
and overall survival after neoadjuvant T-FAC by :
BRCA status
Path CR
TNBC
Arun B et al. J Clin Oncol 2011;29:3739-3746

30. -

31. Expanded Commercial Cancer Genetic
Testing is Here

32. TP53 Germline
Deletion in Patient
With t-AML
BR 37 +
OV 39
R-OV 42
AML 42
3
Link DC et al. JAMA 2011;305:1568-1576

33. Pharmacogenetics:
Predicting Efficacy and Toxicity

34. =
Breast Cancer

35. A Paradigm Shift – The Genomic View of Cancer
From Anatomy… From
KIT Germline
(Imatinib)
• Lung
Tumor Blood
Genomic Genomic
• Breast Profiling EGFR Profiling
(Erlotinib)
•Prostate HER2
(Trastuzumab)
• Colon
BRAF
(PLX4032)
• Brain
PIK3CA
(BEZ235)

36. Potential Findings from Sequencing DNA from Tumor
& Blood of DFCI Cancer Patients in PCMP
• Tumor genome: treatment targets, predictors of response
• Personal genome:
• Variation in drug metabolizing genes that affect dose or
choice of agent
• Mutations in genes that confer  risk of the patient’s
cancer and related cancers (e.g, BRCA, HNPCC),
important to patient and family
• Mutations in genes associated with Non-Cancer
conditions that could be more important to relatives
(e.g., long QT; Fragile X)

39. Learn more about the
DFCI Gene Display.
Gene Display in the Yawkey Center for Cancer Care

40. Audience Q&A
What about people who are adopted
and don’t know anything
about their family history?

41. Audience Q&A
What is does the insurance
industry think about
preventative surgeries?

42. Audience Q&A
For insurance purposes,
do you have to build a case
to justify preventative surgery
based on genetic testing?

43. Resources and Additional Information
• Check out the Cancer Genetics and Prevention Program
at Dana-Farber.
• Watch Dr. Judy Garber discuss her work as the director
of Cancer Genetics and Prevention Program.
• View more resources available through DFCI for patients
and families dealing with cancer.
To schedule an appointment at DFCI, click here.