1. An Overview of Clinical Cancer Genetics
Mónica Alvarado, MS, CGC
Certified Genetic Counselor
Regional Administrator, Genetic Services
Kaiser Permanente, Southern California

3. New cases in U.S. each year
Breast cancer: >185,000
Colorectal cancer: >150,000
Ovarian cancer: > 25,000
If 5% to 10% of these are due to hereditary cancer syndromes then…Each year between 18,000 to 36,000 newly diagnosed patients would be appropriate for referral to a cancer genetic counselor
Reports indicate that only about 5% to 7% of patients who have a personal/family history of cancer suggestive of hereditary cancer are ever referred for genetic counseling.

4. GENETIC vs. INHERITED
CANCER IS ALWAYS GENETIC
BUT RARELY INHERITED

5. Cancer Arises From Gene Mutations
Germline mutations
Somatic mutations
Parent
Child
All cells affected in offspring
Somatic mutation (eg, breast)
Mutation in egg or sperm
Occur in nongermline tissues
Are nonheritable
Present in egg or sperm
Are heritable
Cause cancer family syndromes

6. When to Suspect Hereditary Cancer Syndrome
Cancer in 2 or more close relatives (on same side of family)
Early age at diagnosis (< 45 yrs)
Multiple primary tumors
Bilateral or multiple rare cancers
Constellation of tumors consistent with specific cancer syndrome (eg, breast and ovary, colon & endometrium)
Evidence of autosomal dominant transmission
Triple negative breast cancer plus any one of the above

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

8. Syndrome Gene Cancers Hereditary Breast/Ovarian BRCA1 BRCA2
Breast, Ovarian, Pancreas, Others
Lynch Syndrome/Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
MLH1 MSH2 MSH6
PMS2
Colorectal (CRC), Endometrial,
Gastric, Ovarian, Other GI, Urinary tract
Familial Adenomatous Polyposis (FAP)
APC
Colorectal, Duodenal, Thyroid, Brain

9. Colorectal Cancer: >150,000 cases annually in the US
Sporadic (~60%)
Familial (~30%)
Rare syndromes (~4%)
FAP (<1%)
HNPCC (3-5%)
Slide 2
HNPCC: Autosomal Dominant Inheritance of Colorectal Cancer Risk
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States, with more than 130,000 cases diagnosed annually. In general, CRC is classified into three categories, based on increasing hereditary influence and cancer risk:
Sporadic CRC comprises about 60% of cases. Patients with sporadic CRC do not have a notable family history of CRC nor do they have, by definition, an identifiable inherited gene mutation that accelerates cancer development.
Familial CRC comprises up to 30% of cases and refers to patients who have at least one blood relative with CRC or an adenoma. However, no specific germline mutation or clear pattern of inheritance is identifiable. Familial CRC probably has multifactorial causes, such as shared exposure to carcinogens or interactions between the environment and multiple or weakly penetrant genes.
Hereditary CRC syndromes account for approximately 10% of CRC. These autosomal dominant disorders confer the highest risk of colorectal cancer and result from inheritance of single gene mutations in highly penetrant cancer susceptibility genes. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary CRC syndrome, comprising about 3% to 5% of all CRCs. Familial adenomatous polyposis (FAP) is responsible for less than 1% of all CRC, while several rare disorders, such as Peutz-Jeghers syndrome and juvenile polyposis, make up the remaining small fraction.
References
Liu B, Parsons R, Papadopoulos N, et al. Analysis of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients. Nature Medicine 1996;2:
Ivanovich JL, Read TE, Ciske DJ. A practical approach to familial and hereditary colorectal cancer. American Journal of Medicine 1999;107:68-77.
Nat Med 1996; 2:169-74

10. Familial Risk for Colorectal Cancer
70%
Approximate
lifetime
CRC risk to age 70 yrs
(%)
17%
10% 6% 8% 2%
None
One 1°
One 1° and two 2°
One 1° age <45
Two 1°
HNPCC mutation
Aarnio M et al. Int J Cancer 64:430, 1995
Houlston RS et al. Br Med J 301:366, 1990
St John DJ et al. Ann Intern Med 118:785, 1993
Affected family members 4

11. Lynch Syndrome (HNPCC)- About 3% of all Colorectal Cancer
Early (but variable) onset of CRC:
Average age of onset of CRC is 45 years
Defects in one of 4 mismatch repair genes:
MLH1, MSH2, MSH6, PMS2
Tumors tend to be right sided
90% or more of CRC tumors exhibit microsatellite instability
Muir-Torre syndrome is a variant of HNPCC associated with sebaceous adenomas

12. LS Increases the Risk of Colorectal Cancer
By age 50
By age 70
Slide 5
HNPCC Increases the Risk of Colorectal Cancer
Without medical intervention, most people with inherited mutations in the MMR genes will develop colorectal cancer. The risk of colorectal cancer in mutation carriers is at least 25% by age 50 and about 80% by age 70. By comparison, the risk of colorectal cancer by age 70 in the general population is about 2%.
Early onset of colorectal cancer is a hallmark of HNPCC. The average age of diagnosis of HNPCC-associated colorectal cancer is 45 years, and some patients develop the disease in their teens or twenties. It must be emphasized that although adenomatous polyps may form at a relatively early age in patients with HNPCC, a profusion of polyps is not a feature of HNPCC.
HNPCC-associated colorectal cancers also appear to be biologically different from sporadic colorectal cancers. Compared with sporadic colorectal cancer, HNPCC-associated tumors most commonly develop in the right side of the colon, with nearly 70% found proximal to the splenic flexure. For this reason, endoscopic surveillance in HNPCC families should be performed with colonoscopy, not flexible sigmoidoscopy. Several studies also have reported better survival in HNPCC-associated colorectal cancer than sporadic colorectal cancer when matched for cancer stage. In addition, a particular DNA abnormality known as “microsatellite instability” is highly characteristic of HNPCC-associated colorectal cancers but occurs much less frequently in sporadic colorectal cancer.
References
Vasen HFA, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996; 110:
Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. International Journal of Cancer 1999; 81:214-8.
Population Risk
0.2% 2%
LS Risk
>25%
80%
Gastroenterology 1996;110:1020-7
Int J Cancer 1999;81:214-8

13. LS Increases the Risk of Endometrial Cancer
By age 50
By age 70
Slide 6
HNPCC Increases the Risk of Endometrial Cancer
Women who inherit HNPCC-associated germline mutations also have a greatly elevated risk of endometrial cancer. The risk of endometrial cancer in HNPCC is at least 20% by age 50 and up to 60% by age 70, compared with a less than 2% risk by age 70 in the general population.
As with HNPCC-associated colorectal cancer, endometrial cancer in these patients occurs at an unusually young age, usually before age 50. Some studies have reported that if a woman carries an MLH1 or MSH2 mutation, her risk of endometrial cancer may be even higher than her risk of colorectal cancer. Early onset of endometrial cancer should therefore raise suspicion for HNPCC, especially in women with a family history of colorectal cancer or endometrial cancer.
References
Vasen HFA, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996; 110:
Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. International Journal of Cancer 1999; 81:214-8.
Population Risk
0.2%
1.5%
LS Risk
20%
60%
Gastroenterology 1996;110:1020-7
Int J Cancer 1999;81:214-8

14. The Family History Is Key to Diagnosing LS
CRC
dx 50s
CRC
dx 45
CRC
dx 61
CRC
dx 75
Ovarian Ca, dx 64
CRC
dx 48
CRC
dx 52
Endometrial Ca, dx 59 45
CRC
dx 42 32

15. LS: Clinical Characteristics of Colorectal Cancer
Early age of diagnosis
mean age <45 yrs
Predominantly proximal (right) colon cancer
Improved survival
Patients develop similar numbers of adenomas as the general population
3 or more relatives with verified CRC in family
One case a first-degree relative of the other two
Two or more generations
One CRC by age 50
FAP excluded

16. LS Cancer Risks Colorectal: Up to 80% lifetime risk
Endometrial: 30% to 60% lifetime risk
Ovary: % by age 70
Stomach: % by age 70
Other
Urinary tract (4% by age 70)
Small intestine (100-fold relative risk, but < 5%)
Biliary tract (2% by age 70)
Brain (~4% by age 70)
Slide 7
HNPCC Increases the Risks of Other Cancers
HNPCC is also associated with an increased risk of cancers of the stomach and ovary, each estimated to be slightly higher than 10% by age 70. In addition, HNPCC also increases the risks of various rare cancers, including those of the urinary tract, small intestine and biliary tract, and brain, although each of these risks is usually below 5% during a person’s lifetime.
Sebaceous skin tumors also occur in some patients and are a characteristic feature of a rare variant of HNPCC called Muir-Torre syndrome.
References
Vasen HFA, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996; 110:
Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. International Journal of Cancer 1999; 81:214-8.
Gastroenterology 1996;110:
Int J Cancer 1999;81:214-8

17. Management of LS

18. Colonoscopy Prevents Cancer in Mutation Carriers
Proportion free of CRC
Surveillance
81.7%
100
57.8%
No surveillance 80 60 40 5 10 15
Follow-up time (years)
Gastroenterology 118:829, 2000

19. Microsatellite Instability (MSI)
10% to 15% of sporadic tumors have MSI
95% of LS colon tumors have MSI
Can be used as a screening test
If colorectal tumor is MSI-H and family history is positive for CRC very high likelihood of LS

20. IHC tumor test for LS

21. IHC Test & Results Rationale for IHC tumor test
Universal IHC screening detects nearly twice as many cases of LS as targeting younger patients
Cost effective
can be internalized
results point to which MMR genes to analyze
Results
80% all proteins present
Most likely not LS
20% one or more proteins absent
Most will not have LS
Approximately a third of these patients will test positive for a MMR mutation

22. 2011 KPSC IHC Pilot Proposal
Surgery
provide the “IHC fact sheet” to patients scheduled for CRC tumor surgery
Pathology
order reflex IHC testing on all CRC ≤ 50 yrs at diagnosis(~185 to 200 cases/yr)
Immunohistochemistry lab
performs IHC on tumor specimens per protocol
sends all abnormal IHC tumor results (~20% of cases) to surgeon and local genetics contact
Genetics
Arranges follow-up of all abnormal IHC MMR results including:
Contacts patient to offer genetics consultation as needed
Coordinates follow-up tumor & germ line testing and appropriate counseling
Dr. Tiller

23. Lynch Syndrome: Key Points
Most common form of hereditary CRC. Autosomal Dominant inheritance
About 3% or colorectal and endometrial cancers
Uterine/Endometrial cancer second most common after CRC in HNPCC families
Family/Personal history and IHC and/or MSI can help identify affected individuals
Identifying individuals with LS can minimize impact of disorder for them and their family members
High risk of multiple primary CRC and extra-intestinal tumors
Colonoscopic surveillance can improve survival in at-risk individuals For every individual identified with LS there are approx. 3 affected family members. Potential for preventing CRC in unaffected persons 45

24. Familial Adenomatous Polyposis (FAP)
About 1% of all CRC; Incidence 1 in 8,000
Multiple colonic adenomas (100s) beginning in childhood or teen years
Autosomal dominant pattern of CRC:
Average age of CRC is 36
Risk of CRC by age 40 nearly 100%
Mutations in APC gene on 5q
80% are protein truncating mutations
Up to 30% are new mutations

25. Family with FAP Colon CA dx. 47 Age 45 FAP, dx. 27 Colectomy
CRC dx. 31, d. 35
Age 42
FAP dx.38
APC+
Colectomy
Age 40
APC -
Age 18
APC+
FAP dx. 15
Surveillance

26. 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 6

27. Other Cancers Associated with FAP
Cancer Risk Lifetime Risk
Duodenal & periampullary cancer %
Thyroid cancer %
Pancreatic cancer %
Hepatoblastoma (childhood) %
Gastric cancer %
CNS tumors <1 %
Burt, Gastroenterology 2000; 119:837-53

28. Gardner’s Syndrome: A Variant of FAP
Features of FAP plus extraintestinal lesions:
Epidermoid cyst
Desmoid tumors
Osteomas
Dental abnormalities
CHRPE
Soft tissue skin tumors
Jaw osteoma 12

29. Medical Management of FAP
Annual flexible sigmoidoscopy beginning at age 101
Prophylactic total colectomy after polyp detection
chemoprevention:
celecoxib after surgery2
NSAIDs (eg., sulindac) after surgery (investigational)
Subsequent surveillance for rectal and extracolonic tumors
1Gastroenterology 2001; 121:197-7
2Steinbach, NEJM 2000; 342:

30. FAP: Key Points Autosomal dominant with early onset of polyposis
However, up to 30% new mutations (no family hx)
Severe polyposis makes it easier to identify affected individuals
CRC risk is 100% in untreated patients
Genetic testing identifies most APC mutation carriers
Endoscopic surveillance and colectomy can significantly improve survival
Noncarriers can avoid anxiety and unnecessary tests
Genetic testing of children has medical benefit

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

33. BRCA1
Approximately 1 in 500 women may be carriers of alterations in BRCA1
Breast tumors tend to be triple negative (ER, PR and Her2Neu negative), basal type, excess of medullary
Ovarian tumors: epithelial, high grade, mucinous and borderline tumors rare
Specific alterations observed in ~1% Ashkenazi Jewish individuals: 185delAG, 5382insC

34. BRCA2 Gene is twice the size of BRCA1
Breast tumors tend to be ER +, and no specific histopathology observed
Ovarian tumors: epithelial, high grade, mucinous and borderline tumors rare
Wider spectrum of cancer types
Specific alteration in 1.5% of Ashkenazi Jewish individuals: 6174delT

35. BRCA1 and BRCA2 in Ashkenazi Jewish Individuals
1 in 40 will have mutation in BRCA1/2 regardless of family history
Founder effect: 3 mutations account for the majority of carriers
Ashkenazi Jewish heritage must be identified for proper risk assessment and mutation analysis

36. The BRCA1 and 2 Genes

37. BRCA1 & BRCA2-Associated Cancers: Lifetime Risk
ASCO Curriculum: Cancer Genetics & Cancer Predisposition Testing
BRCA1 & BRCA2-Associated Cancers: Lifetime Risk
breast cancer (often < 50 yrs)
40%-85%
Contralateral breast cancer
40-60%
ovarian cancer
10%-40%
male breast cancer elevated (6%)
Pancreas & prostate cancers
may also be elevated
Breast and Ovarian Cancer 10

38. BRCA1/2 Mutations Increase Risk of Breast and Ovarian Cancer
By age By age By age 70
Slide 5
HNPCC Increases the Risk of Colorectal Cancer
Without medical intervention, most people with inherited mutations in the MMR genes will develop colorectal cancer. The risk of colorectal cancer in mutation carriers is at least 25% by age 50 and about 80% by age 70. By comparison, the risk of colorectal cancer by age 70 in the general population is about 2%.
Early onset of colorectal cancer is a hallmark of HNPCC. The average age of diagnosis of HNPCC-associated colorectal cancer is 45 years, and some patients develop the disease in their teens or twenties. It must be emphasized that although adenomatous polyps may form at a relatively early age in patients with HNPCC, a profusion of polyps is not a feature of HNPCC.
HNPCC-associated colorectal cancers also appear to be biologically different from sporadic colorectal cancers. Compared with sporadic colorectal cancer, HNPCC-associated tumors most commonly develop in the right side of the colon, with nearly 70% found proximal to the splenic flexure. For this reason, endoscopic surveillance in HNPCC families should be performed with colonoscopy, not flexible sigmoidoscopy. Several studies also have reported better survival in HNPCC-associated colorectal cancer than sporadic colorectal cancer when matched for cancer stage. In addition, a particular DNA abnormality known as “microsatellite instability” is highly characteristic of HNPCC-associated colorectal cancers but occurs much less frequently in sporadic colorectal cancer.
References
Vasen HFA, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996; 110:
Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. International Journal of Cancer 1999; 81:214-8.
Breast Cancer
Population Risk
<0.5%
~2%
~7%
BRCA Carrier Risk
2 - 3% %
40-85%
Ovarian Cancer
<<<1%
<1% 1%
<<1%
2 - 20% %

39. Identification of women at high risk for HBOC
Family History & Presentation
Two or more cases of breast and/or ovarian cancer on same side of the family
Consider both sides of the family, ethnicity
Ashkenazi Jewish heritage
Early age of onset, multiple primaries, TNBC
Breast cancer <45 yrs at diagnosis
Breast & ovarian cancer in the same woman, multiple breast primaries
TNBC: ER, PR and Her2 negative (BRCA1)
Autosomal dominant pattern of cancer

40. Management of BRCA Mutation Positive Patient
BRCA1 or BRCA2
Mutation
Offer test to
relatives
Lifestyle
Changes
Increased
Surveillance
Chemo-
prevention
Prophylactic
Surgery
Adapted from Myriad Genetics

41. BRCA Carriers: Cancer Screening
Breast cancer screening
Monthly BSE from age 18
Clinical breast exam 2-4 times per year (beginning at age 25)
Annual mammography and MRI starting at age 25 or individualized based on earliest age of onset in family
MRI is most sensitive imaging modality for surveillance of BRCA carriers. 80% to 92% MRI vs 23% to 33% Mammo (based on 4 studies, N=714)
Ovarian cancer screening
Concurrent TVU, Pelvic exam and CA125 q6 months starting at age 35 or 5-10 years earlier than earliest onset in family
No proven benefit

42. Prophylactic Surgery in BRCA1/2 carriers
Prophylactic mastectomy
Reduces risk by ~90%
Total (simple) mastectomy recommended
Nipple sparing mastectomy may be good alternative
Risk-reducing salpingo-oopherectomy
Reduces risk by 85%-95% or more
Must remove ovaries and tubes; hysterectomy currently optional in most centers
Peritoneal washings recommended due to high incidence of occult malignancy
Breast cancer risk reduction
55-70% if done pre-menopausally
Does not eliminate risk for primary peritoneal cancer
Residual risk reported as 1% to 4.3%

44. Chemoprevention for BRCA1/2 Carriers
Breast Cancer
Tamoxifen & Raloxifene: Very little data on carriers; few choose it
Tamoxifen may be less effective in BRCA1 carriers
One case control study reported ~50% contralateral cancer risk reduction from Tamoxifen use in BRCA1/2 carriers
No evidence that Tamoxifen post BSO reduces breast cancer risk
Ovarian Cancer
Oral Contraceptives reduce risk by 50% to 70% with 5 yr use
Data unclear: two large studies reached opposite conclusions on effects of OCs in ovarian cancer risk for BRCA1/2 carriers
Use should be evaluated on case by case basis
Narod et al, Lancet, 2000

45. BRCA Carriers: Timing can influence decision making
How might a newly diagnosed breast cancer patient alter her treatment decisions?
Surgery?
Chemotherapy?
How might her future cancer risk for cancer influence these decisions?
Second breast cancer?
Ovarian cancer?
d. 59
Breast CA
dx. 54 73
Breast CA
dx. 60
d. 53
Breast CA
dx. 42 49
Breast CA
BRCA2 +

46. Could this be HBOC?
How does Ashkenazi Jewish background affect probability of mutation in BRCA1 & 2?
Non Ash.: 1.1%-5.6%
Ash. Jewish: 8.2%-15.6%
How might cousin’s TAH/BSO affect family history of breast and ovarian cancer in this family?
Polish/Hungarian Jewish
Unk CA
d. 52
d.70s
d. 53
Ovarian CA
dx. 51 d 45

47. HBOC: Key Points
Clues in the personal or family history of cancer can help identify individuals who may have an inherited susceptibility to breast or ovarian cancer
Mutations in BRCA1/2:
Can be passed down from the mother or father
Are far more frequent in Ashkenazi Jewish families
Are inherited in autosomal dominant fashion
Genetic testing is offered only when personal and/or family history of cancer suggests inherited susceptibility
Genetic testing can identify mutations in BRCA1/2 and influence risk management, and save lives

48. Cancer Genetics Resources
FORCE:Facing Our Risk of Cancer Empowered; support group for BRCA1/2
Cancer Genetics Services Directory:
Johns Hopkins Digestive Disease Library:
CDC Colorectal Cancer:
Genetics of Cancer: