1. Breast Cancer Risk Assessment and Genetic Testing
Susan W. Caro, RNC, MSN, APNG
Director, Family Cancer Risk Service
Vanderbilt-Ingram Cancer Center

2. Objectives:
1. Appreciate the complex and emerging information about the impact of genetics on breast cancer risk.
2. Identify resources available for assessing genetic risk.
3. Articulate when risk counseling and assessment is recommended.
4. Know the TN resources for genetic risk assessment.

3. In 1990, the National Institutes of Health and the Dept
In 1990, the National Institutes of Health and the Dept. of Energy launched the Human Genome Project, an international effort to map, sequence, and characterize the human genome. Working draft completed in June 2000, published in Science and Nature in February 2001.

4. Why?
Hereditary cancer syndromes are being more clearly defined with increasingly clear recommendations for management.
Clinical genetics tests for hereditary cancer syndromes are available and in some markets are being marketed directly to the consumer.
Recognizing hereditary cancer syndromes provides the opportunity to identify those at significantly increased risk and offer options to identify cancers earlier or prevent cancer in these individuals.
Potential for medico-legal implications of not recognizing hereditary cancer syndromes.
Lynch HT, Paulson JD, Severen M, et al. Failure to Diagnose Hereditary Colorectal Cancer and Its Medicolegal Implications. Dis. Colon Rectum January 1999;42:31-35.

5. Hereditary Cancer Burden in Tennessee?
Breast Cancer ,720 new diagnoses
920 deaths
Colorectal Cancer ,290 new diagnoses
1130 deaths
If ~10% hereditary cancer – 372 new cases of hereditary breast cancer (392 CRC) this year.
Could some of these have been foreseen,
even prevented?
*Excludes carcinoma in situ (CIS, non-invasive cancer) of any site except urinary bladder.
Does not include basal and squamous cell skin cancers (of which there are 1.3 million per year).
American Cancer Society, 2008

6. Prevention (medical)
In medicine, prevention is any activity which reduces the burden of mortality or morbidity from disease. This takes place at primary, secondary and tertiary prevention levels.
Primary prevention avoids the development of a disease. Most population-based health promotion activities are primary preventive measures.
Secondary prevention activities are aimed at early disease detection, thereby increasing opportunities for interventions to prevent progression of the disease and emergence of symptoms.
Tertiary prevention reduces the negative impact of an already established disease by restoring function and reducing disease-related complications.
Wikipedia

7. All cancer is genetic, not all cancer is hereditary.

8. Breast Cancer Genes Found
BRCA1 (for BReast CAncer gene 1) was described in 1990 on chromosome 17, isolated in 1994
BRCA2 was isolated on chromosome 13 in late 1994
BRCA3?

9. The Development of Hereditary Cancer
Tumor
develops
2 normal genes
1 damaged gene
1 normal gene
2 damaged genes
In hereditary cancer, one damaged gene is inherited.
S5: The Development of Hereditary Cancer
A normal cell has two functional copies of each gene. Some genes (including p16) function as tumor suppressors, helping repair DNA damage and keeping the damaged cells from becoming cancerous. In a cell with two functional copies of a specific tumor suppressor gene, if only one copy of the gene is damaged, the cell will still function properly as the second “back up” copy of the gene is still functional. If the other copy of the gene is damaged within the same cell, the tumor suppressor function of the gene is taken away and the cell can become cancerous. This damage can occur through lifestyle, environmental exposures (carcinogens), and most commonly the normal aging process of cells. The chances of both copies of an important tumor suppressor gene being independently knocked out in the same cell are extremely small.
Individuals with hereditary cancer have inherited one nonfunctional copy of a specific tumor suppressor gene in every cell of their body. Therefore these individuals require only one additional mutation to knock out the functional copy of the gene, making cancer development much easier.
Tumor
develops
1 damaged gene
1 normal gene
2 damaged genes
Myriad Genetics, Inc.
© 2006 Myriad Genetic Laboratories, Inc.

10. American Society of Clinical Oncology Guidelines for Genetic Testing
Personal or family history features suggestive of hereditary cancer risk
Test can be adequately interpreted
Test result will aid in diagnosis or influence medical management of the patient and/or family
Slide 19: Guidelines for Cancer Predisposition Testing
For an individual whose personal and/or family history suggests the possibility of a hereditary melanoma syndrome, only a genetic test can confirm whether he/she carries a mutation in the p16 gene. The American Society of Clinical Oncology (ASCO) has recommended that genetic testing be offered when 1) the individual has personal or family history features suggestive of a genetic cancer susceptibility condition, 2) the test can be adequately interpreted, and 3) the results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer.1 These criteria can be applied to identify appropriate candidates for genetic testing for hereditary melanoma.
Reference:
1. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003;21(12):
J Clin Oncol 2003;21:

11. Cancer Syndromes Hereditary Breast Cancer Syndromes
BRCA1, BRCA2, Cowden, CHEK2, Li-Fraumeni
Hereditary Colorectal Cancer Syndromes
HNPCC
FAP
Endocrine Syndromes – VHL, MEN1, MEN2, FMTC
Other – Li Fraumeni, Peutz-Jeghers
DNA Banking

12. Ask – out loud
Ask the question: Do you have a family history of cancer?
Clarify - maternal AND paternal family history
Ask the question again more specifically: Does anyone in your family have a history of breast, ovarian, colon cancer, colon polyps, or other cancers?
Ask the question again at follow up visits, as family histories change over time.
FCRS

13. Listen when your patients voice a concern:
In many health care encounters today, we are focused on the problem at hand and it is difficult to go beyond this.
Not suggesting that every health care provider have an expert knowledge of the complex issues surrounding all of the hereditary cancer syndromes - rather that continual exposure to this information will prompt recognition and referral for more thorough evaluation of the family.
A significant number of our patients seek consultation independently. Their health care providers do not always recognize the significance of family history.

14. Refer
Refer for comprehensive risk assessment and consideration of genetic testing.
Genetic testing is only one aspect of this. There is a great deal to be learned from gathering and documenting the family history and the educational component of the counseling process.
Many patients are concerned as a result of things they have read or been told about insurance discrimination. This is addressed in the counseling session (before any decision for genetic testing is made).

15. Family Cancer Risk Consultation
Should include:
Education about cancer risk in families
Cancer/genetic risk assessment
Discussion of possible risks and benefits of genetic testing
Psychological support, guidance about medical options, and referral for medical or surgical means of early detection or prevention of cancer
Offit, 1998, p. 3

16. Comprehensive Risk Assessment / Consultation
Assess patient’s view of their risk, experience with cancer in the family
Review what is known and not known about cancer risk
Medical history, current surveillance activity
Review family history and draw pedigree
Document cancers in history (medical record and pathology review)
Provide risk assessment - Risks associated with hereditary cancer syndromes under consideration, risks if no recognizable syndrome
Education - Cancers, risks factors, surveillance, basic genetics, cancer genetics
Testing? Benefits, limitations, risks, costs, insurance, process
Recommendations for surveillance or possible preventive measures, discuss implications to others in family.
Interpretation of test results, including psychological, social, and family implications of test results

17. Management Options / Counseling
Review options for increased screening or measures to decrease risk
Discuss efficacy (or lack of efficacy/ or lack of data to support efficacy) of surveillance, prophylactic / risk reducing, or chemopreventive measures
Increasing understanding of utility and consequences of surveillance and intervention options – a moving target.

18. How Much Breast and Ovarian Cancer Is Hereditary?
ASCO Curriculum: Cancer Genetics & Cancer Predisposition Testing
How Much Breast and Ovarian Cancer Is Hereditary?
15%20%
5%–10%
5%–10%
Breast Cancer
Ovarian Cancer
Sporadic
Family clusters
Hereditary
ASCO
Breast and Ovarian Cancer 3

19. Breast and ovarian cancers
Contribution of BRCA1/2 to hereditary breast /ovarian cancer families:
Breast Cancer Families
Breast and ovarian cancers
Breast and Ovarian
Cancer Families
King, Rowell, Love, 1993; Ford, Easton, Stratton, et al, 1998

20. BRCA Mutations and Ashkenazi Jews
185delAG mutation noted in 1% of 850 samples of Ashkenazi Jewish individuals unselected for family history of cancer (studied stored samples from Tay-Sachs research)
Carrier rate 3 X that expected in general population
May account for 16% of breast and 39% of ovarian cancer in AJ women <50
2 other “founder mutations”

21. Male Breast Cancer and BRCA2
Studies of BRCA2 in population- and clinic-based series of male breast cancer patients from the United States and Europe have found carrier frequencies of BRCA2 mutations of 4% - 40%
The percentage of male breast cancer cases that are associated with a BRCA2 mutation varies depending on the population. Figures from various studies (some small):
4% in U.S.;
21% in Sweden;
40% in Iceland.
One study showed that among men with breast cancer and a first-degree relative (e.g., mother or sister) with breast cancer approximately 11% were carriers of a BRCA2 mutation.
For male BRCA2 alteration carriers:
Estimated cumulative risk of male breast cancer is ~6% by age 70
Age of onset not as early as female breast cancer in BRCA2 carriers
BRCA1 may account for more cases of male breast cancer than initially estimated.
(Couch et al. 1996, Thorlacius et al. 1996, Friedman et al. 1997, Csokay et al. 1999)

22. Cumulative Risk of Breast and Ovarian Cancer in
BRCA1 and BRCA2 Mutation Carriers
From Rebbeck,T; J Clin Oncol 18:100s-103s 2000

23. Risks of Breast Cancer with BRCA1 or BRCA2 Mutation
Breast cancer risk by age (women)
BRCA1
BRCA2
Ashkenazi women w/ BRCA1/2
General population US 40
19%
12% 50
50%
28%
33% 2% 60
64%
48% 70
85%
84%
56% 7%
Easton DF, Ford D, Bishop T, and the Breast Cancer Linkage Consortium, Am J Hum Gen 56:
Easton DF, et al., and the Breast Cancer Linkage Consortium, JNCI 91:
Ford D, Easton DF, Stratton M, Narod S, et al., 1998, Am J Hum Genetics 62:
Struewing JP, Harge P, Wacholder W, et al. NEJM, (20):
Ford D, Easton DG, Bishop T, Narod S, Lancet 343:

24. Contralateral Breast Cancer Risk BRCA1/2 Mutation Carriers
BRCA1 or BRCA2
Women w/ prior hx breast cancer
Risk of new breast ca dx by age 70
60%
52%
3%/year
<1% per year

25. Recognition: the first step in management of familial cancer risk
The hope is that increased surveillance and/or interventions may identify cancers early or reduce the risk of cancers.
Risk assessment may also identify those not at increased risk.

26. Cancer Clusters Cancer can happen in a family just by chance
Cancer can cluster in families because of shared environmental exposures (diet, lifestyle, “environment”, work related exposures)
Cancers may be due to inheritance of a single genetic alteration that poses very high risk of cancer
Cancers may be due to inheritance of less penetrant genetic alterations

27. Sporadic/Familial/Hereditary
Sporadic cancers
Age appropriate
Common cancers
Familial Cancer
Occurring in or affecting more members of a family than would be expected by chance” Generally, two or more family members with the same type of cancer, age appropriate
Hereditary Cancer
-Multiple affected family members
Several cases of the same type of cancer or cancers known to be part of an hereditary cancer syndrome (e.g. breast & ovarian, colon & endometrial, sarcoma & breast).
Younger than expected ages of onset - such as breast < 40, colon < 50
Rare cancers in the family such as males with breast cancer
Individuals with multiple primary cancers or multifocal or bilateral cancers
Family history consistent with generation to generation transmission

28. Tools for risk assessment:
Breast cancer risk assessment models - Claus, Gail, BRCAPRO, Frank/Myriad models
Models for other cancers from the literature
Computer/Internet resources
Gene tests, OMIM, NCI website
Ongoing education

29. Models used to calculate breast cancer risks
Claus Model - Age specific risk estimates for breast cancer, considers maternal and paternal history, age at onset, first and second degree relatives (excludes some relatives).
Gail Model - Estimates the chance that a woman of specific age would develop breast cancer, includes age at menarche, childbirth, # of prior biopsies, and first degree relatives. Excludes paternal relatives, non-first degree relatives. Adapted to consider atypical hyperplasias.
Tyrer-Cusick Model – (2004) Uses personal risk factors for breast cancer, and likelihood of BRCA gene mutation and a low penetrance gene to assess breast cancer risk.
Claus EB, Risch N, Thompson WD, 1990;1991;1994;
Gail MH, Brinton LA, Byar EP, et al, 1989; Tyrer J, Duffy SW, Cuzick J. Stat Med 2004; 23:
FCRS

30. Models used to calculate likelihood of BRCA1 or BRCA2 mutation:
BRCAPRO - computer model, uses pedigree to calculate risk based on several different models.
Frank or Myriad Model/Tables - use family history and personal history to estimate risk of mutation in BRCA1 or BRCA2.
BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) – University of Cambridge computer model to assess risk of BRCA1/2 mutation.
Euhus D, Berry D, Parmigiani G, Iverson E, 1998; Frank TS, Manley SA, Olopade OI, et al, 1997, Antoniou AC, Hardy R, Walker L, Evans DG, Shenton A, Eeles R, Shanley S, Pichert G, Izatt L, Rose S, Douglas F, Eccles D, Morrison PJ, Scott J, Zimmern RL, Easton DF, Pharoah PD.
J Med Genet Jul;45(7): Epub 2008 Apr 15.

31. Characteristics of those families appropriate for consideration for BRCA1 or BRCA2 testing (including patient’s personal history)
several breast cancers or breast and ovarian cancer
two or more ovarian cancers in one family
presence of bilateral cancers of the breast or ovary
cancers diagnosed at younger than expected ages
multiple affected relatives, demonstrating an autosomal dominant pattern of inheritance
presence of individuals diagnosed with more than one cancer, e.g. breast and ovarian
breast and/or ovarian cancer and Ashkenazi (Eastern European) Jewish heritage
male breast cancer

32. Cindy’s Story Alice D. 50 ? stomach X 3 No CA Bessie D.91 Br Dx 91 ?
Renee
65 yo
Ov dx 46
Br dx 52
Kate
61 yo
John
66 yo
Janice
61 yo
Cindy
34 yo
+ BRCA2
mutation
Jason
31 yo
Jane
28 yo
Rick
Colon dx 31
D. 33
Susan
30 yo
James
5 yo
Katherine
3 yo
John Jr.
6 yo
Caroline
2 yo
FCRS

33. Cindy’s Risk Assessment
Gail Model
Race - Caucasian
Age - 34
Age Menarche - 13
Age 1st live birth - 28
# Mother, Sister, Daughter with Breast Cancer - 1
# previous biopsy - 0
5 year risk = 0.5% lifetime risk = 19.2%
Claus Model
Using Table of One First Degree Relative
Predicted cumulative probability of breast cancer by age:
39 = .8%
49 = 2.3%
59 = 4.9%
69 = 8.2%
79 = 11%
Benichou J, Gail M, Mulvihill J JCO 14:103-10
Claus EB, Risch N, Thompson WD, CANCER 73:
FCRS

34. Hereditary Breast/Ovarian Cancer Syndrome
Br ca 44
Ov ca 52
d. 79
d. Br ca 42
d. 94 ht dz
L br ca 42
R br ca 55
Oophorectomy (BSO) 53
+ BRCA2 3
70-80
No cancer 75 3
+BRCA2
Bil mastectomy
Bil Salingo-oophorectomy 36 5 3
30-50
No cancer 5 2
FCRS

35. - Risk Perception - Everyone’s is Unique
Individual’s view of “high risk”, “common”, “rare”, “unlikely” is colored by their experience and psychological make-up.
Half-full vs. half-empty
Experience with statistics (“I will be the <1% who develops ….”)
Personal experience with cancer or cancer scares, caring for others with cancer (especially if repeatedly or recently)
Relationships and age influence reaction - parent’s cancer and child or adolescent vs. adult, siblings with cancer, friends with cancer.
Page DL, Caro SW, Dupont SD, 1998.

36. Testing Process Counsel/Education Gather pedigree and documentation
Test affected individual for mutation
If family + for mutation, then can test unaffected individuals
If + mutation in family, - mutation in individual, individual risk is close to population risk
If no identified mutation in family, risk is estimated based on history and empiric data

37. Outcome of process Clarify risks of cancer
Identify individuals who may not be aware of increased risk
Identify individuals who may not be at increased risk
Identify those appropriate for increased cancer surveillance, or measures to decrease risk (prophylactic surgery, chemoprevention), or those appropriate for research on surveillance or chemoprevention

38. Options for Women at Risk
Increased Surveillance
Risk-reducing Surgery
Medical Intervention
FCRS

39. Increased Surveillance
Breast Cancer
Clinical examination every 6 months
Mammogram yearly beginning age 25-35
MRI (ACS 2007)
Monthly BSE
Prompt evaluation of abnormal findings
Ovarian Cancer
Ca-125
Pelvic color-doppler ultrasound every 6-12 months
Pelvic examination every 6-12 months

40. ACS Recommendations for Breast MRI Screening as an Adjunct to Mammography 2007
Recommend Annual MRI Screening (Based on Evidence*)  
BRCA mutation   
First-degree relative of BRCA carrier, but untested   
Lifetime risk 20–25% or greater, as defined by BRCAPRO or other models that are largely dependent on family history
Recommend Annual MRI Screening (Based on Expert Consensus Opinion )   
Radiation to chest between age 10 and 30 years  
 Li-Fraumeni syndrome and first-degree relatives   
Cowden and Bannayan-Riley-Ruvalcaba syndromes and first-degree relatives
Insufficient Evidence to Recommend for or Against MRI Screening    
Lifetime risk 15–20%, as defined by BRCAPRO or other models that are largely dependent on family history   
Lobular carcinoma in situ (LCIS) or atypical lobular hyperplasia (ALH)   
Atypical ductal hyperplasia (ADH)  
Heterogeneously or extremely dense breast on mammography   
Women with a personal history of breast cancer, including ductal carcinoma in situ (DCIS)
Recommend Against MRI Screening (Based on Expert Consensus Opinion)   
Women at <15% lifetime risk
* Evidence from nonrandomized screening trials and observational studies.
Based on evidence of lifetime risk for breast cancer.
Payment should not be a barrier. Screening decisions should be made on a case-by-case basis, as there may be particular factors to support MRI. More data on these groups is expected to be published soon.
CA Cancer J Clin 2007; 57:75-89

41. Risk-Reducing Surgery
Oophorectomy
Unfortunately not 100% effective in eliminating ovarian cancer risk, as intraabdominal carcinomatosis has occurred (2-4%)
Questions - hysterectomy?
HRT?, do we screen after BSO
Bilateral oophorectomy reduced risk of breast cancer in BRCA1 mutation carriers. (RR=0.53). HRT did not negate reduction in risk.
Mastectomy
Total mastectomy vs.. subcutaneous mastectomy?
Not 100% effective, true risk reduction unclear, >90%.
Hugely personal decisions.
Rebbeck TR, Levin AM, Eisen A, et al. JNCI 91(17):1475, Stuewing JP, Watson P, Easton DF, et al JNCI Monographs :330; Eisen A, Rebbeck TR, Wood WC,Weber BL. JCO 18(9)”1980; May Hartmann LC, Daniel JS, Woods JE, et al. NEJM 340(2):77-84, Jan 14, 1999;

42. Medical Interventions
Ovarian Cancer
Oral contraceptives have been shown to decrease the risk of ovarian cancer in the general population.
In women with mutations in BRCA1 or BRCA2 that risk reduction was also documented, with 60% reduction (RR=0.4) with use of 6 years or more.
Breast Cancer
Risk reducing medications should be discussed based on current understanding.
Narod SA, Risch H, Moslehi R, et al. NEJM 1998, Aug 13;339(7):
Fisher B, Costantino JP, Wickerman DL, et al. JNCI, 1998; 90(18):

43. Misconceptions about genetic testing:
Testing is not covered by insurance. In most instances insurance covers the cost of testing like any other medical expense.
Testing is complicated. True and false – choosing the appropriate test is not always simple, there are significant opportunities for misinterpretation. Seek consultation with a health care provider (nurse practitioner, genetic counselor, MD) specializing in hereditary cancer.
Testing will cause you to lose your insurance. Concerns exist about genetic discrimination, but after nearly 15 years of clinical testing, no significant problems have been seen. Members of group health insurance plans have protection under Federal Law (HIPPA, 1996). GINA signed into law May 2008, extends protections from discrimination based on genetic information to those with private health insurance

44. “Walking with the Ghosts of My Grandmothers” a painting by Hollis Sigler on the cover of the journal Science October, 1994

45. Hereditary Diffuse Gastric Cancer Syndrome
Autosomal dominant inheritance
Germline mutations in CDH1/E-Cadherin Gene (described in hereditary gastric families in 1998)
Initially found in Maori families, since described in families from many ethnic groups.
Penetrance thought to be 70%,
Also increased risk of colon cancer and breast cancer

46. Cowden syndrome
An autosomal dominantly inherited hamartoma syndrome with an incidence of
at least 1/200,000 (probably an underestimate)
(hamartomas are benign, disorganized growths)
characterized by multiple hamartomas that can occur
in any organ of the body
pathognomonic cutaneous feature is the trichilemmoma,
a benign tumor derived from outer-root sheath epithelium of a hair follicle
Carries a high risk of breast, thyroid, and endometrial cancers
Variable expression
Highly penetrant:
Usually presents by the late teens to the late 20’s
90% of individuals with CS have symptoms by age 20
By the 3rd decade, 99% of affected individuals would
have developed mucocutaneous lesions
Age-dependent penetrance: only 10% exhibit symptoms by age 10

47. Cowden syndrome
Associated with inherited alterations in the gene, PTEN
(‘phosphatase and tensin homolog deleted on chromosome ten’),
also sometimes called MMAC1 (‘mutated in multiple advanced cancer’) which was isolated in 1997
PTEN is located on chromosome 10q23
Function of PTEN:
Tumor suppressor
Controls pathway for regulation of cell proliferation and
cell survival
Alterations in PTEN also associated with
Bannayan-Riley-Ruvalcaba (BRR) syndrome and a small percentage
of cases of juvenile polyposis syndrome (JPS).

48. Cancer Risks Associated with Cowden Syndrome:
Female Breast Cancer 25%-50% lifetime risk (vs ~11% in general pop.)
Average age of diagnosis may be around age 38-46
Thyroid Carcinoma 3%-10% lifetime risk (vs 1% in general population)
Non-medullary
Usually follicular, but can be papillary
Endometrial Cancer %
Other cancers may be associated with Cowden syndrome:
Genitourinary Mucocutaneous Male Breast Gastrointestinal
Central Nervous System medulloblastomas are more common
Other, e.g. liposarcoma

49. Li-Fraumeni Syndrome
Initially described by Frederick Li and Joseph Fraumeni (1969) as syndrome associated with sarcomas and other diverse tumors.
Associated cancer include soft-tissue sarcoma, osteosarcoma, early-onset breast cancer, brain tumors, adrenocortical carcinoma, and leukemias, primarily acute leukemia. (Was also called SBLA for Sarcoma, Breast/Brain, Leukemia, and Adrenal)
Inherited in an autosomal dominant manner.
Other reports have associated other cancers - including melanoma, cancers of the stomach, pancreas, colon, and esophagus, and gonadal germ cell tumors.
Gene mutations TP53 (1990) on 17p13, possibly others

50. DNA BANKING
If genetic testing is not possible or not informative, DNA banking is a relatively inexpensive and simple procedure that can save a sample of the affected person’s DNA for future testing.

51. Resources to find cancer genetics professionals in your area:
genetests.org

52. Disparities….

53. Family Cancer Risk Service of the Vanderbilt-Ingram Cancer Center is made possible by support from:
Tennessee Breast Cancer Coalition
Susan G. Komen Foundation, Greater Nashville Affiliate (past)
Our physician consultants:
Mark Kelley, Ingrid Meszoely,
Marta Crispens, John Phay, Paul Wise
And the individuals and families who seek counsel
From Generation to Generation © 1998
Jay M. Rotberg, artist and sculptor

54. Family Cancer Risk Service of the Vanderbilt-Ingram Cancer Center
Susan Caro, RNC, MSN, APNG
Director
Kate McReynolds, MSc, RN
Telephone:
(615)
or TOLL FREE:
From Generation to Generation © 1998
Jay M. Rotberg, artist and sculptor

55. Selected Hereditary Cancer Syndromes
Hereditary Breast/ovarian cancer
BRCA1, BRCA2, CHEK2 Other?
Breast, ovarian prostate, pancreatic r (BRCA2), ? Colon and other cancers
Site specific breast cancer
BRCA1, BRCA2
Breast
Site specific ovarian cancer
Ovarian
Li-Fraumeni Syndrome
TP53, CHEK2
Breast, sarcomas, adrenocortical carcinoma, leukemia, brain tumors
Cowden
PTEN
Breast, thyroid, benign lesions of skin, breast, thyroid; renal cell carcinoma
Peutz-Jegher Syndrome
STK11
Breast cancer, benign ovarian tumors, testicular tumors, pancreatic cancer, polyps (ureter, bladder, GI tract, renal pelvis, characteristic skin lesions (melanin spots, lips, buccal mucosa
Familial adenomatous polyposis
APC, MYH
Polyposis, colorectal cancer, thyroid gastric cancer, periampullary carcinoma, hepatoblastoma
Variant of FAP - Attenuated FAP
APC
<100 colorectal polyps, later age onset CRC, gastric, duodenal adenomas or cancer
Variant of FAP - Gardner’s Syndrome
Osteomas of skull and mandible, CHRPE, dental anomalies, lymphangiomas, lipomas, desmoids
HNPCC (Lynch Syndrome)
MLH1, MSH2, MSH6
, PMS1, PMS2,
Colorectal cancer (often right sided and multifocal), endometrial ca, ovarian ca, small bowel, stomach, pancreas, ureter, renal pelvis
Turcot’s Syndrome
APC, MMR genes
Colorectal adenomas, CRC, primary brain tumors (mudulloblastoma APC, glioblastoma MMR)
OMIM, Elsas LJ, Trepanier A. Cancer Genetics in Primary Care. Postgraduate Medicine 107(4): , April 2000., Offit K. Clinical Cancer Genetics, Wiley-Liss, 1998, New York.

56. Selected Hereditary Cancer Syndromes (cont’d)
MEN
MEN1, RET
Multiple endocrine cancers
Retinoblastoma
RB1
Retinoblastoma, often bilateral and < 1 year of age, also associated increased risk of sarcoma, melanoma, brain tumors
Von Hippel-Lindau
VHL
Renal cell carcinoma, retinal angioma, cerebellar hemangioblastoma, pheochromocytoma, pancreatic cysts, islet cell tumor
Prostate cancer
HPC1, BRCA1, p53
Earlier age onset prostate cancer, maybe part of other syndromes
Pancreatic cancer
BRCA2, MADH4, TP53, CDKN2A, ARMET, +++
Other syndromes, HNPCC, HBOC, Li-Fraumeni, VHL, melanoma, hereditary pancreatitis, site specific pancreatic ca
Melanoma
P16, CDK4, others
Melanoma, dysplastic nevi, pancreatic ca
OMIM, Elsas LJ, Trepanier A. Cancer Genetics in Primary Care. Postgraduate Medicine 107(4): , April 2000., Offit K. Clinical Cancer Genetics, Wiley-Liss, 1998, New York

57. Stigmata of Selected Syndromes Associated with Susceptibility to Cancer
Syndrome Major Cancer Risks Selected physical findings
Cowden Syndrome
Breast cancer
Facial papules, oral “cobblestone” papules, macrocephaly
Down Syndrome
Acute leukemia
Characteristic facies, round head, congenital heart disease
Fancomi Anemia
Upper extremity malformations, increased skin pigmentation
FAP (Gardner’s subtype)
Colon cancer
Retinal pigmentation, sebaceous cysts, osteomas, impacted teeth, exostoses, , desmoids, florid polyposis
Muir-Torre syndrome
Colon cancer, skin tumors
Sebaceous adenomata, keratocanthomata, basal cell carinomas,
Multiple Endocrine Neoplasia type 2b
Medullary thyroid carcinoma, pheochromocytoma,
Enlarged and nodular lips, Marfanoid habitus
Peutz-Jegher syndrome
Breast, colon cancers
Dark spots on lips, perioral areas, buccal mucosa and extremeties
Turcot syndrome
Colon cancer, brain tumors
Polyps, café-au-lait spots, sebaceous cysts on skin
“WAGR” syndrome (Wilm’s tumor, aniridia, genitourinary abnormalities and mental retardation)
Wilm’s tumor
Aniridia, genitourinary malformations
Offit, K. Clinical Cancer Genetics, Risk Counseling & Management, Wiley-Liss, New York, 1998.

58. RED FLAGS – Think about hereditary susceptibility when you see:
Breast Cancer at age less than 50
Ashkenazi Jewish heritage and breast or ovarian
More than one ovarian cancer in a family, or breast and ovarian cancer
Men with breast cancer
More than one pancreatic cancer in a family
Colorectal cancer less than 50 years of age
Polyposis
Pheochromocytoma
Medullary thyroid cancer