1. Oncologic Genetic Syndromes and Screening
Brad T Tinkle, MD PhD
Director of AMG Genetics
6th Annual Trends in Hematology/Oncology
March 2, 2013

2. Disclosures
No financial disclosures

3. Objectives
Review the role of genetic susceptibility in various cancer types
Discuss the genetic syndromes and testing options of various cancer types
Describe the role that genetics health professionals offer

4. Genetics in Cancer
5-10% of all malignancies are due to highly penetrant hereditary cancer predisposition syndromes [Ballinger, 2012]
Over 400 cancer-related genes have been identified
May account for many familial cancers
Caution! Current clinical testing may include some of these genes of lower-risk

5. Breast Cancer Most prevalent type of cancer in women
2nd leading cause of cancer death in the US
New cases in 2012: 229,060 (estimated)
Deaths in 2012: 39,920 (estimated)
15%-20%
Sporadic
Family clusters
Hereditary
5%–10%

6. Ovarian Cancer 22,000 newly diagnosed in the US annually
1.4% lifetime risk
~45% 5-year survival rate
4.6x RR if mother had ovarian cancer and 1.6x RR is sister [Ziogas et al., 2009]
Sporadic
Hereditary
5%–10%

7. Endometrial Cancer 47,130 newly diagnosed in 2012 (estimated)
Lifetime risk is estimated to be 2.5%
8,010 estimated deaths in 2012
Most common heritable form is Lynch syndrome (a.k.a. hereditary non-polyposis coli) which represents 2-3% of all cases
May also be related to Cowden (PTEN Hamartoma Tumor syndrome) and Peutz-Jeghers

8. Colorectal Cancer 4th most common cancer diagnosis in US
1 in 20 Americans will develop CRC
In 2012, expected number of new cases: 143,460
Expected deaths due to CRC: 51,690
Death rate is declining – early detection and prevention 20 40 60 80
100
General population
Personal h/o CRC
Inflammatory bowel disease
HNPCC mutation
FAP 5%
15%-20%
15%–40%
70%–80%
>95%
Lifetime risk (%)

9. Gastric Cancer Estimated 21,320 new diagnoses in the US (2012)
Estimated 10,540 deaths in the US (2012)
4th leading cause of cancer deaths worldwide
5 year survival of 20%
3-10% are hereditary
Hereditary diffuse gastric cancer
Hereditary breast/ovarian cancer
Lynch syndrome
Li-Fraumeni syndrome
Familial Adenomatous Polyposis
Juvenile polyposis
Peutz-Jeghers

10. Pancreatic Cancer Estimated 43,920 new diagnoses in the US (2012)
4th leading cause of cancer-related deaths in the US
Estimated deaths 37,390 in 2012
5-10% are hereditary
Associated with familial forms of pancreatitis
Breast-ovarian cancer syndrome (BRCA2 and PALB2)
Familial multiple melanoma with % lifetime risk
Higher risk if first-degree relative with pancreatic ca.
Lynch syndrome 0.4-4% lifetime risk
Peutz-Jeghers 8-36% risk
Solomon S et al. Cancer J 2012;18:
Bartsch DK, et al. Nat Rev Gastroenterol Hepatol 2012;9:

11. Melanoma 76,250 new cases in the US in 2012 (estimated)
9,180 estimated attributable deaths in 2012
~10% hereditary
Familial atypical mole-melanoma syndrome
Accounts 5-7% of all melanoma
May be associated with HBOCS (BRCA2)

12. Prostate Cancer
Most frequently diagnosed cancer in US men - 36% of all cancers
Lifetime risk for men in US: 15-20%
241,000 new cases diagnosed in 2012 (estimated)
5-10% is heritable
~40% under 55y
Higher in families with
breast/ovarian cancer
5-10%

13. Cancer Syndromes

14. Genetic Syndromes
There are those with dysmorphic or characteristic features that also have a tumor predisposition
Beckwith-Wiedemann syndrome
Bloom syndrome
Diamond-Blackfan
Down syndrome
Fanconi anemia
Neurofibromatosis type I and II
Gorlin syndrome (basal cell nevus syndrome)
Rothmund-Thomson syndrome
Tuberous sclerosis
Werner syndrome

15. Hereditary Breast Cancer Syndromes
Hereditary breast-ovarian cancer (5% of all breast cancer)
Li-Fraumeni (~1%)
PTEN hamartoma (<1%)
Peutz-Jeghers (<1%)
Hereditary diffuse gastric cancer syndrome
Also:
Autoimmune lymphoproliferative (ALPS)
Ataxia telangiectasia
Bloom syndrome
Familial melanoma
Werner syndrome
Xeroderma pigmentosa

16. Heritable Ovarian Cancer
Lifetime risk varies from 12-60%
Often earlier than those of the general population
6-15% breast/ovarian cancer syndrome
Also includes:
Lynch syndrome
Peutz-Jeghers syndrome

17. Hereditary CRC Syndromes
Accounts for 5-10% of all CRC cases
Polyposis types:
Adenomatous
Familial adenomatous polyposis (<1%)
MYH-associated polyposis (<1%)
Hamartomatous
Juvenile polyposis (<1%)
Peutz-Jeghers
Cowden (PTEN)
Lynch syndrome (2-3%)
Often not polyps but can have and still increased cancer risk
Seldom in:
Bloom, hereditary diffuse gastric cancer syndrome, and Li-Fraumeni

18. Breast/Ovarian Cancer Syndrome
Primarily BRCA1 and BRCA2
Frequency of carriers 1 in 300 (BRCA1) to 1 in 800 (BRCA2)
Ashkenazi Jewish (1 in 40)
Accounts for >90% of families with breast and ovarian cancers

19. Breast-Ovarian Cancer Syndrome
Of those with BRCA1 mutations:
50-80% risk of invasive breast carcinoma-females
~1% risk for males
Up to 60% risk of serous ovarian carcinoma
Up to 30% risk of prostate cancer
1-3% risk of pancreatic
Of those with BRCA2 mutations:
40-85% risk of invasive breast carcinoma-females
6-7% risk for males
Up to 35% risk of serous ovarian carcinoma
Up to 39% risk of prostate cancer
2-7% risk of pancreatic
Van der Kolk et al. Breast Cancer Res Treat 2010;124:

20. HBOCS- Tumor Characteristics
Breast tumor often originates from breast epithelia cells
Basal keratin positive
More commonly a/w with invasive lobular and ductal carcinoma as well as DCIS
More likely to be high-grade malignancies and lymph node positive
Estrogen receptor negative
Progesterone receptor negative
Her2/neu negative
>90% ovarian serous adenocarcinoma

21. Li-Fraumeni Syndrome Prevalence: Up to 1 in 20,000
Inheritance: Autosomal dominant
Gene: TP53
Lifetime risk of cancer:
50% by age 30-35y
90% by 60y
Female lifetime risk is 90%
Male lifetime risk is 70%
57% risk of a second primary

22. LFS- Diagnostic Criteria
Proband with sarcoma <45yoa
First-degree relative with any cancer <45yoa
First- or second-degree relative with any cancer <45yoa or sarcoma at any age
LFS-related cancers include:
Breast cancer
Most common LFS-related cancer
Lifetime risk 49%
<1% overall of total breast cancers; however, more likely with diagnosis <30yoa (up to 7%)
More likely to be triple positive
Soft tissue and bone sarcomas
Brain tumors
Choroid plexus tumors
Adrenocortical carcinoma
LFS accounts for 80% of childhood ACC
Leukemia
Bronchoalveolar cancer
NCCN Guidelines: Genetic/Familial High-Risk Assessment: Breast and Ovarian
Masciari S et al. Breast Cancer Res Treat 2012;133:

23. Li-Fraumeni Syndrome Noncarrier Affected with cancer TP53-carrier
Bilateral Breast, 40 50
Breast, 40
Osteosarcoma, 42
Leukemia, 33
Breast, 35
Brain tumor, 32
Soft tissue sarcoma, 7
Leukemia, 6
ASCO

24. PTEN Hamartoma Syndrome
A.k.a Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome
Prevalence: 1 in ,000
Inheritance: Autosomal dominant
Gene: PTEN
Planchon S M et al. J Cell Sci 2008;121:

25. PTEN Hamartomatous Syndrome
25-85% lifetime risk of breast cancer
<1% overall of all breast cancer
Average age of diagnosis 38-46y
5-28% lifetime risk of endometrial cancer
3-35% lifetime risk of non-medullary thyroid (follicular) cancer
40-93% lifetime risk of polyps (hamartomatous)
9% lifetime risk of CRC
Ganglioneuroma
13% of PTEN mutation-associated Cowden syndrome patients developed CRC <50yoa
Strongly a/w Lhermitte-Duclos (dysplastic gangliocytoma)
May also be associated with renal cancer and melanoma

26. PTEN Physical Features
Macrocephaly
Facial papules (trichilemmomas)
≥2 pathognomic?
Oral mucosal papillomatosis
99% incidence
Acral keratoses
Macrocephalic
No unusual skin lesions or pigmentation
BrCa at 42yoa

27. Breast Cancer- When to Refer
Breast cancer <50yoa
Triple negative breast cancer
11-28% have BRCA1 mutations
Two breast cancer primaries in a single individual
~30% risk of second primary in 10 years for BRCA1/2
Breast or ovarian cancer at any age in those of Ashkenazi Jewish ancestry
Breast cancer at any age and…
≥1 close relative* with breast cancer <50yoa
≥1 close relative* with epithelial ovarian cancer at any age
≥2 close relatives* with breast cancer and/or pancreatic cancer at any age
NCCN Guidelines: Genetic/Familial High-Risk Assessment: Breast and Ovarian
*Includes third degree relatives

28. When to Refer (2)
A combination of breast cancer with one or more of the following in close relatives:
Thyroid cancer
Sarcoma
Endometrial cancer
Pancreatic cancer
Brain tumors
Diffuse gastric cancer
Dermatologic manifestations and/or macrocephaly
Leukemia/lymphoma
Ovarian cancer with a family history of breast and/or ovarian cancer
Male breast cancer
4-14% due to BRCA2
NCCN Guidelines: Genetic/Familial High-Risk Assessment: Breast and Ovarian

29. Lynch Syndrome
A.k.a. hereditary nonpolyposis colorectal cancer; includes Muir-Torre (sebaceous adenomas)
Incidence: 1 in 440
Accounts for:
2-10% of all CRC
2% of ovarian cancers
2-5% of endometrial
9-20% of those <50y
Autosomal dominant
Multiple genes (MLH1, MSH2, MSH6,
MSH3, PMS1, PMS2, TACS (EPCAM), TD1)
Chr 2
MSH2
PMS1
MSH6

30. Lynch Syndrome- Cancer Risks
22-92% lifetime risk of CRC
Mean age of 44yo (MLH1 or MSH2)
6-19% lifetime risk of gastric cancer
More common in Japan
20-70% risk of endometrial cancer
MSI-IHC testing recommended
4-12% risk of ovarian cancer
18% hepatobiliary
5-10% urinary tract cancers
May also develop:
Small bowel, pancreatic cancer
Skin: (sebaceous carcinomas, keratocanthomas, and epitheliomas)
Brain tumors, especially glioblastoma

31. Lynch Syndrome- Amsterdam II
Amsterdam II criteria (all have to be met):
≥3 family members, one of whom is a first-degree relative of the other two, with HNPCC-related cancers (CRC, endometrial, stomach, small bowel, hepatobiliary, renal pelvic, or ureteral cancer)
Two successive generations
One or more HNPCC-related cancer diagnosed before 50yoa
Used to make a clinical diagnosis of Lynch syndrome and does not take into account all possible Lynch syndrome-related tumors

32. Lynch Syndrome- Bethesda
Modified Bethesda criteria (any of the following):
CRC diagnosed <50yoa
Presence of synchronous or metachronus CRC, or other HNPCC-related tumors (CRC, endometrial, gastric, ovarian, pancreatic, ureteral, biliary tract and brain tumor) regardless of age
CRC with microsatellite instability-high <60yoa
CRC in ≥1 first-degree relatives with HNPCC-related tumor with one cancer <50yoa
CRC in ≥2 first- or second-degree relatives at any age
Used to guide additional testing such as MSI/IHC

33. Lynch Syndrome- MSI Microsatellite instability
Microsatellites are highly-repetitive DNA sequence
Susceptible to dynamic changes if not for the mismatch repair genes
MSI-high= instability >30% of cells
MSI-low= instability <30% of cells
MSI stable= no evidence of MSI

34. Lynch- MSI Caveats 90% of inherited tumors are MSI-high
MSI-high can be caused by many somatic (not inherited) events, most notably BRAF methylation/mutation
Some Lynch syndrome patients will have MSI-low or MSI-stable testing
Immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6, PMS1, PMS2) recommended as adjunctive analysis

35. Lynch- Genetic Testing
If met Amsterdam II criteria, recommend genetic testing
If met Bethesda, testing of the tumor sample by MSI/IHC recommended initially with consideration of genetic testing
If MSI-high and IHC positive (i.e. absence of one of the proteins) the probability of Lynch is high therefore genetic testing recommended

36. Familial Adenomatous Polyposis
A.k.a Turcot or Gardner syndromes
1 in 6-20,000 live births
Due to genetic defect in APC
If negative, consider MYH testing
Accounts for <1% of all CRC
Hallmark is the adenomatous polyposis
20-100% penetrance in the duodenum
100% lifetime risk of CRC with average age of cancer diagnosis of 39y

37. FAP: Age and Development of Adenomas and CRC
% of patients with neoplasia
CRC
General population 20 40 60 80
Bussey HJR. Familial Polyposis Coli, 1975
Petersen GM et al. Gastro 100:1658, 1991
Age 11

38. FAP- Associated Risks 4-12% lifetime risk of other intestinal cancers
0.5-2% gastric
5% duodenal
1-2% risk of pancreatic and non-medullary thyroid
0.6% risk of hepatoblastoma before 6yoa with 1-2% lifetime
10-30% lifetime risk of desmoid tumors
Also a/w medulloblastoma as well as gliomas and ependymoma
CHRPE- congenital hypertrophy of the retinal pigmented epithelium

39. Peutz-Jeghers Syndrome
Prevalence: 1 in ,000
Inheritance: Autosomal dominant
Gene: STK11
Hamartomatous and adenomatous polyposis especially of the small intestine
37-93% lifetime risk of cancer
38-66% risk of gastrointestinal
2-39% CRC
29% gastric
11-36% pancreatic
30-54% risk of breast cancer
Lifetime uterine cancer risk is 9-21%
Lung 15% lifetime risk
Includes ovarian and sex cord tumors
Labial and oral mucosal hyperpigmentation- may fade with time

40. Letterman’s Top 10 Genetic Cancers
Adrenocortical carcinoma (LiFraumeni and BWS)
Carcinoid tumors (MEN I)
Diffuse gastric cancer (Hereditary Diffuse Gastric Cancer)
Fallopian tube (HBOCS)
Leiomyosarcoma (HLRCC, Lynch, Rb)
Medullary thyroid carcinoma (MEN 2)
Paraganglioma/pheo (MEN 2, VHL, NF1, PGL)
Renal cell carcinoma- chromophobe, hybrid oncocytotic, oncocytoma histology (Britt-Hogg-Dube)
Sebaceous carcinoma (Lynch)
Sex cord tumor with annular tubule (PJS)
Banks et al. Familial Cancer 2013;12:1-18.

41. Genetic Services

42. When to Suspect Hereditary Cancer Syndrome
Cancer in 2 or more close relatives
Early age at diagnosis
Multiple primary tumors
Bilateral or multiple cancers
Constellation of tumors consistent with specific cancer syndrome (e.g. breast and ovary)
Evidence of autosomal dominant transmission

43. Genetic Counseling- A Multistep Process
Detailed and extensive family history
Ethnic-risk evaluation
Cancer cluster recognition
Breast-ovarian-pancreatic
Macrocephaly-skin lesions-breast cancer
Gather necessary medical records
Determine who best to test
Insurance and insurability questions
Test selection
Pre- and post-test counseling
Psychosocial support
Test result interpretation
Help with informing family members of risk

44. Taking a Cancer Family History
Obtain at least a three-generation pedigree
Ask about all individuals in the family and record:
Age at cancer diagnosis, age at and cause of death
Primary vs metastatic cancer
Precursor lesions, bilateral cancer
Physical features
Birth defects
Other diagnoses
Record ethnicity and race

45. Clarify Family History
Verbally reported pedigree
Revised pedigree based on pathology reports
Stomach Ca
Prostate Ca
Bone Ca
d. 59
Breast Ca
dx 45
Ovarian Ca
dx 43, d. 49
BPH
dx 54

46. Testing The More Appropriate Person in the Family
Colon Ca, 42
Test first, if possible
Colon Ca, 38
d.45
Colon Ca, 45
Person seeking counseling (proband)
If a mutation is found in an affected person, testing will be more informative for other family members

47. ASCO- Genetic testing
A personal or family history suggesting genetic cancer susceptibility
Test can be adequately interpreted and put into clinical context
Results will aid in the diagnosis OR influence the management of the patient/family

48. Informed Consent: Benefits of Genetic Testing
Improved cancer risk management
Relief from uncertainty and anxiety about cancer risk
Information for individual and family members
Lifestyle decision making

49. Informed Consent: Potential Risks of Genetic Testing
Psychological distress
Anxiety/fear
Guilt
Depression
Grief
Loss of privacy
Discrimination by employers and insurers
Change in family dynamics
False sense of security

50. Informed Consent: Limitations of Genetic Testing
Not all mutations are detectable
Uncertain significance of some mutations
Negative result is fully informative only if mutation has been identified in family
Results indicate probability, not certainty, of developing cancer
Unproven efficacy of most interventions
ASCO

51. Possible Testing Results: Beyond Positive or Negative
Variants of Uncertain Significance (VUS)
Amino acid substitutions
Frequency 11% at Myriad, > in African American
Determine significance several ways:
Observed with deleterious mutation
Population studies (frequency >1%)
Biochemical, evolutionary models
Linkage in large families
ASCO

52. Implications For The Entire Family
Consider the impact of testing on all family members
Ultimately, testing is the individual’s choice
ASCO

53. THANK YOU!

54. References
Shannon KM, Chittenden A. Genetic testing by cancer: breast. Cancer J 2012;18:
Jasperson KW. Genetic testing by cancer: colon (polyposis syndromes). Cancer J 2012;18:
Senter L. Genetic testing by cancer: colon (nonpolyposis syndromes). Cancer J 2012;18:
Daniels MS. Genetic testing by cancer site: uterus. Cancer J 2012;18:
Chan-Smutko G. Genetic testing by cancer: urinary tract. Cancer J 2012;18:
Axilbund JE, Wiley EA. Genetic testing by cancer: pancreas. Cancer J 2012;18:
Chun N, Ford JM. Genetic testing by cancer site: stomach. Cancer J 2012;18:
Pilarski R, Nagy R. Genetic testing by cancer: endocrine system. Cancer J 2012;18:
Gabree M, Seidel M. Genetic testing by cancer: skin. Cancer J 2012;18:
Schneider KA. Counseling about cancer: strategies for genetic counseling, 3rd ed. Wiley-Blackwell, 2012.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) “Genetic/Familial High-Risk Assessment: Breast and Ovarian”, version