Oncologic Genetic Syndromes and Screening

Brad T Tinkle, MD PhD

Director of AMG Genetics

6th Annual Trends in Hematology/Oncology

March 2, 2013

Disclosures

• No financial disclosures

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

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

http://www.sanger.ac.uk/genetics/GCP/Census

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)

SporadicFamily clustersHereditary

5%–10%

15%-20%

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]

SporadicHereditary

5%–10%

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

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

0 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 (%)

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

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 0.6-31% 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;18:485-91.Bartsch DK, et al. Nat Rev Gastroenterol Hepatol 2012;9:445-54.

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)

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%

Cancer Syndromes

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

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

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

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

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

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;124:643-51.

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

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

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 1.2012 Guidelines: Genetic/Familial High-Risk Assessment: Breast and OvarianMasciari S et al. Breast Cancer Res Treat 2012;133:1125-30.

ASCO

Li-Fraumeni Syndrome

Bilateral Breast, 40

Leukemia, 33

Brain tumor, 32

Breast, 40Osteosarcoma, 42

Breast, 35

Soft tissue sarcoma, 7 Leukemia, 6

Noncarrier

Affected with cancer

TP53-carrier

50

PTEN Hamartoma Syndrome

• A.k.a Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome

• Prevalence: 1 in 200-250,000

• Inheritance: Autosomal dominant

• Gene: PTEN

Planchon S M et al. J Cell Sci 2008;121:249-253

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

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

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

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

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

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

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

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

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

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

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

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

0

20

40

60

80

100

FAP: Age and Development of Adenomas and CRC

% of patients with neoplasia

AgeBussey HJR. Familial Polyposis Coli, 1975 Petersen GM et al. Gastro 100:1658, 1991

20 40 60 80

FAP

General population

Adenomas

CRC

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

Peutz-Jeghers Syndrome• Prevalence: 1 in 25-280,000• 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

Letterman’s Top 10 Genetic Cancers1. Adrenocortical carcinoma (LiFraumeni and BWS)

2. Carcinoid tumors (MEN I)

3. Diffuse gastric cancer (Hereditary Diffuse Gastric Cancer)

4. Fallopian tube (HBOCS)

5. Leiomyosarcoma (HLRCC, Lynch, Rb)

6. Medullary thyroid carcinoma (MEN 2)

7. Paraganglioma/pheo (MEN 2, VHL, NF1, PGL)

8. Renal cell carcinoma- chromophobe, hybrid oncocytotic, oncocytoma histology (Britt-Hogg-Dube)

9. Sebaceous carcinoma (Lynch)

10. Sex cord tumor with annular tubule (PJS)

Banks et al. Familial Cancer 2013;12:1-18.

Genetic Services

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

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

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

Clarify Family History

Verbally reported pedigreeRevised pedigree based on

pathology reports

Stomach Ca

Prostate Ca

Bone Cad. 59

Breast Cadx 45d. 59

Ovarian Cadx 43, d. 49

BPHdx 54

If a mutation is found in an affected person, testing will be more informative for other family members

Colon Ca, 42

Colon Ca, 38d.45

Colon Ca, 45 Person seeking

counseling (proband)

Test first, if possible

Testing The More Appropriate Person in the Family

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

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

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

ASCO

• 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

Informed Consent: Limitations of Genetic Testing

ASCO

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

Implications For The Entire Family

ASCO

• Consider the impact of testing on all family members

• Ultimately, testing is the individual’s choice

THANK YOU!

References• Shannon KM, Chittenden A. Genetic testing by cancer: breast. Cancer J

2012;18:310-319.• Jasperson KW. Genetic testing by cancer: colon (polyposis syndromes). Cancer J

2012;18:328-333.• Senter L. Genetic testing by cancer: colon (nonpolyposis syndromes). Cancer J

2012;18:334-337.• Daniels MS. Genetic testing by cancer site: uterus. Cancer J 2012;18:338-342.• Chan-Smutko G. Genetic testing by cancer: urinary tract. Cancer J 2012;18:343-

349.• Axilbund JE, Wiley EA. Genetic testing by cancer: pancreas. Cancer J

2012;18:350-354.• Chun N, Ford JM. Genetic testing by cancer site: stomach. Cancer J

2012;18:355-363.• Pilarski R, Nagy R. Genetic testing by cancer: endocrine system. Cancer J

2012;18:364-371.• Gabree M, Seidel M. Genetic testing by cancer: skin. Cancer J 2012;18:372-380.• 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 1.2012.