GENETIC PREDISPOSITION TO CANCER

Review the role of genetic susceptibility in various cancer types

Discuss the genetic syndromes and testing options of various cancer types

OBJECTIVES

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

GENETICS IN 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)

BREAST CANCER

SporadicSporadicFamily clustersFamily clustersHereditaryHereditary

5%–10%

15%20%

• 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]

OVARIAN CANCER

SporadicHereditary

5%–10%

• 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

ENDOMETRIAL 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

COLORECTAL CANCER

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 (%)

• 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

GASTRIC 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

PANCREATIC CANCER

• 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)

MELANOMA

• 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

PROSTATE CANCER

5-10%

CANCER 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

GENETIC 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

HEREDITARY BREAST CANCER SYNDROMES

• 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

HERITABLE OVARIAN CANCER

• 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

BREAST-OVARIAN CANCER SYNDROME

• 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

HBOCS- TUMOR CHARACTERISTICS

• 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

HEREDITARY CRC SYNDROMES

• 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

LI-FRAUMENI SYNDROME

• 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

LFS- DIAGNOSTIC CRITERIA

• Prevalence: 1 in 200-250,000

• Inheritance: Autosomal dominant

• Gene: PTEN

PTEN HAMARTOMA SYNDROME

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

• 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 HAMARTOMATOUS SYNDROME

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 <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

BREAST CANCER- WHEN TO REFER

• 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

WHEN TO REFER (2)

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

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

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

• 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

FAMILIAL ADENOMATOUS POLYPOSIS

0

20

40

60

80

100

FAP: AGE AND DEVELOPMENT OF ADENOMAS AND CRC

% of patients with neoplasia

Age20 40 60 80

FAP

General population

Adenomas

CRC

• 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

FAP- ASSOCIATED RISKS

• 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

PEUTZ-JEGHERS SYNDROME

Labial and oral mucosal hyperpigmentation- may fade with time

1. 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)

LETTERMAN’S TOP 10 GENETIC CANCERS