Genetic predipositio to cancer

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Genetic predipositio to cancer

  1. 1. GENETIC PREDISPOSITION TO CANCER
  2. 2. OBJECTIVES  Review the role of genetic susceptibility in various cancer types  Discuss the genetic syndromes and testing options of various cancer types
  3. 3. 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
  4. 4. 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% 5%–10% Sporadic Family clusters Hereditary
  5. 5. 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] 5%–10% Sporadic Hereditary
  6. 6. 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
  7. 7. 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 5% General population 15%-20% Personal h/o CRC 15%–40% Inflammatory bowel disease HNPCC mutation 70%–80% FAP >95% 0 20 40 60 80 100 Lifetime risk (%)
  8. 8. 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
  9. 9. 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
  10. 10. 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)
  11. 11. 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%
  12. 12. CANCER SYNDROMES
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. 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
  20. 20. 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
  21. 21. 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 – Leukemia – Bronchoalveolar cancer LFS accounts for 80% of childhood ACC
  22. 22. PTEN HAMARTOMA SYNDROME • Prevalence: 1 in 200-250,000 • Inheritance: Autosomal dominant • Gene: PTEN Planchon S M et al. J Cell Sci 2008;121:249-253
  23. 23. 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
  24. 24. PTEN PHYSICAL FEATURES • • Macrocephaly •Macrocephalic Facial papules (trichilemmomas) •No unusual skin lesions or pigmentation – ≥2 pathognomic? • Oral mucosal papillomatosis – 99% incidence • Acral keratoses •BrCa at 42yoa
  25. 25. 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
  26. 26. ( 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
  27. 27. LYNCH SYNDROME • A.k.a. hereditary nonpolyposis colorectal cancer; includes Muir-Torre (sebaceous adenomas) • Incidence: 1 in 440 • Accounts for: MSH6 – 2-10% of all CRC MSH2 – 2% of ovarian cancers – 2-5% of endometrial • 9-20% of those <50y • Autosomal dominant • Multiple genes (MLH1, MSH2, MSH6, PMS1 MSH3, PMS1, PMS2, TACS (EPCAM), TD1) Chr 2
  28. 28. 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
  29. 29. LYNCH SYNDROME- AMSTERDAM II • Amsterdam II criteria (all have to be met): – ≥3 family members, one of whom is a firstdegree 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 diagnosed before 50yoa cancer
  30. 30. LYNCH SYNDROME- BETHESDA • Modified Bethesda following): criteria (any of the – 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
  31. 31. 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
  32. 32. 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
  33. 33. 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
  34. 34. 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
  35. 35. FAP: AGE AND DEVELOPMENT OF ADENOMAS AND CRC 100 % of patients with neoplasia FAP Adenomas 80 CRC 60 40 General population 20 0 20 40 Age 60 80
  36. 36. 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
  37. 37. 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 • • 29% gastric • – – – – 2-39% CRC 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
  38. 38. LETTERMAN’S TOP 10 GENETIC CANCERS 1. 2. 3. 4. 5. 6. 7. 8. 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) 9. Sebaceous carcinoma (Lynch) 10. Sex cord tumor with annular tubule (PJS)

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