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Evaluation of Hereditary Syndromes That Include Pancreatic Cancer

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Evaluation of Hereditary Syndromes That Include Pancreatic Cancer Evaluation of hereditary syndromes that include pancreatic cancer UPR CCC 04/12/13 Jeffrey N. Weitzel, M.D. Chief, Division of Clinical Cancer Genetics Cancer Screening & Prevention Program City of Hope Comprehensive Cancer Center and Beckman Research Institute PANCREATIC CANCER Worldwide estimates: • Incidence- 232,306 • Deaths- 227,000 A deadly disease CA Cancer J Clin 2012 PANCREATIC CANCER Non-Genetic Risk Factors Cigarette Smoking • Doubles Risk • Causes 26% of pancreatic cancer Obesity • Increases risk by ~70% Diabetes • Longterm (>10yrs) 2-Fold increase (Everhart 1995) • 1% of new-onset diabetics develop pancreatic cancer within 3 years (Chari 2005) DDx: Start with Pathology Adenocarcinoma = >75% 5-year survival <5% Endocrine (AKA: islet cell) = ~ 1% Hormone-producing; control blood sugar levels Insulinoma, gastrinoma, VIPoma, glucagonoma, somatostatinoma, non-functional “oma’s” Slower-growing better prognosis 5-year survival 50-70% if surgically resectable DDx: Endocrine pancreatic tumor(s) MEN1 VHL NF1 TSC sporadic MEN 1 and MEN 2 MEN 1 MEN 2 Anterior Pituitary Thyroid C-cells (MTC) Parathyroid Parathyroid Adrenal Adrenal medulla cortex (pheochromocytoma) Pancreatic islet cells Germline mutations Germline mutations in MEN1, chr 11 in RET, chr 10 Genetics of MEN 1: The Menin Gene Mutations in the MENIN (MEN1) gene on chromosome 11q13 Cloned in 1997 Tumor suppressor gene Involved in transcriptional regulation/cell growth and regulation > 400 distinct mutations identified throughout the gene; most are protein truncating MEN 1 mutation - Epidemiology Two of the three main tumor types must be present (parathyroid, pancreatic, pituitary) Germline MEN1 mutations detected in 80-90% in families/cases with 2 or more major features >30% families with 1 major and 1 or more MEN1- associated tumors 10% de novo Penetrance: >50% by age 20 and 100% by age 60 MEN 1 – Hyperparathyroidism (HPT) Generally the first manifestation Average age of diagnosis 14yrs, 80%-100% by age 40 Tumors usually multiglandular, hyperplastic Symptoms of HPT Fatigue, weakness Hypertension, nervousness Constipation, anorexia, nausia Polyuria, polydypsia, nocturia Kidney stones, bone disease MEN 1- Gastro-Entero-Pancreatic Tumors Gastrinoma (50%) Major cause of morbidity and mortality Manifests as Zollinger-Ellison syndrome (peptic ulcer disease) Insulinoma (10%) Hypoglycemia VIPoma (2%) Watery diarrhea, hypokalemia, achlorhydria Glucagonoma (2%) Hyperglycemia, weight loss, anemia, skin rash Somatostatinoma, Pancreatic polypeptidoma, Enterochromaffin-like cell (ECL) Carcinoids MEN 1 – Screening Regimen Age (y) to Biochemical tests Imaging tests, q 3 Tumor start annually years Parathyroid adenoma 8 Calcium (esp Ca2+), None parathyroid hormone Gastrinoma 20 Gastrin None Insulinoma 5 Glucose, insulin None Other enteropancreatic 20 Chromogranin-A Somatostatin tumors receptor scintigraphy, CT or MRI Anterior pituitary tumors 5 Prolactin MRI Thymus or bronchial 20 None CT carcinoid von Hippel-Lindau Risk for benign cystic pancreatic lesions Also a risk for islet cell tumors (5-7%) Generally found in individuals with otherwise normal pancreas Malignant potential (<10%) Better prognosis than sporadic malignancies Main tumors: RCC, pheo, hemangioblastoma Annual abdominal ultrasound beginning at age 16, possible baseline MRI/CT, biochemical screening Familial Pancreatic Adenocarcinoma Associated with several hereditary syndromes/genes: Hereditary pancreatitis (PRSS1- cationic trypsinogen gene) Hereditary breast-ovarian cancer syndrome (BRCA2) FAMMM sydrome (p16/CDKN2A) Peutz-Jeghers syndrome (STK11/serine-threonine kinase) Lynch Syndrome (HNPCC) (MLH1, MSH2, MSH6 and PMS2) FAP (APC) PALB2 ATM Pancreatitis Cystic Fibrosis Risk to homozygotes maybe as high as 30% due to pancreatitis Risk to heterozygotes Sharer et al. 1998 studied 134 patients with chronic pancreatitis • 13.4% were CFTR mutation carriers (including T5 alleles) Pezzilli et al. 2003 studied 46 patients with chronic pancreatitis • 19.6% were CFTR mutation carriers (including T5 alleles) Hereditary Pancreatitis PRSS1 gene Penetrance of 80% 40% risk for pancreatic cancer by age 70 Risk increased by paternal-line transmission, possibly as high as 70% Smoking increases risk Begin screening 10 years after pancreatitis diagnosis Hereditary Pancreatitis – not subtle EUROPAC study: 112 families, 14 countries PRSS1 mutations in >80% of affected families Median onset of symptoms at 12 years over 70% symptomatic by age 20 years Median of 1.88 attacks per year 70/75 patients (93%) required hospital treatment pancreatitis BRCA1- and BRCA2-Associated Cancers: Lifetime Risk Breast cancer 50%-85% (often early age at onset) Second primary breast cancer 40%-60% Ovarian cancer 15%-45% Absolute risk likely to be higher than 10% - Prostate cancer Absolute risk 10% or lower - Male breast cancer - Fallopian tube cancer - Pancreatic cancer ASCO Population Relative Cancer Risks and 95% CI by Mutation status and Cancer Site Risch et al. J Natl Cancer Inst 2006;98:1694-1706 First degree relatives of patients with BRCA1 (n=534); BRCA2 (n=446) Age specific cancer risks in Dutch BRCA2 mutation carriers* For all presented cancer sites, p for difference is <0.001. *Among 1,811 at 50% carrier probability Most striking risks are for earlier onset for pancreas, pharynx and prostate van Asperen CJ et al: Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 42:711-9, 2005 Estimated cumulative risks for pancreas and prostate cancer in BRCA2 mutation carriers by sex and age van Asperen CJ et al: Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 42:711-9, 2005 BRCA2 Mutations, Relative Risks (RR), and Lifetime Risk of Pancreatic Cancer in Jewish Patients and Controls PAC (n = 145) Controls (n = 5,318) Mutation No. (%) No. (%) RR (95% CI) LRP RR LRC BRCA2 6 (4.1) 59 1.1 3.85 (2.1 to 10.8) 1.3% 3.85 4.9% 6174delT Abbreviations: LRP, lifetime risk of pancreatic adenocarcinoma in the general population LRC, lifetime risk of pancreatic adenocarcinoma in the BRCA2 heterozygotes Ferrone et al: BRCA Germline Mutations in Jewish Patients with Pancreatic Adenocarcinoma. JCO 27:433-438, 2009 BRCA and Prostate Cancer • BRCA1 and BRCA2 mutations increase prostate cancer risk - BRCA1: relative risk 1-2 - BRCA2: relative risk 4-7 • BRCA2 may result in early onset prostate cancer • BRCA1 and BRCA2 are unlikely to account for a high percentage of familial prostate cancer • BRCA2 may account for 2% of early onset PC and 5% of familial prostate cancer • HOXB13 and CHEK2 mutations may also play a role in prostate cancer susceptibility Familial Atypical Multiple Mole Melanoma (FAMMM) p16: cyclin dependent kinase (CDKN2A) at 9p21 Somatic mutations in 75-85% of pancreatic cancer Pancreatic cancer only present in some CDKN2A families Risk by age 75 is ~17% (10-40 fold increase) Phenotypically expressed FAMMM in 12% of families with familial pancreatic cancer Individuals with CDKN2A mutations should be considered for pancreatic cancer screening Melanoma and Pancreatic cancer 2 fold increase in risk in individuals diagnosed with melanoma <50 y Reports of pancreatic cancer in families lacking CDKN2A mutations, but uncommon Peutz-Jeghers Syndrome Serine threonine kinase 11 (STK11) gene at 19p13 Literature review found the risk for pancreatic cancer to be 132 times the general population (Giardiello et al. 2000) Risk by age 65 of 11-36% EUS every 1-2 years beginning at age 30 HNPCC MLH1 and MSH2 mutations reported in kindreds with pancreatic cancer Reported more frequently in Korean, Taiwanese, and Finnish families, less frequently in Dutch families Tumors are often MSI high Often of Medullary histology Not all kindreds meeting Amsterdam criteria for HNPCC have been found to have germ line mutation despite MSI high and absence of MLH1 expression Risk of pancreatic cancer up to 4%, but not well defined Familial Adenomatous Polyposis APC gene at 5q21-22 RR 4.5 (1.2-11.4 CI) ~2% lifetime risk of pancreatic cancer Consider EUS after age 20 Giardiello (1993) Gut 34:1394 Pancreatoblastomas Reported in individuals with APC mutations and Beckwith-Wiedemann Syndrome <1% of all pancreatic tumors Often occur in children Potentially similar mechanism to hepatoblastoma PALB2 (partner and localizer of BRCA2) Cancer Risks (Casadei et al. 2011): Breast: 2.3-fold by 55 yo; 3.4-fold by 85 yo Male Breast CA: 4-fold Pancreas CA: 6-fold Prevalence in BrCa: 0-2% of unselected BrCa’s (ethnicity-based 3.4% (33/972) non-AJ FBC; 0/172 AJ FBC Prevalence in FPC: 3-4% (Jones 2009; Slater 2010) Hereditary Pancreatic cancer risk Cancer Discovery 2: 41–6, 2011 WGS on 16 subjects in 6 families, followed by WES on 22 subjects from 10 families; 2.4% (4/166) of familial pancreatic cancer probands carried deleterious ATM mutations Progression Model Pancreatic Intraepithelial Neoplasia Klapman J, Malafa MP: Early detection of pancreatic cancer: why, who, and how to screen. Cancer Control 15:280-7, 2008 Screening for pancreatic cancer Three common precursor neoplastic lesions: Intraductal papillary mucinous neoplasms (IPMN) Mucinous cystic neoplasm (MCN) Pancreatic intraepithelial neoplasm (PanIN) IPMN- papillary or rarely flat epith neoplasm arise from main duct or main branch ducts >1cm can be visualized by multidetector CT, MRI, US, or EUS Branch ducts are most common in high risk individuals Screening for pancreatic cancer PanIN- papillary or flat noninvasive epith neoplasms arise in smaller pancreatic ducts usually <5mm
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