Genetic testing and pancreatic disease
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1 Genetic testing and pancreatic disease February 2 d, 2018 Yale Pancreas Symposium 2018: Multidisciplinary Management of Pancreatic Cancer Xavier Llor, M.D., PhD. Associate Professor of Medicine Co-Director, Cancer Genetics and Prevention Program Smilow Cancer Center S L I D E 1
2 No conflicts of interest to disclose S L I D E 2
3 Impact of heredity on Pancreatic Cancer Increased risk of PC in relatives of patients with PC compared to healthy controls: OR average = 3 RR in cohort studies 1.8 (95% CI: ) Petersen GM. Seminars in Oncology 2016: S L I D E 3
4 Risk of Pancreatic Cancer National Familial Pancreas Tumor Registry: 838 kindreds* SEARCH study group of IACR**: 7.8% of patients with PC have family hx/0.6% of controls On average, 13-fold difference between cases and controls *Klein AP, et al. Genetic Epidemiol. 2002;23: **Ghadirian P, et al. Int J Pancreatology 1991;10: S L I D E 4
5 Susceptibility loci associated with Pancreatic Cancer Patterns consistent with autosomal dominant inheritance of rare suscept. gene/s GWAS study 7,683 PC individuals/14,397 controls of European descent: multiple susceptibility loci for PC identified. Wolpin BM, et al. Nat Genet 2014; 46 (9): S L I D E 5
6 Familial Pancreatic Cancer Familial Pancreatic Cancer (FPC): a kindred that contains at least a pair of 1 st degree relatives affected with pancreatic adenocarcinoma 5-10% of patients with Pancreatic Cancer (PC) fit criteria for FPC PC risk higher with increasing number of individuals affected in the family*: SIR=4.6 (95% CI, ) with 1 affected 1 st degree relative SIR=32 (95% CI, ) with 3 affected 1 st degree relatives No single genetic defect associated with FPC outside known hereditary multi cancer syndromes *Klein AP, et al. Cancer Res 2004; 64 (7): S L I D E 6
7 Hereditary diseases and Pancreatic Cancer Association of pancreatic cancer with: Hereditary cancer syndromes: -Hereditary breast cancer: -Peutz-Jeghers: -Familial atypical multiple mole/ melanoma syndrome (FAMMM): -Lynch syndrome: -Ataxia-telangiectasia: BRCA 1/2, PALB2 STK11 CDKN2A MLH1, MSH2, PMS2, MSH6 ATM Hereditary pancreatitis: PRSS1 *Klein AP, et al. Cancer Res 2004; 64 (7): S L I D E 7
8 Genetic mutations in familial pancreatic cancer PACGENE consortium study*: 727 unrelated probands with family history of PC, 521 (72%) meeting criteria for FPC Rate of mutations in: BRCA1,2; PALB2; CDKN2A Probability of testing positive up to 10.4% depending on FHx *Zhen DB, et al. Genet Med 2015; 17 (7): S L I D E 8
9 Genetic mutations in familial pancreatic cancer 302 patients from Mayo (300 included in the PACGENE consortium study)* Genes: 21 additional genes tested. -Genes known to be associated with PC (16): BRCA1, BRCA2, PALB2, CDKN2A, MLH1, MSH2, MSH6, PMS2, EPCAM, STK11, ATM, BMPR1A, SMAD4, CDK4, and TP53 -Genes with not known association with PC (9): BARD1, BRIP1, CDH1, CHEK2, MUTYH/MYH, NBN, PTEN, RAD51C, and RAD51D *Chaffee KG, et al. Genetics in Medicine 2018 Jan;20(1): S L I D E 9
10 Genetic mutations in familial pancreatic cancer Rate of hereditary cancer gene mutations in FPC: 12% Rate of hereditary cancer gene mutations in familial, non FPC patients: 4.3% *Chaffee KG, et al. Genetics in Medicine 2018 Jan;20(1): S L I D E 10
11 Risk of developing Pancreatic Adenocarcinoma Petersen GM. Seminars in Oncology 2016: S L I D E 11
12 Life time risk of pancreatic cancer by inherited syndrome Syndrome Gene Lifetime risk (%) Hereditary pancreatitis PRSS Familial Atypical Multiple Mole p16/cdkn2a Melanoma (FAMMM) Peutz-Jeghers syndrome STK11/LKB HBOCS BRCA1/ Lynch syndrome MLH1,MLH2 4 MSH6, PMS2 Grover S./Syngal S. Gastroenterology 2010: 139: S L I D E 12
13 Familial Pancreatic Cancer In up to 88% of FPC the potential inherited genetic defects are still unaccounted for FPC now defined as families with 2 or more 1 st degree relatives who do not meet criteria for a known PCassociated genetic predisposition syndrome* Actual contribution of inherited genetic defects on pancreatic adenocarcinoma overall unknown *Syngal S, et al. Am J Gastroenterol 2015; 110: S L I D E 13
14 Individuals at risk for FPC (i) Individuals with a known genetic syndrome associated with pancreatic cancer, including hereditary breast ovarian cancer syndrome, familial atypical multiple melanoma and mole syndrome (FAMMM), PJS, Lynch Syndrome, or other gene mutations associated with an increased risk of pancreatic adenocarcinoma (ii) Individuals with two relatives with pancreatic adenocarcinoma, where one is a FDR (iii) Individuals with three or more relatives with pancreatic cancer (iv) Individuals with a history of hereditary pancreatitis *Syngal S, et al. Am J Gastroenterol 2015; 110: S L I D E 14
15 Genetic testing for Pancreatic Cancer 1. Patients with clinical criteria for FPC should have genetic testing that includes at least: BRCA1/2, PALB2, ATM, CDKN2A 2. If personal and/or family history criteria for: PJS, Lynch Syndrome, hereditary pancreatitis, include the corresponding genes: STK11/LKB1 MLH1,MLH2, MSH6, PMS2, EPCAM PRSS1 *Syngal S, et al. Am J Gastroenterol 2015; 110: S L I D E 15
16 Surveillance for Pancreatic Cancer 1. Known mutation carriers from hereditary syndromes associated with increased PC risk: PJS (STK11/LKB1), FAMMM (CDKN2A) 2. Members of FPC kindreds with a PC-affected FDR 3. Mutation carriers of families with hereditary breast CA syndrome (BRCA1/2, PALB2, ATM), and Lynch Syndrome (MLH1,MLH2, MSH6, PMS2, EPCAM), with a first or second degree relative with PC Very low quality of evidence *Syngal S, et al. Am J Gastroenterol 2015; 110: S L I D E 16
17 Thank you S L I D E 17
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