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Genetics of Pancreatic Cancer

Genetics of Pancreatic Cancer. Gloria M. Petersen, Ph.D. Mayo Clinic Rochester, Minnesota. Pancreatic Cancer Action Network – Chicago Symposium. Genetics of Pancreatic Cancer. Why we study families with pancreatic cancer What are genes and DNA?

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Genetics of Pancreatic Cancer

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  1. Genetics of Pancreatic Cancer Gloria M. Petersen, Ph.D. Mayo Clinic Rochester, Minnesota Pancreatic Cancer Action Network – Chicago Symposium

  2. Genetics of Pancreatic Cancer • Why we study families with pancreatic cancer • What are genes and DNA? • New discoveries in genetics of pancreatic cancer

  3. Pancreatic Cancer: Risk Factors • Age • Race • Smoking • Obesity • Diabetes • Chronic Pancreatitis • Family history • Genes /Shared environment

  4. 10% of pancreatic cancer patients have a first degree relative with pancreatic cancer Studies show that the risk for a parent, sibling or child of a pancreatic cancer patient to also develop this cancer is 2 to 5 times higher than the risk in the general population. Positive Family History

  5. German/Polish English/Irish 2 2 2 2 Pancreas Ca, dx 65 d. 70 d. 85 d. 80 2 2 2 2 1 1 Pancreas Ca, dx 62 67 55 65 Diabetes, dx 45 59 52 3 1 Pancreas Ca, dx 54 35 30 Three-Generation Family Tree • First degree relatives • Second degree • Third degree

  6. Familial Pancreatic Cancer Mayo 627 Dx 79 NS Dx 58 NS Dx 58 S Dx 79 NS Dx unk NS Dx 87 Working definition: Families in which at least two first degree relatives have been diagnosed with pancreatic cancer. Hruban and Petersen, 1997 Dx 57 S NS = Nonsmoker S = Smoker

  7. Family History is one way to: • Identify who is at risk • Refer for genetic risk counseling • Recommend who needs checkups more often

  8. Genetics of Pancreatic Cancer • Why we study families with pancreatic cancer • What are genes and DNA? • New discoveries in genetics of pancreatic cancer

  9. Every human being is genetically unique.

  10. 46 Human Chromosomes p Centromere q (Chromosome 5)

  11. Gene Nucleus Cell Chromosomes Adenine (A) Thymine (T) Cytosine (C) Guanine (G) Protein Chromosomes, DNA, and Genes

  12. ? CANCER NORMAL How do geneticists study cancer?

  13. DNA Sequencing

  14. Genetics of Pancreatic Cancer • Why we study families with pancreatic cancer • What are genes and DNA? • New discoveries in genetics of pancreatic cancer

  15. Hereditary Disorders and Genes Associated with Pancreas Cancer Gene PRSS1 (Cationic trypsinogen) P16 (CDKN2A) BRCA2 APC, MSH2, MLH1 STK11/LKB1 FANCC, FANCG Disorder Hereditary Pancreatitis Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM) BRCA2 Hereditary Colorectal Cancers Peutz-Jeghers Syndrome Fanconi Anemia genes

  16. Family history of some cancers is associated with younger age of onset of pc Ovarian Cancer Breast Cancer McWilliams RR et al. Clin Gastro Hepatol 4:1143, 2006 Melanoma

  17. McWilliams R et al. Gut 54:1661, 2005 Cystic Fibrosis Gene (CFTR) and Younger Onset Pancreatic Cancer • Cystic fibrosis (CF) is a hereditary disorder • CF is caused by dysfunction of cellular membrane and regulation of ions • Altered CFTR protein impairs glandular secretion • Result is chronic lung disease, pancreatic insufficiency

  18. CFTR Mutation Carrier Rates 8.4 9.00 8.00 7.00 6.00 4.1 5.00 Percent CFTR Percent Percent Mutation Carriers 4.00 3.00 2.00 1.00 0.00 Young Onset PC Under age 60 N=166 Control Group N=5,349 McWilliams R et al. Gut 54:1661, 2005; Cancer 116: 203-9, 2010 CFTR Mutations Associated with Younger Onset PC OR 2.2 (95% CI 1.2-3.3) P=0.006 • 2010 update: Results remain significant (OR=1.82) with larger number (~950) tested; OR=1.4 all ages • Sequencing suggests 16% of patients have two different mutations on both chromosomes 12 ΔF508 1 R117H 1 N1303K

  19. Is There A Genetic Connection Between Melanoma and Pancreatic Cancer? • Methods: • 1,537 pancreatic adenocarcinoma patients • Mutation analysis of CDKN2A gene • Results: • 9(0.6%)carried germline mutations in CDKN2A • Carriers were more likely to have: • Family history of pancreatic cancer(p= 0.003); carrier rate 3.3% • Family history of melanoma(p= 0.03); carrier rate 5.3% • Personal history of melanoma(p= 0.01) McWilliams RR et al.Eur J Hum Genetics, 2011 Apr;19(4):472-8.

  20. Genetic susceptibility to pancreatic cancer Sporadic ~85% ? Young onset (<60) sporadic ~20% Familial pancreatic cancer ~10% Known cancer genes (~5%)

  21. Associations with DNA Repair Genes

  22. PanScan – a GWAS PanScan 1 Amundadottir L, Kraft P, Stolzenberg-Solomon RZ, et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nature Genetics 41:986-90, September, 2009. 2000 pairs PanScan 2 Petersen GM, Amundadottir A, Fuchs CS, et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nature Genetics, Feb 2010. 3,850 pairs

  23. All Studies GWAS Results: ABO Blood Group

  24. ABO Blood Groups and Cancer Gastric Cancer - well established Increased risk for blood group A Pancreatic Cancer -Possibly risk with ABO  Risk Bodmer and Bonilla Nat Gen 2008

  25. Blood GroupRisk A 1.32 AB 1.51 B 1.72 JNCI 2009; 101:424-431

  26. Genetic polymorphisms and GxE interactions Sporadic ~70% ? Young onset (<60) sporadic ~20% Known genetic syndromes ~3% Familial pancreatic cancer <10% Genetic susceptibility is heterogeneous

  27. How do we find new genes that confer susceptibility to familial PC? Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium Funded by NCI grant R01 CA97075 • Prospective accrual of FPC kindreds • Whole genome scan • Linkage analysis • TGEN • As of February 2011: • 31,184 screened • 2,509 with +FHx enrolled (16,297 mbrs) • 8,316 family enrolled 5.5 million genotypes tested! Petersen GM et al. Cancer Epi Biomarkers Prev, 15:704, 2006

  28. New familial pancreatic cancer gene: PALB2 • 96 FPC patients screened for PALB2 mutations (90 Caucasian) • Average onset age: 66.7 years (in non PALB2 kindreds, 65.3) • Previous published study: no mutations in 1,084 normal controls. Jones S, Hruban RH, Kamiyama M, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science, 324:217, 2009.

  29. Where are genes for inherited pancreatic cancer? • Others: • FANCC (9q) • CFTR (7q) • PJS (19p) • MMR (2p, 3p) • APC (5q) • PALLD (4q) PRSS1 At least 3 other genomic regions involved P16, PALB2 BRCA2

  30. Genetic susceptibility to pancreatic cancer Genetic polymorphisms and GxE interactions (DNA Repair, ABO, CLPTM1L-TERT, NR5A) Sporadic ~70% ? Young onset (<60) sporadic ~20% CFTR Familial pancreatic cancer <10% BRCA2, p16, PALB2, etc. Known genetic syndromes ~3% Hereditary pancreatitis, FAMMM, etc.

  31. Conclusions • Research has shown that there are individuals at increased risk for developing pancreatic cancer • Genetic susceptibility is heterogeneous • Limited genetic testing is available • Our work continues to better understand the genetics and to help patients

  32. Johns Hopkins University • Ralph Hruban, M.D. • Mike Goggins, M.D. • Alison Klein, Ph.D. • Mimi Canto, M.D. • PACGENE collaborators • Melissa Bondy, Ph.D. – MDA • Steve Gallinger, M.D. – U Toronto • Ann Schwartz, Ph.D. - Wayne SU • Sapna Syngal, M.D. – DFCI • Kevin Brown, Ph.D. - TGEN • Daniela Seminara, Ph.D. – NCI • Henry Lynch, M.D. – Creighton U • Ctr for Inherited Disease Research • David Hogg, Ph.D. • PanScan Collaborators - NCI • Patricia Hartge, Ph.D. • Robert Hoover, Ph.D. • Stephen Chanock, Ph.D. • Laufey Amundadottir, Ph.D. • Mayo Clinic • Rob McWilliams, MD • Mariza de Andrade, Ph.D. • Kari Rabe, M.S. • Bill Bamlet, M.S. • Suresh Chari, M.D. • Wilma Lingle, Ph.D. • Fergus Couch, Ph.D. • Ed Highsmith, M.D. • Julie Cunningham, Ph.D. • Thomas Smyrk, M.D. • Hugues Sicotte, Ph.D. • Traci Hammer, Cindy Chan, Jodie Cogswell, Bridget Eversman • RO1 CA97075 • SPORE (P50 CA 102701) • Pancreatic Cancer Action Network Collaborators & Acknowledgments

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