Michael Skaro1, Neha Nanda1, Christian Gauthier1, Matthäus Felsenstein1, Zhengdong Jiang1, Miaozhen Qiu2, Koji Shindo1, Jun Yu3, Danielle Hutchings1, Ammar A Javed4, Ross Beckman4, Jin He4, Christopher L Wolfgang5, Elizabeth Thompson6, Ralph H Hruban6, Alison P Klein7, Michael Goggins8, Laura D Wood6, Nicholas J Roberts9. 1. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. 2. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medical Oncology, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. 3. The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. 4. Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. 5. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. 6. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. 7. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. 8. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland. 9. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: nrobert8@jhmi.edu.
Abstract
BACKGROUND & AIMS: Many patients with pancreatic adenocarcinoma carry germline mutations associated with increased risk of cancer. It is not clear whether patients with intraductal papillary mucinous neoplasms (IPMNs), which are precursors to some pancreatic cancers, also carry these mutations. We assessed the prevalence of germline mutations associated with cancer risk in patients with histologically confirmed IPMN. METHODS: We obtained nontumor tissue samples from 315 patients with surgically resected IPMNs from 1997 through 2017, and we sequenced 94 genes with variants associated with cancer risk. Mutations associated with increased risk of cancer were identified and compared with individuals from the Exome Aggregation Consortium. RESULTS: We identified 23 patients with a germline mutation associated with cancer risk (7.3%; 95% confidence interval, 4.9-10.8). Nine patients had a germline mutation associated with pancreatic cancer susceptibility (2.9%; 95% confidence interval, 1.4-5.4). More patients with IPMNs carried germline mutations in ATM (P < .0001), PTCH1 (P < .0001), and SUFU (P < .0001) compared with controls. Patients with IPMNs and germline mutations associated with pancreatic cancer were more like to have concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations (P < .0320). CONCLUSIONS: In sequence analyses of 315 patients with surgically resected IPMNs, we found that almost 3% to carry mutations associated with pancreatic cancer risk. More patients with IPMNs and germline mutations associated with pancreatic cancer had concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations. Genetic analysis of patients with IPMNs might identify those at greatest risk for cancer.
BACKGROUND & AIMS: Many patients with pancreatic adenocarcinoma carry germline mutations associated with increased risk of cancer. It is not clear whether patients with intraductal papillary mucinous neoplasms (IPMNs), which are precursors to some pancreatic cancers, also carry these mutations. We assessed the prevalence of germline mutations associated with cancer risk in patients with histologically confirmed IPMN. METHODS: We obtained nontumor tissue samples from 315 patients with surgically resected IPMNs from 1997 through 2017, and we sequenced 94 genes with variants associated with cancer risk. Mutations associated with increased risk of cancer were identified and compared with individuals from the Exome Aggregation Consortium. RESULTS: We identified 23 patients with a germline mutation associated with cancer risk (7.3%; 95% confidence interval, 4.9-10.8). Nine patients had a germline mutation associated with pancreatic cancer susceptibility (2.9%; 95% confidence interval, 1.4-5.4). More patients with IPMNs carried germline mutations in ATM (P < .0001), PTCH1 (P < .0001), and SUFU (P < .0001) compared with controls. Patients with IPMNs and germline mutations associated with pancreatic cancer were more like to have concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations (P < .0320). CONCLUSIONS: In sequence analyses of 315 patients with surgically resected IPMNs, we found that almost 3% to carry mutations associated with pancreatic cancer risk. More patients with IPMNs and germline mutations associated with pancreatic cancer had concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations. Genetic analysis of patients with IPMNs might identify those at greatest risk for cancer.
Authors: Aaron McKenna; Matthew Hanna; Eric Banks; Andrey Sivachenko; Kristian Cibulskis; Andrew Kernytsky; Kiran Garimella; David Altshuler; Stacey Gabriel; Mark Daly; Mark A DePristo Journal: Genome Res Date: 2010-07-19 Impact factor: 9.043
Authors: Marcia Irene Canto; Michael Goggins; Ralph H Hruban; Gloria M Petersen; Francis M Giardiello; Charles Yeo; Elliott K Fishman; Kieran Brune; Jennifer Axilbund; Constance Griffin; Syed Ali; Jeffrey Richman; Sanjay Jagannath; Sergey V Kantsevoy; Anthony N Kalloo Journal: Clin Gastroenterol Hepatol Date: 2006-05-06 Impact factor: 11.382
Authors: Andrew D Rhim; Paul E Oberstein; Dafydd H Thomas; Emily T Mirek; Carmine F Palermo; Stephen A Sastra; Erin N Dekleva; Tyler Saunders; Claudia P Becerra; Ian W Tattersall; C Benedikt Westphalen; Jan Kitajewski; Maite G Fernandez-Barrena; Martin E Fernandez-Zapico; Christine Iacobuzio-Donahue; Kenneth P Olive; Ben Z Stanger Journal: Cancer Cell Date: 2014-05-22 Impact factor: 31.743
Authors: Kaye M Reid-Lombardo; Kellie L Mathis; Christina M Wood; William S Harmsen; Michael G Sarr Journal: Ann Surg Date: 2010-01 Impact factor: 12.969
Authors: Sarah P Thayer; Marina Pasca di Magliano; Patrick W Heiser; Corinne M Nielsen; Drucilla J Roberts; Gregory Y Lauwers; Yan Ping Qi; Stephan Gysin; Carlos Fernández-del Castillo; Vijay Yajnik; Bozena Antoniu; Martin McMahon; Andrew L Warshaw; Matthias Hebrok Journal: Nature Date: 2003-09-14 Impact factor: 49.962
Authors: Adam Auton; Lisa D Brooks; Richard M Durbin; Erik P Garrison; Hyun Min Kang; Jan O Korbel; Jonathan L Marchini; Shane McCarthy; Gil A McVean; Gonçalo R Abecasis Journal: Nature Date: 2015-10-01 Impact factor: 49.962
Authors: Monkol Lek; Konrad J Karczewski; Eric V Minikel; Kaitlin E Samocha; Eric Banks; Timothy Fennell; Anne H O'Donnell-Luria; James S Ware; Andrew J Hill; Beryl B Cummings; Taru Tukiainen; Daniel P Birnbaum; Jack A Kosmicki; Laramie E Duncan; Karol Estrada; Fengmei Zhao; James Zou; Emma Pierce-Hoffman; Joanne Berghout; David N Cooper; Nicole Deflaux; Mark DePristo; Ron Do; Jason Flannick; Menachem Fromer; Laura Gauthier; Jackie Goldstein; Namrata Gupta; Daniel Howrigan; Adam Kiezun; Mitja I Kurki; Ami Levy Moonshine; Pradeep Natarajan; Lorena Orozco; Gina M Peloso; Ryan Poplin; Manuel A Rivas; Valentin Ruano-Rubio; Samuel A Rose; Douglas M Ruderfer; Khalid Shakir; Peter D Stenson; Christine Stevens; Brett P Thomas; Grace Tiao; Maria T Tusie-Luna; Ben Weisburd; Hong-Hee Won; Dongmei Yu; David M Altshuler; Diego Ardissino; Michael Boehnke; John Danesh; Stacey Donnelly; Roberto Elosua; Jose C Florez; Stacey B Gabriel; Gad Getz; Stephen J Glatt; Christina M Hultman; Sekar Kathiresan; Markku Laakso; Steven McCarroll; Mark I McCarthy; Dermot McGovern; Ruth McPherson; Benjamin M Neale; Aarno Palotie; Shaun M Purcell; Danish Saleheen; Jeremiah M Scharf; Pamela Sklar; Patrick F Sullivan; Jaakko Tuomilehto; Ming T Tsuang; Hugh C Watkins; James G Wilson; Mark J Daly; Daniel G MacArthur Journal: Nature Date: 2016-08-18 Impact factor: 49.962
Authors: Michael J Pflüger; James F Griffin; Wenzel M Hackeng; Satomi Kawamoto; Jun Yu; Peter Chianchiano; Eunice Shin; Gemma Lionheart; Hua-Ling Tsai; Hao Wang; Neda Rezaee; Richard A Burkhart; John L Cameron; Elizabeth D Thompson; Christopher L Wolfgang; Jin He; Lodewijk A A Brosens; Laura D Wood Journal: Ann Surg Date: 2020-11-17 Impact factor: 13.787
Authors: Elizabeth D Thompson; Nicholas J Roberts; Laura D Wood; James R Eshleman; Michael G Goggins; Scott E Kern; Alison P Klein; Ralph H Hruban Journal: Mod Pathol Date: 2020-07-23 Impact factor: 7.842
Authors: Fabienne Lesueur; Douglas F Easton; Anne-Laure Renault; Sean V Tavtigian; Jonine L Bernstein; Zsofia Kote-Jarai; Rosalind A Eeles; Dijana Plaseska-Karanfia; Lidia Feliubadaló; Banu Arun; Natalie Herold; Beatrix Versmold; Rita Katharina Schmutzler; Tú Nguyen-Dumont; Melissa C Southey; Leila Dorling; Alison M Dunning; Paola Ghiorzo; Bruna Samia Dalmasso; Eve Cavaciuti; Dorothée Le Gal; Nicholas J Roberts; Mev Dominguez-Valentin; Matti Rookus; Alexander M R Taylor; Alisa M Goldstein; David E Goldgar; Dominique Stoppa-Lyonnet; Nadine Andrieu Journal: Fam Cancer Date: 2021-06-14 Impact factor: 2.375
Authors: Naziheh Assarzadegan; Elizabeth Thompson; Kevan Salimian; Matthias M Gaida; Lodewijk A A Brosens; Laura Wood; Syed Z Ali; Ralph H Hruban Journal: Langenbecks Arch Surg Date: 2021-05-28 Impact factor: 2.895
Authors: Bo Huang; Maria A Trujillo; Kohei Fujikura; Miaozhen Qiu; Fei Chen; Matthäus Felsenstein; Cancan Zhou; Michael Skaro; Christian Gauthier; Anne Macgregor-Das; Danielle Hutchings; Seung-Mo Hong; Ralph H Hruban; James R Eshleman; Elizabeth D Thompson; Alison P Klein; Michael Goggins; Laura D Wood; Nicholas J Roberts Journal: J Pathol Date: 2020-09-19 Impact factor: 9.883