Germline mutations in Japanese familial pancreatic cancer patients

// Erina Takai 1, * , Shinichi Yachida 1, * , Kyoko Shimizu 2 , Junji Furuse 3 , Emi Kubo 4 , Akihiro Ohmoto 1 , Masami Suzuki 1 , Ralph H. Hruban 5 , Takuji Okusaka 4 , Chigusa Morizane 4 , Toru Furukawa 6 1 Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan 2 Department of Gastroenterology, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan 3 Department of Medical Oncology, Kyorin University School of Medicine, Mitaka, Japan 4 Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan 5 Department of Pathology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 6 Institute for Integrated Medical Sciences, Tokyo Women’s Medical University, Tokyo, Japan * These authors have contributed equally to this work Correspondence to: Toru Furukawa, email: furukawa.toru@twmu.ac.jp Keywords: pancreatic cancer, familial predisposition, BRCA2, ATM, PALB2 Received: July 10, 2016 Accepted: September 29, 2016 Published: October 6, 2016 ABSTRACT Clinicopathologic and genetic features of familial pancreatic cancer (FPC) in Asian countries remain largely unknown. The main purpose of this study was to determine the prevalence of FPC and to define causative FPC-predisposition genes in a Japanese cohort with pancreatic ductal adenocarcinoma (PDAC).We reviewed 1,197 patients with a pathologically proven PDAC and found that 88 (7.3%) were FPC patients who had at least one first-degree relative with PDAC. There were no significant differences between the FPC cases and sporadic cases in terms of gender, age, tumor location, stage, family history of any cancer except PDAC, and personal history of smoking, other cancers, diabetes mellitus and chronic pancreatitis. In the FPC patients, we then investigated the prevalence of germline mutations in 21 genes associated with hereditary predispositions for pancreatic, breast and ovarian cancers by means of the next-generation sequencing using a custom multiple-gene panel. We found that eight (14.5%) of the 54 FPC patients with available germline DNA carried deleterious mutations in BRCA2 , PALB2 , ATM , or MLH1 . These results indicate that a significant fraction of patients with PDAC in Japan have a family history of pancreatic cancer, and some of them harbor deleterious causative mutations in known FPC predisposition genes.