Whole exome sequencing reveals recurrent mutations in BRCA2 and FAT genes in acinar cell carcinomas of the pancreas.
Acinar cell carcinoma of the pancreas is a rare tumor with a poor prognosis. Compared to pancreatic ductal adenocarcinoma, its molecular features are poorly known. We studied a total of 11 acinar cell carcinomas, including 3 by exome and 4 by target sequencing. Exome sequencing revealed 65 nonsynonymous mutations and 22 indels with a mutation rate of 3.4 mutations/Mb per tumor, on average. By accounting for not only somatic but also germline mutations with loss of the wild-type allele, we identified recurrent mutations of BRCA2 and FAT genes. BRCA2 showed somatic or germline premature termination mutations, with loss of the wild-type allele in 3 of 7 tumors. FAT1, FAT3, and FAT4 showed somatic or germline missense mutations in 4 of 7 tumors. The germline FAT mutations were with loss of the wild-type allele. Loss of BRCA2 expression was observed in 5 of 11 tumors. One patient with a BRCA2-mutated tumor experienced complete remission of liver metastasis following cisplatinum chemotherapy. In conclusion, acinar cell carcinomas show a distinct mutation pattern and often harbor somatic or germline mutations of BRCA2 and FAT genes. This result may warrant assessment of BRCA2 abrogation in patients with the carcinoma to determine their sensitivity to chemotherapy.
1] Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan [2] Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan.
Toru
T
Furukawa
1] Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan [2] Department of Surgery, Kyorin University School of Medicine, Mitaka, Japan.
Hitomi
H
Sakamoto
Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan.
Shoko
S
Takeuchi
Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan.
Mitra
M
Ameri
1] Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan [2] Department of Gastroenterology, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
Yuko
Y
Kuboki
Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan.
Toshiyuki
T
Yamamoto
Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
Takashi
T
Hatori
Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
Masakazu
M
Yamamoto
Department of Surgery, Kyorin University School of Medicine, Mitaka, Japan.
Masanori
M
Sugiyama
Department of Pathology, Showa University School of Medicine, Tokyo, Japan.
Nobuyuki
N
Ohike
Department of Pathology, Saitama Medical University International Medical Center, Hidaka, Japan.
Hiroshi
H
Yamaguchi
Department of Pathology, Saitama Medical University International Medical Center, Hidaka, Japan.
Michio
M
Shimizu
Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan.
Noriyuki
N
Shibata
Department of Gastroenterology, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
Kyoko
K
Shimizu
Department of Gastroenterology, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
Keiko
K
Shiratori
D000368:Aged; D000483:Alleles; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D018267:Carcinoma, Acinar Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019295:Computational Biology / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059472:Exome; D005260:Female; D024522:Genes, BRCA2; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis
D015820:Cadherins