title: Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer.
abstract: Approximately 5-10% of all breast and/or ovarian cancer cases are considered as inherited. BRCA1 and BRCA2 tumor suppressor genes account for a high penetrance of hereditary cases, but familial cases without mutations in these genes can also occur. Despite their low penetrance, other hereditary cancer-related genes are known to be associated with breast and ovarian cancer risk. However, the extent to which these genes prevail in breast and ovarian cancer remains to be elucidated. To estimate the frequency of mutations in these predisposition genes, we analyzed the germline mutations of 25 hereditary cancer-related genes in 155 patients using targeted next-generation sequencing. These subjects included 11 BRCA1/2 mutation-positive cases and 144 negative cases. Of these, three patients (1.9%) had pathogenic mutations in ATM, MRE11A, or MSH6, all of which have a central role in DNA repair and the mismatch repair pathway. The MSH6 splice-site mutation (IVS6+1G>T) was predicted to be pathogenic, as demonstrated by in vitro and immunohistochemical analyses. These results suggested deficiencies in cellular DNA repair functions result in the development of breast and ovarian cancer.
authors.affiliation: Genome Analysis Center, Yamanashi Prefectural Central Hospital 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Hirotsu
authors.affiliation: Department of Breast Surgery, Yamanashi Prefectural Central Hospital 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagomi
authors.affiliation: Department of Gynecology, Yamanashi Prefectural Central Hospital 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Sakamoto
authors.affiliation: Genome Analysis Center, Yamanashi Prefectural Central Hospital 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan ; Pathology Division, Laboratory Department, Yamanashi Prefectural Central Hospital 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Amemiya
authors.affiliation: Pathology Division, Laboratory Department, Yamanashi Prefectural Central Hospital 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Oyama
authors.affiliation: Genome Analysis Center, Yamanashi Prefectural Central Hospital 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan ; Department of Gastroenterology, Yamanashi Prefectural Central Hospital 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: Genome Analysis Center, Yamanashi Prefectural Central Hospital 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan ; Department of Gastroenterology, Yamanashi Prefectural Central Hospital 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan ; Graduate School of Medicine, The University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
keywords: Breast and ovarian cancer; DNA repair; gene panel; next-generation sequencing