Hirotsu Yosuke, Nakagomi Hiroshi, Sakamoto Ikuko, Amemiya Kenji, Oyama Toshio, Mochizuki Hitoshi, Omata Masao
Genome Analysis Center, Yamanashi Prefectural Central Hospital 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan.
Department of Breast Surgery, Yamanashi Prefectural Central Hospital 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan.
Mol Genet Genomic Med. 2015 Sep;3(5):459-66. doi: 10.1002/mgg3.157. Epub 2015 May 12.
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.
所有乳腺癌和/或卵巢癌病例中约5-10%被认为是遗传性的。BRCA1和BRCA2肿瘤抑制基因在遗传性病例中具有高外显率，但这些基因无突变的家族性病例也可能发生。尽管其他遗传性癌症相关基因的外显率较低，但已知它们与乳腺癌和卵巢癌风险相关。然而，这些基因在乳腺癌和卵巢癌中的普遍程度仍有待阐明。为了估计这些易感基因的突变频率，我们使用靶向二代测序分析了155例患者中25个遗传性癌症相关基因的种系突变。这些受试者包括11例BRCA1/2突变阳性病例和144例阴性病例。其中，3例患者（1.9%）在ATM、MRE11A或MSH6中有致病性突变，所有这些基因在DNA修复和错配修复途径中都起着核心作用。如体外和免疫组化分析所示，MSH6剪接位点突变（IVS6+1G>T）被预测为致病性突变。这些结果表明细胞DNA修复功能缺陷导致乳腺癌和卵巢癌的发生。
