Whole exome sequencing reveals recurrent mutations in BRCA2 and FAT genes in acinar cell carcinomas of the pancreas.
Whole exome sequencing reveals recurrent mutations in BRCA2 and FAT genes in acinar cell carcinomas of the pancreas.
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DOI：
10.1038/srep08829
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发表时间：
2015-03-06
影响因子：
4.6
通讯作者：
Shiratori K
中科院分区：
文献类型：
--
作者：
Furukawa T;Sakamoto H;Takeuchi S;Ameri M;Kuboki Y;Yamamoto T;Hatori T;Yamamoto M;Sugiyama M;Ohike N;Yamaguchi H;Shimizu M;Shibata N;Shimizu K;Shiratori K
摘要胰脏腺泡细胞癌是一种罕见且预后不良的肿瘤。与胰腺导管腺癌相比，其分子特征知之甚少。我们共研究了11例腺泡细胞癌，包括3例外显子组和4例靶向测序。外显子组测序显示65个非同义突变和22个indel，平均每个肿瘤的突变率为3.4个突变/Mb。通过解释体细胞突变和野生型等位基因缺失的种系突变，我们鉴定了BRCA 2和FAT基因的复发性突变。BRCA 2表现为体细胞或生殖细胞的提前终止突变，7例肿瘤中有3例野生型等位基因丢失。FAT 1、FAT 3和FAT 4在7例肿瘤中的4例中显示体细胞或生殖系错义突变。生殖系FAT突变伴随野生型等位基因的丢失。在11个肿瘤中的5个中观察到BRCA 2表达缺失。1例BRCA 2突变肿瘤患者在顺铂化疗后肝转移完全缓解。总之，腺泡细胞癌显示出独特的突变模式，并经常携带BRCA 2和FAT基因的体细胞或种系突变。这一结果可能需要评估癌症患者的BRCA 2废除，以确定他们对化疗的敏感性。
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.
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