Novel somatic and germline mutations in cancer candidate genes in glioblastoma, melanoma, and pancreatic carcinoma
Novel somatic and germline mutations in cancer candidate genes in glioblastoma, melanoma, and pancreatic carcinoma
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DOI：
10.1158/0008-5472.can-07-0065
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发表时间：
2007-04-15
期刊：
影响因子：
11.2
通讯作者：
Bardelli, Alberto
中科院分区：
文献类型：
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作者：
Balakrishnan, Asha;Bleeker, Fonnet E.;Bardelli, Alberto
最近对注释良好的人类蛋白质编码基因或共有编码序列的系统序列分析导致鉴定出189个在乳腺癌和结直肠癌中显示体细胞突变的基因。基于它们的突变发生率，这些基因的一个子集被鉴定为癌症候选（CAN）基因，因为它们可能与癌症有关。我们评估了19个CAN基因在高度侵袭性肿瘤中的突变谱：胶质母细胞瘤、黑色素瘤和胰腺癌。在其他变化中，我们发现了EPLA3，MLL3，TECTA，FBXW7和OBSCN中的新体细胞突变，影响了以前在人类癌症中未发现突变的氨基酸。有趣的是，我们还发现了OBSCN的种系核苷酸变体，该变体先前被报道为体细胞突变。我们的研究结果确定了胶质母细胞瘤，黑色素瘤和胰腺癌的特定遗传病变，并表明CAN基因及其突变谱是肿瘤特异性的。一些突变的基因，如酪氨酸激酶EPHA3，显然是适合药物干预，并可能代表这些不可治愈的癌症的新的治疗靶点。我们还推测，与其他癌基因和肿瘤抑制基因类似，影响OBSCN的突变可能与癌症易感性有关。
A recent systematic sequence analysis of well-annotated human protein coding genes or consensus coding sequences led to the identification of 189 genes displaying somatic mutations in breast and colorectal cancers. Based on their mutation prevalence, a subset of these genes was identified as cancer candidate (CAN) genes as they could be potentially involved in cancer. We evaluated the mutational profiles of 19 CAN genes in the highly aggressive tumors: glioblastoma, melanoma, and pancreatic carcinoma. Among other changes, we found novel somatic mutations in EPLA3, MLL3, TECTA, FBXW7, and OBSCN, affecting amino acids not previously found to be mutated in human cancers. Interestingly, we also found a germline nucleotide variant of OBSCN that was previously reported as a somatic mutation. Our results identify specific genetic lesions in glioblastoma, melanoma, and pancreatic cancers and indicate that CAN genes and their mutational profiles are tumor specific. Some of the mutated genes, such as the tyrosine kinase EPHA3, are clearly amenable to pharmacologic intervention and could represent novel therapeutic targets for these incurable cancers. We also speculate that similar to other oncogenes and tumor suppressor genes, mutations affecting OBSCN could be involved in cancer predisposition.