Mutation analysis of adenomas and carcinomas of the colon: Early and late drivers.
Mutation analysis of adenomas and carcinomas of the colon: Early and late drivers.
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DOI：
10.1002/gcc.22539
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Slattery ML
中科院分区：
文献类型：
--
作者：
Wolff RK;Hoffman MD;Wolff EC;Herrick JS;Sakoda LC;Samowitz WS;Slattery ML
结直肠癌(CRC)约占美国所有新诊断癌症病例的8%。我们使用来自18个个体的三联体样本(结肠癌、结肠腺瘤和正常组织)的完整外显子序列数据来评估基因突变率。在2204个突变的基因中，APC、TTN、TP53、KRAS、OBSCN、SOX9、PCDH17、SIGLEC10、MYH6和BRD9与早期致癌基因一致，因为它们在多发性腺瘤和多发性癌中发生了突变。在≥12.5%的微卫星稳定型癌中有5 2个基因发生突变，但在任何腺瘤中均未发生突变，这与肿瘤进展过程中的晚期驱动事件相一致。为了获得更准确的突变频率，对148对癌症/正常组织中的38个基因进行了测序。其中8个基因，APC、TP53、ATM、CSMD3、LRP1B、RYR2、BIRC6和MUC17，在20%的癌症中存在突变。有趣的是，除了与Wnt信号调节失调相关的APC外，还有四个基因的突变都被归类为早期驱动事件。大多数通常与结肠癌相关的基因，包括APC、TP53和KRAS，都被归类为在腺瘤和癌中都发生突变的早期驱动基因。将基因归类为潜在的早期和晚期驱动事件，指向可能有助于剖析参与肿瘤启动和进展的途径的候选基因。
Colorectal cancer (CRC) accounts for about 8% of all new cancer cases diagnosed in the US. We used whole exome sequence data from triplet samples (colon carcinoma, colon adenoma, and normal tissue) from 18 individuals to assess gene mutation rates. Of the 2 204 genes that were mutated, APC, TTN, TP53, KRAS, OBSCN, SOX9, PCDH17, SIGLEC10, MYH6, and BRD9 were consistent with genes being an early driver of carcinogenesis, in that they were mutated in multiple adenomas and multiple carcinomas. Fifty‐two genes were mutated in ≥12.5% of microsatellite stable (MSS) carcinomas but not in any of the adenomas, in line with the profile of a late driver event involved in tumor progression. Thirty‐eight genes were sequenced in a larger independent set of 148 carcinoma/normal tissue pairs to obtain more precise mutation frequencies. Eight of the genes, APC, TP53, ATM, CSMD3, LRP1B, RYR2, BIRC6, and MUC17, contained mutations in >20% of the carcinomas. Interestingly, mutations in four genes in addition to APC that are associated with dysregulation of Wnt signaling, were all classified as early driver events. Most of the genes that are commonly associated with colon cancer, including APC, TP53, and KRAS, were all classified as being early driver genes being mutated in both adenomas and carcinomas. Classifying genes as potential early and late driver events points to candidate genes that may help dissect pathways involved in both tumor initiation and progression.
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