APC mutations and other genetic and epigenetic changes in colon cancer
APC mutations and other genetic and epigenetic changes in colon cancer
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DOI：
10.1158/1541-7786.mcr-06-0398
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发表时间：
2007-02-01
影响因子：
5.2
通讯作者：
Albertsen, Hans
中科院分区：
文献类型：
--
作者：
Samowitz, Wade S.;Slattery, Martha L.;Albertsen, Hans
结肠癌中腺瘤性息肉病 (APC) 突变、BRAF V600E 突变和 CpG 岛甲基化表型 (CIMP) 之间的关系尚未被探索。此外，对于突变簇区（MCR）APC突变的肿瘤比例也存在争议； APC、Ki-ras 和 p53 突变在同一肿瘤中发生的频率如何；以及 APC 突变是否发生在散发性微卫星不稳定肿瘤中。因此，对先前评估了 CIMP、微卫星不稳定性、BRAF、Ki-ras 和 p53 的 90 例结肠腺癌中的 APC 基因进行了测序。 APC突变与BRAF突变（P=0.0003）和CIMP突变（P=0.02）呈负相关，与p53和Ki-ras突变直接相关（P=0.04）。略多于一半的 APC 突变发生在 MCR 之外，移码突变比无义突变更有可能发生在 MCR 中（28 例中有 21 例，40 例中有 12 例，P=0.0003）。 APC 突变发现于散发性微卫星不稳定肿瘤中，并且更可能是短核苷酸重复中的移码（P=0.007）。在同一肿瘤中同时发生 APC、Ki-ras 和 p53 突变的情况并不常见 (11.1%)。总之，仅限于 MCR 的分析将错过一半以上的 APC 突变，并错误地描述其突变谱。大多数结肠癌含有 APC、Ki-ras 和 p53 突变的传统观点是不正确的。在散发性微卫星不稳定肿瘤中，微卫星不稳定可能先于 APC 突变的获得。 APC 突变与其他遗传和表观遗传改变的关系进一步加剧了结肠癌本已令人印象深刻的遗传异质性。
Relationships between adenomatous polyposis coli (APC) mutations, BRAF V600E mutations, and the CpG island methylator phenotype (CIMP) in colon cancer have not been explored. In addition, controversies exist about the proportion of tumors with APC mutations in the mutation cluster region (MCR); how commonly APC, Ki-ras, and p53 mutations occur in the same tumor; and whether APC mutations occur in sporadic microsatellite-unstable tumors. The APC gene was therefore sequenced in 90 colonic adenocarcinomas previously evaluated for CIMP, microsatellite instability, BRAF, Ki-ras, and p53. APC mutations were inversely related to BRAF mutations (P=0.0003) and CIMP (P=0.02) and directly related to p53 and Ki-ras mutations (P=0.04). Slightly more than half of APC mutations occurred outside of the MCR, and frameshift mutations were more likely than nonsense mutations to occur in the MCR (21 of 28 versus 12 of 40, P=0.0003). APC mutations were found in sporadic microsatellite-unstable tumors and were more likely to be frameshifts in short nucleotide repeats (P=0.007). The occurrence of APC, Ki-ras, and p53 mutations together in the same tumor was uncommon (11.1%). In conclusion, an analysis restricted to the MCR will miss more than half of APC mutations as well as mischaracterize their mutational spectrum. The conventional wisdom that most colon cancers contain APC, Ki-ras, and p53 mutations is incorrect. Microsatellite instability may precede acquisition of APC mutations in sporadic microsatellite-unstable tumors. The relationships of APC mutations to other genetic and epigenetic alterations add to the already impressive genetic heterogeneity of colon cancer.