MLH1-silenced and non-silenced subgroups of hypermutated colorectal carcinomas have distinct mutational landscapes.
MLH1-silenced and non-silenced subgroups of hypermutated colorectal carcinomas have distinct mutational landscapes.
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DOI：
10.1002/path.4087
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发表时间：
2013-01
影响因子：
7.3
通讯作者：
Wheeler, David
中科院分区：
文献类型：
--
作者：
Donehower, Lawrence A.;Creighton, Chad J.;Schultz, Nikolaus;Shinbrot, Eve;Chang, Kyle;Gunaratne, Preethi H.;Muzny, Donna;Sander, Chris;Hamilton, Stanley R.;Gibbs, Richard A.;Wheeler, David
大约15%的结直肠癌（CRC）呈现高突变基因型，伴有高水平的微卫星不稳定性（MSI - H）以及DNA错配修复缺陷。这些肿瘤与大多数结直肠癌不同，通常为二倍体，经常出现MLH1 DNA错配修复基因的表观遗传沉默，并且临床预后较好。作为癌症基因组图谱联盟的一项辅助研究，该联盟最近通过全外显子组测序分析了224例结直肠癌，我们将35例（15.6%）具有高突变基因型的CRC与非高突变基因型的CRC进行了比较。我们发现，22例（63%）高突变CRC表现出MLH1基因的转录沉默、BRAF V600E基因突变频率高以及APC和KRAS突变不常见，这种突变模式与非高突变的对应肿瘤显著不同。然而，其余13例（37%）高突变CRC没有MLH1沉默，包含突变率最高的肿瘤（“超高突变”CRC），并且APC和KRAS突变发生率较高，但BRAF突变不常见。这些模式在一组250例经外显子组测序的CRC独立验证集中得到了证实。对mRNA和微小RNA表达特征的分析表明，与非高突变CRC相比，具有MLH1沉默的高突变CRC的WNT信号水平大幅降低，BRAF信号增强。我们的研究结果表明，高突变CRC包括一个与大多数CRC在恶性转化途径上根本不同的亚组。检查CRC中MLH1的表达状态以及APC、KRAS和BRAF突变的频率可能提供一种有用的诊断工具，它可以补充标准的微卫星不稳定性检测，并影响治疗决策。
Approximately 15% of colorectal carcinomas (CRC) exhibit a hypermutated genotype accompanied by high levels of microsatellite instability (MSI-H) and defects in DNA mismatch repair. These tumors, unlike the majority of colorectal carcinomas, are often diploid, exhibit frequent epigenetic silencing of the MLH1 DNA mismatch repair gene, and have a better clinical prognosis. As an adjunct study to The Cancer Genome Atlas consortium that recently analyzed 224 colorectal cancers by whole exome sequencing, we compared the 35 CRC (15.6%) with a hypermutated genotype to those with a non-hypermutated genotype. We found that 22 (63%) of hypermutated CRC exhibited transcriptional silencing of the MLH1 gene, a high frequency of BRAF V600E gene mutations and infrequent APC and KRAS mutations, a mutational pattern significantly different from their non-hypermutated counterparts. However, the remaining 13 (37%) hypermutated CRC lacked MLH1 silencing, contained tumors with the highest mutation rates (“ultramutated” CRC), and exhibited higher incidences of APC and KRAS mutations, but infrequent BRAF mutations. These patterns were confirmed in an independent validation set of 250 exome-sequenced CRC. Analysis of mRNA and microRNA expression signatures revealed that hypermutated CRC with MLH1 silencing had greatly reduced levels of WNT signaling and increased BRAF signaling relative non-hypermutated CRC. Our findings suggest that hypermutated CRC include one subgroup with fundamentally different pathways to malignancy than the majority of CRC. Examination of MLH1 expression status and frequencies of APC, KRAS, and BRAF mutation in CRC may provide a useful diagnostic tool that could supplement the standard microsatellite instability assays and influence therapeutic decisions.
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影响因子：
29.4
作者：
Boland CR;Goel A
通讯作者：
Goel A
影响因子：
50.3
作者：
Singh A;Greninger P;Rhodes D;Koopman L;Violette S;Bardeesy N;Settleman J
通讯作者：
Settleman J
影响因子：
3.7
作者：
Albuquerque, Cristina;Baltazar, Celia;Fodde, Riccardo
通讯作者：
Fodde, Riccardo
影响因子：
5.3
作者：
Lustig, B;Jerchow, B;Behrens, J
通讯作者：
Behrens, J
影响因子：
24.5
作者：
Ogino S;Nosho K;Kirkner GJ;Kawasaki T;Meyerhardt JA;Loda M;Giovannucci EL;Fuchs CS
通讯作者：
Fuchs CS