Colorectal Cancers Show Distinct Mutation Spectra in Members of the Canonical WNT Signaling Pathway According to Their Anatomical Location and Type of Genetic Instability
Colorectal Cancers Show Distinct Mutation Spectra in Members of the Canonical WNT Signaling Pathway According to Their Anatomical Location and Type of Genetic Instability
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DOI：
10.1002/gcc.20786
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发表时间：
2010-08-01
影响因子：
3.7
通讯作者：
Fodde, Riccardo
中科院分区：
文献类型：
--
作者：
Albuquerque, Cristina;Baltazar, Celia;Fodde, Riccardo
目前还不清楚WNT基因的突变谱是否在不同类型的结直肠肿瘤中存在差异。我们分析了52例结直肠肿瘤中特定WNT基因的突变，并对以前的研究进行了荟萃分析。值得注意的是，突变谱之间存在显着差异。我们先前已经表明，在家族性腺瘤性息肉病中，APC体细胞突变被选择为肿瘤形成提供“恰到好处”的WNT信号传导水平。在这里，我们发现APC突变包含至少两个β-连环蛋白下调基序（20 a.a.在微卫星不稳定（MSI-H）肿瘤中，截短（保留少于两个重复）的频率显著高于微卫星稳定（MSS）肿瘤（P = 0.0009）。此外，在检测到两个APC命中的情况下，选择保留两个20 a.a.重复在MSI-H肿瘤中变得明显（P = 0.001）。无论MSI状态如何，这种类型的突变在近端结肠肿瘤中比远端结肠肿瘤更常见（P = 0.0008）。在MSI-H肿瘤中，CTNNB 1突变在HNPCC中的发生率显著高于散发性病变（28%比6%，P < 10-6），并且优先在近端结肠中检测到，与MSI状态无关（P = 0.017）。总之，在结直肠肿瘤中观察到的WNT基因突变谱可能是选择特定水平的β-连环蛋白信号传导的结果，在特定的解剖位置和遗传不稳定形式的背景下，最适合肿瘤形成。我们认为，这可能是MMR缺陷的肿瘤在近端结肠的优先位置的基础。(C)2010 Wiley-Liss，Inc.
It is unclear whether the mutation spectra in WNT genes vary among distinct types of colorectal tumors. We have analyzed mutations in specific WNT genes in a cohort of 52 colorectal tumors and performed a meta-analysis of previous studies. Notably, significant differences were found among the mutation spectra. We have previously shown that in familial adenomatous polyposis, APC somatic mutations are selected to provide the "just-right" level of WNT signaling for tumor formation. Here, we found that APC mutations encompassing at least two beta-catenin down-regulating motifs (20 a.a. repeats) are significantly more frequent in microsatellite unstable (MSI-H) than in microsatellite stable (MSS) tumors where truncations retaining less than two repeats are more frequent (P = 0.0009). Moreover, in cases where both APC hits are detected, selection for mutations retaining a cumulative number of two 20 a.a. repeats became apparent in MSI-H tumors (P = 0.001). This type of mutations were also more frequent in proximal versus distal colonic tumors, regardless of MSI status (P = 0.0008). Among MSI-H tumors, CTNNB1 mutations were significantly more frequent in HNPCC than in sporadic lesions (28% versus 6%, P < 10-6) and were preferentially detected in the proximal colon, independently of MSI status (P = 0.017). In conclusion, the observed spectra of WNT gene mutations in colorectal tumors are likely the result from selection of specific levels of beta-catenin signaling, optimal for tumor formation in the context of specific anatomical locations and forms of genetic instability. We suggest that this may underlie the preferential location of MMR deficient tumors in the proximal colon. (C) 2010 Wiley-Liss, Inc.