Mismatch repair deficiency commonly precedes adenoma formation in Lynch Syndrome-Associated colorectal tumorigenesis
Mismatch repair deficiency commonly precedes adenoma formation in Lynch Syndrome-Associated colorectal tumorigenesis
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DOI：
10.1038/modpathol.2017.39
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发表时间：
2017-08-01
期刊：
影响因子：
7.5
通讯作者：
Hiraoka, Nobuyoshi
中科院分区：
文献类型：
--
作者：
Sekine, Shigeki;Mori, Taisuke;Hiraoka, Nobuyoshi
林奇综合征是一种由错配修复基因的胚系突变引起的癌症易感综合征。MMR缺陷是Lynch综合征相关性结直肠腺癌的一个普遍特征；然而，目前尚不清楚MMR缺陷表型是在肿瘤发生过程中获得的。为了探讨这一问题，本研究检测了Lynch综合征相关的结直肠腺瘤和腺癌的基因改变和MMR状态，并与散发性腺瘤进行了比较。在与Lynch综合征相关的结直肠肿瘤中，86例腺瘤和所有腺癌中有68例(79%)是MMR缺乏的，而所有散发性腺瘤都是MMR熟练的，通过微卫星不稳定性测试和MMR蛋白的免疫组织化学确定。测序分析发现，大多数散发性腺瘤(58/84，69%)和精通MMR的Lynch综合征相关腺瘤(13/18，72%)存在APC或CTNNB1突变。然而，在MMR缺陷的Lynch综合征相关腺瘤中，APC或CTNNB1突变较少(25/68，37%)，RNF43突变较多(45/68，66%)。此外，影响重复序列的移码突变占MMR缺陷腺瘤26个APC突变中的14个(54%)，而这些移码突变在Lynch综合征患者的MMR熟练的腺瘤(1/12，8%)和散发性腺瘤(3/52，6%)中很少见。与Lynch综合征相关的腺癌表现出类似于MMR缺陷性腺瘤的突变特征。考虑到WNT通路的激活足以驱动结直肠腺瘤的形成，在Lynch综合征相关腺瘤中WNT通路基因的不同突变特征表明MMR缺陷通常先于腺瘤的形成。
Lynch syndrome is a cancer predisposition syndrome caused by germline mutations in mismatch repair (MMR) genes. MMR deficiency is a ubiquitous feature of Lynch syndrome-associated colorectal adenocarcinomas; however, it remains unclear when the MMR-deficient phenotype is acquired during tumorigenesis. To probe this issue, the present study examined genetic alterations and MMR statuses in Lynch syndrome-associated colorectal adenomas and adenocarcinomas, in comparison with sporadic adenomas. Among the Lynch syndrome-associated colorectal tumors, 68 of 86 adenomas (79%) and all adenocarcinomas were MMR-deficient, whereas all the sporadic adenomas were MMR-proficient, as determined by microsatellite instability testing and immunohistochemistry for MMR proteins. Sequencing analyses identified APC or CTNNB1 mutations in the majority of sporadic adenomas (58/84, 69%) and MMR-proficient Lynch syndrome-associated adenomas (13/18, 72%). However, MMR-deficient Lynch syndrome-associated adenomas had less APC or CTNNB1 mutations (25/68, 37%) and frequent frameshift RNF43 mutations involving mononucleotide repeats (45/68, 66%). Furthermore, frameshift mutations affecting repeat sequences constituted 14 of 26 APC mutations (54%) in MMR-deficient adenomas whereas these frameshift mutations were rare in MMR-proficient adenomas in patients with Lynch syndrome (1/12, 8%) and in sporadic adenomas (3/52, 6%). Lynch syndrome-associated adenocarcinomas exhibited mutation profiles similar to those of MMR-deficient adenomas. Considering that WNT pathway activation sufficiently drives colorectal adenoma formation, the distinct mutation profiles of WNT pathway genes in Lynch syndrome-associated adenomas suggest that MMR deficiency commonly precedes adenoma formation.