WNT Pathway Gene Mutations Are Associated With the Presence of Dysplasia in Colorectal Sessile Serrated Adenoma/Polyps
WNT Pathway Gene Mutations Are Associated With the Presence of Dysplasia in Colorectal Sessile Serrated Adenoma/Polyps
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DOI：
10.1097/pas.0000000000000877
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发表时间：
2017-09-01
影响因子：
5.6
通讯作者：
Hiraoka, Nobuyoshi
中科院分区：
文献类型：
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作者：
Hashimoto, Taiki;Yamashita, Satoshi;Hiraoka, Nobuyoshi
无蒂锯齿状腺瘤/息肉（SSA/Ps）被认为是结直肠锯齿状癌的主要前体。为了更好地表征从SSA/Ps到癌的进展过程，我们使用靶向下一代测序和免疫组织化学分析了46例具有异型增生的SSA/Ps和45例没有异型增生的SSA/Ps。在分析的WNT通路基因中，RNF 43、APC和ZNRF 3的蛋白截短突变分别在23例（50%）、4例（9%）和3例（7%）异型增生SSA/Ps中被鉴定。相比之下，无异型增生的SSA/Ps很少有WNT通路基因突变，除了3个病变有RNF 43突变（7%）。SSA/P均不具有CTNNB 1突变或RSPO融合。因此，WNT通路基因突变在有异型增生的SSA/Ps中比在无异型增生的SSA/Ps中更常见（P=3.0 × 10（-8））。一致的是，核β-连环蛋白积累和MYC过表达，表明活跃的WNT信号，存在于大多数的SSA/Ps与异型增生，但在那些没有异型增生罕见。BRAF（86%）或KRAS突变（7%）在大多数SSA/Ps中被确定，无论是否存在异型增生。MLH 1在14例SSA/Ps中表达缺失（30%）。大多数MLH 1缺陷型SSA/Ps伴异型增生患者有RNF 43突变（86%），其中大多数是涉及单核苷酸重复序列的移码突变。相比之下，MLH 1保留病变的RNF 43突变频率较低，无热点（34%），4例有APC突变（13%）。这些结果表明，WNT通路基因突变参与发育异常的SSA/Ps和MLH 1缺陷和MLH 1保留的SSA/Ps发育异常表现出不同的突变谱的WNT通路基因。
Sessile serrated adenoma/polyps (SSA/Ps) are believed to be the major precursor of serrated pathway-derived colorectal carcinomas. To better characterize the process of progression from SSA/Ps to carcinomas, we analyzed 46 SSA/Ps with dysplasia and 45 SSA/Ps without dysplasia using targeted next-generation sequencing and immunohistochemistry. Among the WNT pathway genes analyzed, protein-truncating mutations of RNF43, APC, and ZNRF3 were identified in 23 (50%), 4 (9%), and 3 (7%) SSA/Ps with dysplasia, respectively. In contrast, SSA/Ps without dysplasia rarely had WNT pathway gene mutations, except for 3 lesions with RNF43 mutations (7%). None of the SSA/Ps had CTNNB1 mutations or RSPO fusions. Thus, WNT pathway gene mutations were more common in SSA/Ps with dysplasia than in SSA/Ps without dysplasia (P=3.0 x 10(-8)). Consistently, nuclear beta-catenin accumulation and MYC overexpression, indicative of active WNT signaling, were present in most of the SSA/Ps with dysplasia, but were rare in those without dysplasia. BRAF (86%) or KRAS mutations (7%) were identified in the majority of SSA/Ps, regardless of the presence or absence of dysplasia. MLH1 expression was lost in 14 SSA/Ps with dysplasia (30%). The majority of MLH1-deficient SSA/Ps with dysplasia had RNF43 mutations (86%), most of which were frame-shift mutations involving mononucleotide repeats. In contrast, MLH1-retained lesions had less frequent RNF43 mutations with no hot spots (34%), and 4 had APC mutations (13%). These results suggest that WNT pathway gene mutations are involved in the development of dysplasia in SSA/Ps and that MLH1-deficient and MLH1-retained SSA/Ps with dysplasia exhibit distinct mutation profiles of WNT pathway genes.