Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations.
Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations.
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DOI：
10.1053/j.gastro.2014.08.041
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发表时间：
2014-12
期刊：
影响因子：
29.4
通讯作者：
Pritchard CC
中科院分区：
文献类型：
--
作者：
Haraldsdottir S;Hampel H;Tomsic J;Frankel WL;Pearlman R;de la Chapelle A;Pritchard CC
Lynch综合征患者在编码MMR蛋白MLH 1、MSH 2、MSH 6和PMS 2的基因的单个等位基因中携带种系突变;当第二个等位基因突变时，可能会发生癌症。增加对Lynch综合征的筛查已经确定了患有MMR缺陷的肿瘤患者，但编码MMR蛋白的基因中没有种系突变。我们使用下一代测序技术研究了MMR基因无种系突变的患者中MMR缺陷型肿瘤是否获得了体细胞突变。我们分析了来自32例结直肠癌或子宫内膜癌患者的血液和肿瘤样本，这些患者参加了俄亥俄州的Lynch综合征筛查研究，并被发现患有MMR缺陷的肿瘤（基于免疫组化分析中的微卫星不稳定性和/或MMR蛋白的缺失，没有MLH 1的超甲基化），但MMR基因没有种系突变。用ColoSeq对肿瘤DNA进行MLH 1、MSH 2、MSH 6、PMS 2、EPCAM、POLE和POLD 1测序，并确定突变频率。根据免疫组织化学，32例患者中有22例（69%）发现在MMR编码蛋白质的基因中有两个体细胞（肿瘤）突变，这些蛋白质从肿瘤样本中丢失。在10例无MMR基因体细胞突变的肿瘤中，3例有可能导致MMR缺陷的杂合性丢失的体细胞突变，6例被发现为假阳性结果（19%），1例没有已知与MMR缺陷相关的突变。所有发现具有体细胞MMR突变的肿瘤都具有高度突变表型（>12个突变/Mb）; 6个具有>200个/Mb的突变频率，并且其中5个在编码DNA聚合酶的POLE中具有体细胞突变。一些患者在筛查Lynch综合征时发现患有MMR缺陷的肿瘤，但MMR基因中没有可识别的种系突变。我们发现，这些患者中几乎有70%获得MMR基因的体细胞突变，导致肿瘤细胞的高度突变表型。患有MMR缺陷的结肠癌或子宫内膜癌患者不能通过生殖系突变来解释，可能需要对MMR基因中的肿瘤突变进行分析，以指导未来的监测指南。
Patients with Lynch syndrome carry germline mutations in single alleles of genes encoding the MMR proteins MLH1, MSH2, MSH6 and PMS2; when the second allele becomes mutated, cancer can develop. Increased screening for Lynch syndrome has identified patients with tumors that have deficiency in MMR, but no germline mutations in genes encoding MMR proteins. We investigated whether tumors with deficient MMR had acquired somatic mutations in patients without germline mutations in MMR genes using next-generation sequencing. We analyzed blood and tumor samples from 32 patients with colorectal or endometrial cancer who participated in Lynch syndrome screening studies in Ohio and were found to have tumors with MMR deficiency (based on microsatellite instability and/or absence of MMR proteins in immunohistochemical analysis, without hypermethylation of MLH1), but no germline mutations in MMR genes. Tumor DNA was sequenced for MLH1, MSH2, MSH6, PMS2, EPCAM, POLE and POLD1 with ColoSeq and mutation frequencies were established. Twenty-two of 32 patients (69%) were found to have two somatic (tumor) mutations in MMR genes encoding proteins that were lost from tumor samples, based on immunohistochemistry. Of the 10 tumors without somatic mutations in MMR genes, 3 had somatic mutations with possible loss of heterozygosity that could lead to MMR deficiency, 6 were found to be false-positive results (19%), and 1 had no mutations known to be associated with MMR deficiency. All of the tumors found to have somatic MMR mutations were of the hypermutated phenotype (>12 mutations/Mb); 6 had mutation frequencies >200 per Mb, and 5 of these had somatic mutations in POLE, which encodes a DNA polymerase. Some patients are found to have tumors with MMR deficiency during screening for Lynch syndrome, yet have no identifiable germline mutations in MMR genes. We found that almost 70% of these patients acquire somatic mutations in MMR genes, leading to a hypermutated phenotype of tumor cells. Patients with colon or endometrial cancers with MMR deficiency not explained by germline mutations might undergo analysis for tumor mutations in MMR genes, to guide future surveillance guidelines.
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影响因子：
29.4
作者：
Rodriguez-Soler, Maria;Perez-Carbonell, Lucia;Jover, Rodrigo
通讯作者：
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作者：
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AALTONEN, LA