MonoSeq Variant Caller Reveals Novel Mononucleotide Run Indel Mutations in Tumors with Defective DNA Mismatch Repair.
MonoSeq Variant Caller Reveals Novel Mononucleotide Run Indel Mutations in Tumors with Defective DNA Mismatch Repair.
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DOI：
10.1002/humu.23036
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发表时间：
2016-10
期刊：
影响因子：
3.9
通讯作者：
Goodfellow, Paul J.
中科院分区：
文献类型：
--
作者：
Walker, Christopher J.;Miranda, Mario A.;O'Hern, Matthew J.;Blachly, James S.;Moyer, Cassandra L.;Ivanovich, Jennifer;Kroll, Karl W.;Eisfeld, Ann-Kathrin;Sapp, Caroline E.;Mutch, David G.;Cohn, David E.;Bundschuh, Ralf;Goodfellow, Paul J.
下一代测序已经彻底改变了癌症遗传学，但准确检测重复DNA序列中的突变，特别是单核苷酸检测，仍然是一个挑战。这是一个特别关注的肿瘤与缺陷的错配修复（MMR）积累链滑移突变。我们开发了MonoSeq来改善monoclantide运行中的indel突变检测，并使用MonoSeq来研究子宫内膜癌中的链滑移突变，这是一种经常丢失MMR的肿瘤类型。我们进行了广泛的桑格测序以验证克隆和亚克隆MonoSeq突变调用。在542例原发性子宫内膜癌（223例MMR缺陷）中，对81个含有monopoltide的区域进行测序。我们的分析显示，MMR缺陷肿瘤的总体突变率比MMR正常肿瘤高20-30倍。MonoSeq分析发现了几个以前未报道的突变，包括ARID 5 B末端外显子A7运行中的新热点。ARID 5 B indel突变在MMR缺陷和MMR正常肿瘤中均可见，表明生物选择。对肿瘤mRNA的分析揭示了可能导致新肽翻译的突变转录本的存在。改进的检测monopoltide运行链滑移突变有明确的意义，全面的突变检测与缺陷的MMR肿瘤。插入缺失移码突变和所得的抗原肽可以帮助指导免疫治疗策略。
Next-generation sequencing has revolutionized cancer genetics, but accurately detecting mutations in repetitive DNA sequences, especially mononucleotide runs, remains a challenge. This is a particular concern for tumors with defective mismatch repair (MMR) that accumulate strand-slippage mutations. We developed MonoSeq to improve indel mutation detection in mononucleotide runs, and used MonoSeq to investigate strand-slippage mutations in endometrial cancers, a tumor type that has frequent loss of MMR. We performed extensive Sanger sequencing to validate both clonal and sub-clonal MonoSeq mutation calls. Eighty-one regions containing mononucleotide runs were sequenced in 542 primary endometrial cancers (223 with defective MMR). Our analyses revealed that the overall mutation rate in MMR-deficient tumors was 20–30-fold higher than in MMR normal tumors. MonoSeq analysis identified several previously unreported mutations, including a novel hotspot in an A7 run in the terminal exon of ARID5B.The ARID5B indel mutations were seen in both MMR-deficient and MMR normal tumors, suggesting biologic selection. Analysis of tumor mRNAs revealed the presence of mutant transcripts that could result in translation of neopeptides. Improved detection of mononucleotide run strand-slippage mutations has clear implications for comprehensive mutation detection in tumors with defective MMR. Indel frameshift mutations and the resultant antigenic peptides could help guide immunotherapy strategies.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
1.8
作者：
Cantarella C;D'Agostino N
通讯作者：
D'Agostino N
影响因子：
12.3
作者：
Huse SM;Huber JA;Morrison HG;Sogin ML;Welch DM
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Welch DM
影响因子：
3.5
作者：
Gan C;Love C;Beshay V;Macrae F;Fox S;Waring P;Taylor G
通讯作者：
Taylor G
影响因子：
4.3
作者：
Bragg LM;Stone G;Butler MK;Hugenholtz P;Tyson GW
通讯作者：
Tyson GW