Candidate colorectal cancer predisposing gene variants in Chinese early-onset and familial cases.
Candidate colorectal cancer predisposing gene variants in Chinese early-onset and familial cases.
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DOI：
10.3748/wjg.v21.i14.4136
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发表时间：
2015-04
影响因子：
4.3
通讯作者：
Junxiao Zhang;L. Fu;Richarda M. de Voer;Marc-Manuel Hahn;P. Jin;Chen-Xi Lv;E. Verwiel;M. Ligtenberg
中科院分区：
文献类型：
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作者：
Junxiao Zhang;L. Fu;Richarda M. de Voer;Marc-Manuel Hahn;P. Jin;Chen-Xi Lv;E. Verwiel;M. Ligtenberg
目的 研究全外显子组测序是否可以作为一种有效方法来识别早发性或家族性 CRC 病例中已知或新型结直肠癌 (CRC) 易感基因。方法 我们对 23 名中国患者进行了全外显子组测序，这些患者来自 21 个年龄≤ 40 岁诊断为非息肉病 CRC 的家庭，或来自多个受影响的 CRC 家庭且至少有 1 名一级亲属在年龄≤ 55 岁诊断为 CRC 的患者。使用 SureSelect 人类全外显子试剂盒第 2 版（安捷伦科技）对血液中的基因组 DNA 进行外显子组序列富集，并在 Illumina HiSeq 2000 平台上进行测序。通过分析流程处理数据，以寻找已知或新型 CRC 易感基因中的罕见种系变异。结果 桑格测序总共鉴定并确认了 23 个基因的 32 个种系变异。在 21 个家族中的 6 个家族 (29%) 中，我们在 3 个已知的 CRC 易感基因中发现了 7 个突变，包括 MLH1（5 名患者）、MSH2（1 名患者）和 MUTYH（双等位基因，1 名患者），其中 5 个被报告为致病基因。在其余 15 个家族中，我们在 19 个基因中发现了 20 个罕见且新颖的潜在有害变异，其中 6 个是截短突变。在 EIF2AK4 保守区域 (p.Glu738_Asp739insArgArg) 中发现的一个先前未报告的变异代表了一种中国本土变异，与由 100 名健康中国人组成的对照组（结肠镜检查得分为阴性）相比，该变异在我们的早发 CRC 患者队列中显着丰富（33.3% vs 7%，P < 0.001）。结论 早发型或家族性 CRC 病例的全外显子组测序可作为识别已确定和新型候选 CRC 易感基因中已知和潜在致病变异的有效方法。
AIM To investigate whether whole-exome sequencing may serve as an efficient method to identify known or novel colorectal cancer (CRC) predisposing genes in early-onset or familial CRC cases. METHODS We performed whole-exome sequencing in 23 Chinese patients from 21 families with non-polyposis CRC diagnosed at ≤ 40 years of age, or from multiple affected CRC families with at least 1 first-degree relative diagnosed with CRC at ≤ 55 years of age. Genomic DNA from blood was enriched for exome sequences using the SureSelect Human All Exon Kit, version 2 (Agilent Technologies) and sequencing was performed on an Illumina HiSeq 2000 platform. Data were processed through an analytical pipeline to search for rare germline variants in known or novel CRC predisposing genes. RESULTS In total, 32 germline variants in 23 genes were identified and confirmed by Sanger sequencing. In 6 of the 21 families (29%), we identified 7 mutations in 3 known CRC predisposing genes including MLH1 (5 patients), MSH2 (1 patient), and MUTYH (biallelic, 1 patient), five of which were reported as pathogenic. In the remaining 15 families, we identified 20 rare and novel potentially deleterious variants in 19 genes, six of which were truncating mutations. One previously unreported variant identified in a conserved region of EIF2AK4 (p.Glu738_Asp739insArgArg) was found to represent a local Chinese variant, which was significantly enriched in our early-onset CRC patient cohort compared to a control cohort of 100 healthy Chinese individuals scored negative by colonoscopy (33.3% vs 7%, P < 0.001). CONCLUSION Whole-exome sequencing of early-onset or familial CRC cases serves as an efficient method to identify known and potential pathogenic variants in established and novel candidate CRC predisposing genes.