PDF(Pubmed)
Abstract：
UNASSIGNED: The increase in incidence of colorectal cancer in young patients of African ancestry coupled with increased aggressiveness has warranted investigation of the heritable nature of these cancers. Only a limited number of published reports of hereditary colorectal cancer in indigenous African populations have been reported and no systematic screening of these groups has been performed previously. We aimed to investigate causative germline variants and to establish the incidence of pathogenic/likely pathogenic germline variants in the known colorectal cancer genes in indigenous African colorectal cancer patients using a next-generation sequencing (NGS) multigene panel.
UNASSIGNED: Patients were selected from two hospitals in Cape Town and Johannesburg, South Africa. Patients with unresolved molecular diagnosis with an age of onset below or at 60 years were selected. Germline DNA samples were analyzed using a 14-gene NGS panel on the Ion Torrent platform. Variant calling and annotation were performed, and variants were classified according to the American College of Medical Genetics and Genomics guidelines. Observed variants were verified by Sanger sequencing and/or long-range PCR.
UNASSIGNED: Out of 107 patients, 25 (23.4%) presented with a pathogenic/likely pathogenic germline variant (PGV). Fourteen PGVs in at least one mismatch repair (MMR) gene were identified and verified in 12 patients (11.2%). Of these MMR gene variants, five were novel. The remaining 10 PGVs were in the APC, BMPR1A, MUTYH, POLD1, and TP53 genes.
UNASSIGNED: The high incidence of PGVs associated with early-onset colorectal cancer in indigenous African patients has important implications for hereditary colorectal cancer risk management. These findings pave the way for personalized genetic screening programs and cascade testing in South Africa. The next step would involve further screening of the unresolved cases using tools to detect copy number variation, methylation, and whole exome sequencing.
UNASSIGNED: Patients were selected from two hospitals in Cape Town and Johannesburg, South Africa. Patients with unresolved molecular diagnosis with an age of onset below or at 60 years were selected. Germline DNA samples were analyzed using a 14-gene NGS panel on the Ion Torrent platform. Variant calling and annotation were performed, and variants were classified according to the American College of Medical Genetics and Genomics guidelines. Observed variants were verified by Sanger sequencing and/or long-range PCR.
UNASSIGNED: Out of 107 patients, 25 (23.4%) presented with a pathogenic/likely pathogenic germline variant (PGV). Fourteen PGVs in at least one mismatch repair (MMR) gene were identified and verified in 12 patients (11.2%). Of these MMR gene variants, five were novel. The remaining 10 PGVs were in the APC, BMPR1A, MUTYH, POLD1, and TP53 genes.
UNASSIGNED: The high incidence of PGVs associated with early-onset colorectal cancer in indigenous African patients has important implications for hereditary colorectal cancer risk management. These findings pave the way for personalized genetic screening programs and cascade testing in South Africa. The next step would involve further screening of the unresolved cases using tools to detect copy number variation, methylation, and whole exome sequencing.
摘要：
■非洲血统的年轻患者结直肠癌发病率的增加以及侵袭性的增加，有必要对这些癌症的遗传性进行研究。仅报道了有限数量的非洲土著人群中遗传性结直肠癌的公开报道，并且以前没有对这些人群进行过系统的筛查。我们旨在研究致病种系变异，并使用下一代测序（NGS）多基因小组确定非洲土著结直肠癌患者已知结直肠癌基因中致病/可能致病种系变异的发生率。
■患者是从开普敦和约翰内斯堡的两家医院中选择的，南非。选择发病年龄在60岁以下或60岁以下的分子诊断未解决的患者。在IonTorrent平台上使用14基因NGS面板分析种系DNA样品。进行了变体调用和注释，和变异根据美国医学遗传学和基因组学学院指南进行分类。通过Sanger测序和/或长程PCR验证观察到的变体。
■在107名患者中，25（23.4％）呈现致病性/可能致病性种系变体（PGV）。在至少一个错配修复（MMR）基因中鉴定出14个PGV，并在12名患者（11.2％）中进行了验证。在这些MMR基因变异中，五是小说。其余10辆PGV在APC中，BMPR1A,MUTYH,POLD1和TP53基因。
■非洲土著患者中与早发性结直肠癌相关的PGV的高发病率对遗传性结直肠癌风险管理具有重要意义。这些发现为南非的个性化基因筛查计划和级联测试铺平了道路。下一步将涉及使用检测拷贝数变异的工具进一步筛选未解决的病例，甲基化,和整个外显子组测序。
■患者是从开普敦和约翰内斯堡的两家医院中选择的，南非。选择发病年龄在60岁以下或60岁以下的分子诊断未解决的患者。在IonTorrent平台上使用14基因NGS面板分析种系DNA样品。进行了变体调用和注释，和变异根据美国医学遗传学和基因组学学院指南进行分类。通过Sanger测序和/或长程PCR验证观察到的变体。
■在107名患者中，25（23.4％）呈现致病性/可能致病性种系变体（PGV）。在至少一个错配修复（MMR）基因中鉴定出14个PGV，并在12名患者（11.2％）中进行了验证。在这些MMR基因变异中，五是小说。其余10辆PGV在APC中，BMPR1A,MUTYH,POLD1和TP53基因。
■非洲土著患者中与早发性结直肠癌相关的PGV的高发病率对遗传性结直肠癌风险管理具有重要意义。这些发现为南非的个性化基因筛查计划和级联测试铺平了道路。下一步将涉及使用检测拷贝数变异的工具进一步筛选未解决的病例，甲基化,和整个外显子组测序。
