Yildiz Safiye, Musarurwa Takudzwa N, Algar Ursula, Chambuso Ramadhani, Rebello George, Goldberg Paul A, Ramesar Raj
UCT/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town and Affiliated Hospitals, Cape Town, South Africa.
The Colorectal Unit of the Department of Surgery, Groote Schuur Hospital and the University of Cape Town, Cape Town, South Africa.
Front Oncol. 2023 Oct 27;13:1253867. doi: 10.3389/fonc.2023.1253867. eCollection 2023.
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.
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.
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.
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.
非洲裔年轻患者中结直肠癌发病率的上升以及侵袭性的增加，使得对这些癌症的遗传特性进行研究成为必要。目前仅有有限数量关于非洲本土人群遗传性结直肠癌的已发表报告，且此前尚未对这些群体进行过系统筛查。我们旨在通过下一代测序（NGS）多基因panel研究非洲本土结直肠癌患者已知结直肠癌基因中的致病种系变异，并确定致病/可能致病种系变异的发生率。
患者选自南非开普敦和约翰内斯堡的两家医院。选取发病年龄在60岁及以下且分子诊断未明确的患者。使用Ion Torrent平台上的14基因NGS panel分析种系DNA样本。进行变异检测和注释，并根据美国医学遗传学与基因组学学会的指南对变异进行分类。通过Sanger测序和/或长片段PCR验证观察到的变异。
在107例患者中，25例（23.4%）存在致病/可能致病种系变异（PGV）。在12例患者（11.2%）中鉴定并验证了至少一个错配修复（MMR）基因中的14个PGV。在这些MMR基因变异中，有5个是新发现的。其余10个PGV存在于APC、BMPR1A、MUTYH、POLD1和TP53基因中。
非洲本土患者中与早发性结直肠癌相关的PGV高发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检测铺平了道路。下一步将使用检测拷贝数变异、甲基化和全外显子测序的工具对未解决的病例进行进一步筛查。
