Department of Clinical Genetics, University Hospital of Southern Denmark, Beriderbakken 4, 7100 Vejle, Denmark.
Department of Genetics and Morphology, Institute of Biological Sciences, University of Brasília-UnB, Brasília 70910-900, DF, Brazil.
Int J Mol Sci. 2024 Sep 24;25(19):10275. doi: 10.3390/ijms251910275.
A hereditary component of breast (BC) and colorectal cancer (CRC) has been described in approximately one-third of these tumor types. BC patients have an increased risk of developing CRC as a second primary tumor and vice versa. Germline genomic variants (NextSeq550, Illumina) were investigated in 24 unrelated BC and/or CRC patients and 7 relatives from 3 index patients. Fifty-six pathogenic or likely pathogenic variants were identified in 19 of 24 patients. We detected single-nucleotide variants (SNVs) in CRC predisposition genes ( and ) and other promising candidates (, , , and ). Eighteen patients presented SNVs or copy number variants (CNVs) in DNA damage repair genes. We also identified SNVs recently associated with BC or CRC predisposition (, , , , and ). The c.1255C>T variant was detected in nine unrelated patients. Each patient presented at least one SNV/CNV in a candidate gene, and most had alterations in more than one gene, reinforcing a polygenic model for BC/CRC predisposition. A significant fraction of BC/CRC patients with a family history of these tumors harbored deleterious germline variants in DNA repair genes. Our findings can lead to strategies to improve the diagnosis, genetic counseling, and treatment of patients and their relatives.
遗传性乳腺癌 (BC) 和结直肠癌 (CRC) 约占这些肿瘤类型的三分之一。BC 患者发生 CRC 的风险增加，反之亦然。对 24 名无关的 BC 和/或 CRC 患者和 3 名指数患者的 7 名亲属进行了种系基因组变异（NextSeq550、Illumina）的研究。在 24 名患者中的 19 名中发现了 56 个致病性或可能致病性的变异。我们检测到 CRC 易感性基因（和）和其他有希望的候选基因（、、、和）中的单核苷酸变异（SNVs）。18 名患者存在 DNA 损伤修复基因中的 SNVs 或拷贝数变异（CNVs）。我们还鉴定了最近与 BC 或 CRC 易感性相关的 SNVs（、、、和）。在 9 名无关患者中检测到 c.1255C>T 变异。每位患者在候选基因中至少有一个 SNV/CNV，大多数患者有一个以上基因的改变，这强化了 BC/CRC 易感性的多基因模型。具有这些肿瘤家族史的 BC/CRC 患者中，有相当一部分存在 DNA 修复基因中的有害种系变异。我们的发现可以为改善患者及其亲属的诊断、遗传咨询和治疗提供策略。
