Colorectal cancer (CRC) incidence in young adults is rising. Identifying genetic risk factors is fundamental for the clinical management of patients and their families. This study aimed to identify clinically significant germline variants among young adults with CRC. Whole-exome sequencing data of blood-derived DNA from 133 unrelated young CRC patients (<55 years of age) underwent a comprehensive analysis of 133 cancer-predisposition/implicated genes. All patient tumors were evaluated for mismatch repair deficiency (dMMR). Among 133 patients (aged 16–54 years), 15% (20/133) had clinically actionable pathogenic or likely pathogenic (P/LP) variants in at least 1 well established cancer-predisposing gene: dMMR genes (6), MUTYH [bi-allelic (2), mono-allelic (3)], RNF43 (1), BMPR1A (1), BRCA2 (4), ATM (1), RAD51C (1), and BRIP1 (1). Five patients (4%) had variants in genes implicated in cancer but where the significance of germline variants in CRC risk is uncertain: GATA2 (1), ERCC2 (mono-allelic) (1), ERCC4 (mono-allelic) (1), CFTR (2). Fourteen (11%) had dMMR tumors. Eighteen (14%) reported a first-degree relative with CRC, but only three of these carried P/LP variants. Three patients with variants in polyposis-associated genes showed no polyposis (one each in MUTYH [bi-allelic], RNF43, and BMPR1A). Approximately one in five young adults in our series carried at least one P/LP variant in a cancer-predisposing/implicated gene; 80% of these variants are currently considered clinically actionable in a familial cancer setting. Family history and phenotype have limitations for genetic risk prediction; therefore multigene panel testing and genetic counseling are warranted for all young adults with CRC regardless of those two factors.

中文翻译：

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青年结直肠癌患者癌症相关基因种系变异的调查

年轻人结直肠癌 (CRC) 的发病率正在上升。识别遗传风险因素是患者及其家属临床管理的基础。本研究旨在确定患有 CRC 的年轻成人中具有临床意义的种系变异。来自 133 名无关年轻 CRC 患者（<55 岁）的血液衍生 DNA 的全外显子组测序数据对 133 个癌症易感性/相关基因进行了综合分析。评估所有患者肿瘤的错配修复缺陷 (dMMR)。在 133 名患者（年龄 16-54 岁）中，15% (20/133) 在至少 1 个公认的癌症易感基因中具有临床可操作的致病性或可能致病性 (P/LP) 变异：dMMR 基因 (6)、MUTYH [双等位基因 (2)、单等位基因 (3)]、RNF43 (1)、BMPR1A (1)、BRCA2 (4)、ATM (1)、RAD51C (1) 和BRIP1 (1)。5 名患者 (4%) 存在与癌症有关的基因变异，但生殖系变异在 CRC 风险中的重要性尚不确定：GATA2 (1)、ERCC2（单等位基因）(1)、ERCC4（单等位基因）(1) , CFTR (2)。十四名 (11%) 患有 dMMR 肿瘤。18 名 (14%) 的一级亲属报告患有 CRC，但其中只有 3 名携带 P/LP 变体。三名患有息肉病相关基因变异的患者未显示息肉病（MUTYH [双等位基因]、RNF43和BMPR1A各一名））。在我们的系列中，大约五分之一的年轻人在癌症易感/牵连基因中携带至少一种 P/LP 变异；这些变异中的 80% 目前被认为在家族性癌症环境中具有临床可操作性。家族史和表型对遗传风险预测有局限性；因此，无论这两个因素如何，所有患有 CRC 的年轻人都需要进行多基因检测和遗传咨询。