Background:Colorectal cancer (CRC) is a leading cause of cancer death, and the incidence and mortality rates among young adults are rising. Although a subset of CRC cases presents with a family history, suggesting a hereditary component, the specific genetic underpinnings remain incompletely understood, particularly in early-onset CRC (EOCRC). This study aimed to discover novel risk genes for EOCRC using exome sequencing and gene-based rare variant burden testing.Methods:Our cohort consisted of 212 European-ancestry cases (174 diagnosed with CRC and 38 with significant polyps) from the South Australian Young Onset Colorectal Polyp and Cancer Study (SAYO) and 31,699 unaffected controls from the Simons Foundation Powering Autism Research for Knowledge (SPARK) cohort. After filtering for ancestry, relatedness, variant quality, and population allele frequency, we performed gene-set and individual-gene burden tests using predicted deleterious missense and loss-of-function variants. Statistical significance was assessed using permutation-corrected binomial testing. An independent validation was conducted in the UK Biobank.Results:Loss-of-function variants in known CRC tumor suppressor genes were significantly enriched in SAYO cases. Gene-level analyses identifiedMEIKINas a novel EOCRC susceptibility candidate (pvalue = 1.0 × 10−7), with supporting enrichment of deleterious missense and loss-of-function variants in distal colon cancer cases from the UK Biobank. Additional genes (STK25,PGBD4,DIRAS3,ATG3,RPS6KA4, andDDX42) demonstrated borderline significance, implicating pathways related to kinetochore assembly, autophagy regulation, and immune signaling. Both predicted gain-of-function and loss-of-function variants contributed to the EOCRC risk, supporting heterogeneous mechanisms of CRC pathogenesis.Conclusions:This study identified novel candidate risk genes for EOCRC, underscoring the role of rare variants and expanding our understanding of the genetic architecture of CRC. Future studies should include functional validation and replication studies on other ancestries to confirm and extend these results.
背景：结直肠癌是癌症死亡的主要原因，其年轻成人的发病率和死亡率正在上升。尽管部分结直肠癌病例具有家族史，提示存在遗传因素，但其具体的遗传基础仍未完全阐明，尤其是在早发性结直肠癌中。本研究旨在利用外显子组测序和基于基因的罕见变异负荷测试，发现早发性结直肠癌的新风险基因。 方法：我们的队列包括来自南澳大利亚早发性结直肠息肉与癌症研究的212例欧洲血统病例（其中174例诊断为结直肠癌，38例为显著息肉），以及来自西蒙斯基金会自闭症研究知识库队列的31,699名未患病对照。经过血统、亲缘关系、变异质量和群体等位基因频率筛选后，我们使用预测的有害错义变异和功能丧失变异进行了基因集和单基因负荷测试。统计显著性通过置换校正的二项式检验进行评估。并在英国生物银行中进行了独立验证。 结果：已知的结直肠癌抑癌基因中的功能丧失变异在SAYO病例中显著富集。基因水平分析鉴定出MEIKIN作为一个新的早发性结直肠癌易感候选基因（p值 = 1.0 × 10−7），并且来自英国生物银行的远端结肠癌病例中有害错义和功能丧失变异的富集结果提供了支持。其他基因（STK25、PGBD4、DIRAS3、ATG3、RPS6KA4和DDX42）显示出临界显著性，涉及与动粒组装、自噬调控和免疫信号相关的通路。预测的功能获得性变异和功能丧失性变异均对早发性结直肠癌风险有贡献，支持了结直肠癌发病机制的异质性。 结论：本研究鉴定出早发性结直肠癌的新候选风险基因，强调了罕见变异的作用，并拓展了我们对结直肠癌遗传结构的理解。未来的研究应包括功能验证和其他血统人群的重复研究，以确认和扩展这些结果。
肿瘤(癌症)患者之家