Background: This study aimed to identify new genes associated with CRC in patients with normal mismatch repair (MMR) protein expression. Method: Whole-genome sequencing (WGS) was performed in seven early-age-onset Malay CRC patients. Potential germline genetic variants, including single-nucleotide variations and insertions and deletions (indels), were prioritized using functional and predictive algorithms. Results: An average of 3.2 million single-nucleotide variations (SNVs) and over 800 indels were identified. Three potential candidate variants in three genes—IFNE, PTCH2 and SEMA3D—which were predicted to affect protein function, were identified in three Malay CRC patients. In addition, 19 candidate genes—ANKDD1B, CENPM, CLDN5, MAGEB16, MAP3K14, MOB3C, MS4A12, MUC19, OR2L8, OR51Q1, OR51AR1, PDE4DIP, PKD1L3, PRIM2, PRM3, SEC22B, TPTE, USP29 and ZNF117—harbouring nonsense variants were prioritised. These genes are suggested to play a role in cancer predisposition and to be associated with cancer risk. Pathway enrichment analysis indicated significant enrichment in the olfactory signalling pathway. Conclusion: This study provides a new spectrum of insights into the potential genes, variants and pathways associated with CRC in Malay patients.

中文翻译：

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具有完整 MMR 蛋白的马来结直肠癌患者的全基因组谱

背景：本研究旨在在错配修复 (MMR) 蛋白表达正常的患者中鉴定与 CRC 相关的新基因。方法：对 7 名早发性马来 CRC 患者进行全基因组测序 (WGS)。使用功能和预测算法优先考虑潜在的种系遗传变异，包括单核苷酸变异和插入和缺失（插入缺失）。结果：平均识别出 320 万个单核苷酸变异 (SNV) 和 800 多个插入缺失。在三名马来 CRC 患者中发现了三种基因中的三种潜在候选变体——IFNE、PTCH2和SEMA3D——它们被预测会影响蛋白质功能。此外，19个候选基因——ANKDD1B、CENPM、CLDN5、MAGEB16、MAP3K14、MOB3C、MS4A12、MUC19、OR2L8、OR51Q1、OR51AR1、PDE4DIP、PKD1L3、PRIM2、PRM3、SEC22B、TPTE、USP29和ZNF117——包含无意义的变体被优先考虑。这些基因被认为在癌症易感性中发挥作用并与癌症风险相关。通路富集分析表明嗅觉信号通路显着富集。结论：这项研究为马来人患者与 CRC 相关的潜在基因、变异和通路提供了新的见解。