School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Urology Institute of Shenzhen University, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, China.
Cell Genom. 2024 Aug 14;4(8):100627. doi: 10.1016/j.xgen.2024.100627. Epub 2024 Aug 2.
Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.
切除修复交叉互补基因 2（ERCC2）编码 DNA 解旋酶 Xeroderma Pigmentosum 组 D，其在转录和核苷酸切除修复中发挥作用。ERCC2 中的点突变是约 10%膀胱癌（BLCAs）的潜在驱动因素，也是顺铂治疗反应的潜在阳性生物标志物。然而，直接归因于 ERCC2 突变的预后意义及其在基因组不稳定性中的致病作用仍知之甚少。我们首先证明，突变型 ERCC2 是 BLCA 预后的独立预测因子。然后，我们使用 ERCC2 野生型（n=343）和突变型（n=39）BLCA 全基因组队列检查了其对体细胞突变景观的影响。ERCC2 突变体中体细胞突变的全基因组分布明显改变，包括 T[C>T]N 富集、复制时间相关性改变和 CTCF-黏合素结合位点突变热点。我们利用这些改变来开发一种用于预测致病性 ERCC2 突变的机器学习模型，这可能有助于为 BLCA 患者的治疗提供信息。
