Jayne A Barbour, Tong Ou, Haocheng Yang, Hu Fang, Noel C Yue, Xiaoqiang Zhu, Michelle W Wong-Brown, Yuen T Wong, Nikola A Bowden, Song Wu, Jason W H Wong
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引用次数: 0
摘要
切除修复交叉互补组 2(ERCC2)编码 DNA 螺旋酶色素沉着病 D 组,它在转录和核苷酸切除修复中发挥作用。ERCC2的点突变是约10%的膀胱癌(BLCA)的潜在诱因,也是顺铂治疗反应的潜在阳性生物标志物。然而,人们对ERCC2突变直接导致的预后意义及其在基因组不稳定性中的致病作用仍然知之甚少。我们首先证明了突变的ERCC2是BLCA预后的独立预测因子。然后,我们利用一组ERCC2野生型(n = 343)和突变型(n = 39)的BLCA全基因组研究了它对体细胞突变景观的影响。在ERCC2突变体中,体细胞突变的全基因组分布发生了显著改变,包括T[C>T]N富集、复制时间相关性改变以及CTCF-粘连素结合位点突变热点。我们利用这些改变开发了一种预测致病性 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。
ERCC2 mutations alter the genomic distribution pattern of somatic mutations and are independently prognostic in bladder cancer.
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.