Clinical Outcome-Related Mutational Signatures Identified by Integrative Genomic Analysis in Nasopharyngeal Carcinoma
Clinical Outcome-Related Mutational Signatures Identified by Integrative Genomic Analysis in Nasopharyngeal Carcinoma
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DOI：
10.1158/1078-0432.ccr-20-2854
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发表时间：
2020-12-15
影响因子：
11.5
通讯作者：
Lung, Maria Li
中科院分区：
文献类型：
--
作者：
Dai, Wei;Chung, Dittman Lai-Shun;Lung, Maria Li
目的 研究癌症遗传改变背后的生物学机制有助于了解病因并确定潜在的预后生物标志物。实验设计：我们对来自五个独立鼻咽癌队列的总共 731 例鼻咽癌病例进行了综合基因组分析，以确定与临床结果相关的遗传事件。结果：除了与衰老、APOBEC 和错配修复 (MMR) 相关的已知突变特征之外，还发现了与衰老、APOBEC 和错配修复 (MMR) 相关的已知突变特征。在发现组（包括三个队列）的 216 例病例中，有 64 例 (29.6%) 发现同源重组缺陷 (BRCAness)。该特征在复发性和转移性肿瘤中更频繁地出现，并且与原发性肿瘤中较短的总生存期（OS）显着相关。在调整临床参数和研究分层后，多变量 Cox 分析揭示了 MMR 和 BRCAness 特征的独立预后价值。具有这两种特征的病例的临床结果比没有这些特征的病例差得多（风险比 (HR)，12.4；P = 0.002]。这种相关性在验证集中得到了证实（HR，8.9；P = 0.003）。BRCAness 特征与 BRCA2 致病性种系或体细胞改变高度相关（7.8% vs. 0%；P = 0.002）。来自前瞻性的靶向测序结果鼻咽癌队列 (N = 402) 显示，携带 BRCA2 种系罕见变异的病例更有可能具有较差的 OS 和无进展生存率。 结论：我们的研究强调了 DNA 修复机制缺陷在鼻咽癌发病机制中的重要性及其对临床意义的预后价值。这些特征将有助于患者分层，以评估鼻咽癌的传统和新的精准医学治疗方法。
Purpose Investigation of biological mechanisms underlying genetic alterations in cancer can assist the understanding of etiology and identify the potential prognostic biomarkcrs.Experimental Design: We performed an integrative genomic analysis for a total of 731 nasopharyngeal carcinoma cases from five independent nasopharyngeal carcinoma cohorts to identify the genetic events associated with clinical outcomes.Results: In addition to the known mutational signatures associated with aging, APOBEC and mismatch repair (MMR), a new signature for homologous recombination deficiency (BRCAness) was discovered in 64 of 216 (29.6%) cases in the discovery set including three cohorts. This signature appeared more frequently in the recurrent and metastatic tumors and significantly correlated with shorter overall survival (OS) in the primary tumors. Independent prognostic value of MMR and BRCAness signatures was revealed by multivariable Cox analysis after adjustment for clinical parameters and stratification by studies. The cases with both signatures had much worse clinical outcome than those without these signatures (hazard ratio (HR), 12.4; P = 0.002]. This correlation was confirmed in the validation set (HR, 8.9; P =0.003). The BRCAness signature is highly associated with BRCA2 pathogenic germline or somatic alterations (7.8% vs. 0%; P = 0.002). Targeted sequencing results from a prospective nasopharyngeal carcinoma cohort (N = 402) showed that the cases carrying BRCA2 germ line rare variants are more likely to have poor OS and progression-free survival.Conclusions: Our study highlights importance of defects of DNA repair machinery in nasopharyngeal carcinoma pathogenesis and their prognostic values for clinical implications. These signatures will be useful for patient stratification to evaluate conventional and new treatment for precision medicine in nasopharyngeal carcinoma.