Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong (SAR), P. R. China.
University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, P. R. China.
Clin Cancer Res. 2020 Dec 15;26(24):6494-6504. doi: 10.1158/1078-0432.CCR-20-2854. Epub 2020 Sep 28.
Investigation of biological mechanisms underlying genetic alterations in cancer can assist the understanding of etiology and identify the potential prognostic biomarkers.
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.
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; = 0.002]. This correlation was confirmed in the validation set (HR, 8.9; = 0.003). The BRCAness signature is highly associated with pathogenic germline or somatic alterations (7.8% vs. 0%; = 0.002). Targeted sequencing results from a prospective nasopharyngeal carcinoma cohort ( = 402) showed that the cases carrying germline rare variants are more likely to have poor OS and progression-free survival.
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.
研究癌症中遗传改变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。
我们对来自五个独立鼻咽癌队列的 731 例鼻咽癌病例进行了综合基因组分析，以确定与临床结局相关的遗传事件。
除了与衰老、APOBEC 和错配修复（MMR）相关的已知突变特征外，在包括三个队列的 216 例发现组病例中的 64 例（29.6%）中发现了一种新的同源重组缺陷（BRCAness）特征。该特征在复发性和转移性肿瘤中更为常见，与原发肿瘤的总生存期（OS）显著相关。多变量 Cox 分析显示，在调整临床参数和按研究分层后，MMR 和 BRCAness 特征具有独立的预后价值。具有这两个特征的病例比没有这些特征的病例临床结局差得多[风险比（HR），12.4；P = 0.002]。这一相关性在验证组中得到了证实（HR，8.9；P = 0.003）。BRCAness 特征与致病性种系或体细胞改变高度相关（7.8%比 0%；P = 0.002）。前瞻性鼻咽癌队列（n = 402）的靶向测序结果显示，携带种系罕见变异的病例更有可能出现较差的 OS 和无进展生存期。
本研究强调了 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，以评估鼻咽癌精准医学中传统和新治疗方法的疗效。
