Clinical Outcome–Related Mutational Signatures Identified by Integrative Genomic Analysis in Nasopharyngeal Carcinoma
- 15 December 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 26 (24), 6494-6504
- https://doi.org/10.1158/1078-0432.ccr-20-2854
Abstract
Purpose: Investigation of biological mechanisms underlying genetic alterations in cancer can assist the understanding of etiology and identify the potential prognostic biomarkers. Experimental design: We performed an integrative genomic analysis for a total of 731 NPC cases from five independent NPC 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 appears more frequently in the recurrent and metastatic tumors and significantly correlated with shorter overall survival in the primary tumors. Independent prognostic value of MMR and BRCAness signatures were revealed by multivariable Cox analysis after adjustment for clinical parameters and stratification by studies. The cases with both signatures have 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 NPC cohort (N=402) show that the cases carrying BRCA2 germline rare variants are more likely to have poor overall survival and progression-free survival. Conclusions: Our study highlights importance of defects of DNA repair machinery in NPC 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 NPC.Keywords
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Funding Information
- SRA (SRP035573, SRA288429)
- NHGRI (phs001244.v1.p1)
- Hong Kong Research (AoE/M-06/08)
- General Research Fund (17103218)
- University of Hong Kong (201611159158)
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