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Clinical Outcome-Related Mutational Signatures Identified by Integrative Author Manuscript Published OnlineFirst on September 28, 2020; DOI: 10.1158/1078-0432.CCR-20-2854 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Clinical Outcome-Related Mutational Signatures Identified by Integrative Genomic Analysis in Nasopharyngeal Carcinoma Wei Dai1,2*, Dittman Lai-Shun Chung1, Larry Ka-Yue Chow1, Valen Zhuoyou Yu1, Lisa Chan Lei1, Merrin Man-Long Leong1, Candy King-Chi Chan1, Josephine Mun-Yee Ko1, Maria Li Lung1* 1Department of Clinical Oncology, University of Hong Kong, Hong Kong (SAR), P. R. China 2University of Hong Kong-Shenzhen Hospital, Shenzhen, P. R. China Running title: Clinical Outcome-Related Mutational Signatures in NPC *Co-corresponding authors: Maria Li Lung, Wei Dai MLL Address: Department of Clinical Oncology, The University of Hong Kong, Room L6- 43, 6/F, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong Email: [email protected] Tel: (852) 3917 9783 Fax: (852) 2816 6279 WD Address: Department of Clinical Oncology, The University of Hong Kong, Room L10- 56, 10/F, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong Email: [email protected] Tel: (852) 3917 6930 Fax: (852) 2816 6279 Conflict of interest The authors declare no potential conflicts of interest Translational relevance In NPC, general consensus for treatment is to use radiotherapy (RT) alone for stage I disease, RT with or without concurrent chemotherapy for stage II and chemoradiotherapy (CRT) for advanced stage disease. However, 15-58% of the cases do not respond well to conventional treatment, and, thus, have poor clinical outcomes. There is a need for biomarkers to assist our understanding of the molecular basis of disease pathogenesis and progression and to aid clinical management in NPC. We have systematically examined the mutation signatures and evaluated their prognostic values in association with clinical outcome. The mutational signature relevant to homologous recombination deficiency (BRCAness) was discovered, which was unappreciated in NPC before. Importantly, independent prognostic values of the BRCAness signature and mismatch repair signature are now revealed. These data show the 1 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 28, 2020; DOI: 10.1158/1078-0432.CCR-20-2854 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. clinical importance of DNA repair pathways in NPC and their potential as prognostic and predictive biomarkers for future clinical studies. 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. 2 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 28, 2020; DOI: 10.1158/1078-0432.CCR-20-2854 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Nasopharyngeal carcinoma (NPC) is a complex disease involving Epstein-Barr virus (EBV) infection, genetic and environmental factors (1). To understand the molecular basis of NPC pathogenesis, we performed genomic studies characterizing the important genetic alterations using whole-exome sequencing (WES) in NPC tissues obtained from cases and xenografts (2,3). Together with the results from other NPC genomic studies, multiple critical genetic alterations including inactivating mutations of negative regulators in the NF-ĸB pathway, mutations in the PI3K/MAPK pathway, and epigenetic regulators were discovered (2,4,5). Mutational signatures are the footprints of mutational processes relevant to endogenous and exogenous factors contributing to tumorigenesis (6). Analysis of mutational signatures helps to decipher the etiology of NPC. Three mutational signatures relevant to aging caused by an endogenous mutational process initiated by spontaneous deamination of 5’-methylcytosine, defective DNA mismatch repair (MMR) and APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family of cytidine deaminases were reported in NPC (2,5). However, our understanding of the molecular basis of NPC is far from complete, as these individual studies typically only profiled between 50 to 110 cases. We interrogated genomic data and clinical information from four published NPC studies and one prospectively collected NPC cohort. By increasing the statistical power to distinguish the infrequent driver events from passengers, we aim to identify the additional genetic events driving tumorigenesis, gain insights in the mechanisms underlying genetic alterations and systematically evaluate their prognostic value. Materials & Methods Patient cohorts and clinical information In the discovery stage, we included Asian NPC patients from three cohorts. The first NPC cohort was obtained from the sequence read archive (SRA) database (accession #SRP035573) from Singapore (SG cohort) and includes 56 Singapore NPC cases (4). Our earlier WES Hong Kong study includes 59 NPC cases (accession #SRA288429) (2), together with twelve additional cases (accession #SRP265671) to make up the HK-1 cohort. The third NPC cohort (HK-2 cohort) includes 97 independent Hong Kong cases from dbGAP-NHGRI (accession #phs001244.v1.p1) (5). None of patients with primary NPC had radiotherapy or 3 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 28, 2020; DOI: 10.1158/1078-0432.CCR-20-2854 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. chemotherapy. In total, 178 primary tumors and 38 recurrent or metastatic NPC were included. The male to female ratio is 3.7. The independent validation cohort including 113 NPC patients was obtained from another genomic study by Sun Yat-Sen University Cancer Center (SYSUCC, Guangzhou, China) (7), and, thus, was named as the GZ cohort. To evaluate the prognostic value of BRCA2 germline pathogenic variants in association with clinical outcome, we examined a total of 420 NPC patients (HK-3) prospectively collected by the Area of Excellence of Hong Kong NPC Tissue Bank. After quality evaluation, 402 patients were included in the analysis for the HK-3 cohort. Following the REMARK recommendations (8), we include full details of clinical parameters in Table 1 and Supplementary Table S1 and their relationship to patient outcome in Tables 2 and 3. The study workflow is illustrated in Supplementary Figure S1. We included the Research Resource Identifiers (RRIDs) for the relevant tools and databases for the genomic analysis. Genomic data processing For the discovery cohort, raw sequencing reads were aligned to the human genome reference (hg19) using Burrows-Wheeler Aligner and were processed according to GATK Best Practices recommendations (version 3.8, RRID:SCR_001876) (9). To combine the samples from different platforms, only overlapping regions (~31Mb) captured from the WES kits for three cohorts were considered. A total of 216 NPC cases were analyzed after removing eight cases that did not pass quality evaluation. Median coverage for tumor tissues for HK-1, HK-2 and SG NPC cohorts is 80-fold, 100-fold and 79-fold, respectively. For the GZ cohort, the mutations were directly obtained from the previous study (7) as independent validation. Identification of germline and somatic single nucleotide variants (SNVs) and INDELs For the germline variants, to ensure the data quality, two levels of quality controls, both variant-based and genotype-based, were applied on called variants. At the variant level, single nucleotide
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