Nasopharyngeal carcinoma (NPC) is an endemic disease prevalent in East Asia and germline variants that confer risk for NPC have previously been identified. However, NPC patients have contrasting phenotypes at presentation that are associated with disparate risks of relapse. We hypothesize that there exist germline variants that are associated with poorer NPC disease trajectories. We performed whole exome sequencing (100x; Illumina NovaSeq) on a cohort of 795 NPC patients and probed the germline genomic landscape in a predominantly Chinese population (N=723; 90.9%). We performed univariable and multivariable - adjusting for known prognostic clinical parameters - Cox regression analyses to discover germline variants that were associated with disease-free survival (DFS). We performed joint genotyping of germline variants following GATK's best practices workflow. We next filtered out common (≥5% allele frequency in East Asian population, or ≥1% in others) and benign variants, retaining only variants classified as pathogenic (P)/likely pathogenic (LP)/variant of unknown significance (VUS) in ClinVar or are predicted to be pathogenic by Combined Annotation Dependent Depletion or Rare Exome Variant Ensemble Learner. For improved statistical power, statistical analyses (uni- and multi-variable Cox regression) were conducted at the gene level, so that contributions across all variants were aggregated for each gene. To reduce false discovery, we focused our analysis only on genes of interest: hallmark-of-cancer genes (COSMIC gene census), DNA damage and mismatch repair genes, as well as genes known to be associated with NPC risk. Genes with variants in fewer than 20 unique patients were also excluded from analysis. We observed germline variants in hallmark-of-cancer genes (FAT1 [N=133; 16.7%] and NOTCH1 [N=39; 4.9%]) and DNA repair genes (SRSF6 [N=32; 4.0%] and POLD1 [N=32; 4.0%]). Additionally, 230 (28.9%) and 180 (22.6%) patients had at least one P/LP/VUS variants in HLA-A and HLA-DRB1, consistent with known literature that variants in HLA genes confer increased NPC risk. Likewise, we observed variants in genes associated with NPC risk such as KMT2C (N=207; 26.0%), SYNE1 (N=151; 19.0%), ARID1A (N=52; 6.5%) and MST1R (N=34; 4.3%). Univariable tests of association identified variants in MMP19 (HR 2.24 with 95% confidence interval [1.30-3.87], P=0.004), MST1R (HR 2.01 [1.14-3.54], P=0.016), TGFBR2 (HR 1.85 [1.09-3.14], P=0.023), NEIL3 (HR 2.08 [1.09-3.94], P=0.025), ETV6 (HR 2.13 [1.09-4.16], P=0.028), FANCD2 (HR 2.11 [1.09-4.13], P=0.030), DDX6 (HD 2.26 [1.06-4.82], P=0.035) POLD1 (HR 1.91 [1.04-3.53], P=0.038) and RECQL4 (HR 1.92 [1.04-3.54], P=0.037) that were significantly associated with inferior DFS. Among them, MMP19, TGFBR2, FANCD2 and RECQL4 remained significant in a clinico-molecular multivariable model that comprised of age, sex, cTN-categories, EBV DNA titer and treatment (C-index = 0.71).
Citation Format: Adelene Y.L. Sim, Enya H.w. Ong, Luo Huang, Kar Perng Low, Dewi Susanti, Terence W.k. Tan, Kam Weng Fong, Yoke Lim Soong, Gek San Tan, Tony K.H. Lim, Joseph T.s. Wee, Darren W.t. Lim, N. Gopalakrishna Iyer, Jacqueline S.G. Hwang, Mohamed E. Abazeed, Jin-Xin Bei, Melvin L.k. Chua. Germline variants associated with poorer disease prognosis in nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2258.