LA-NPC can be subtyped by ascending (A; T3-4N0-1), descending (D; T1-2N2-3) and ascending-descending (AD; T3-4N2-3) at diagnosis, depending on the extent of tumor spread. These phenotypes differ by prognoses, but germline and somatic molecular drivers underpinning their tumorigenesis are unknown. We aimed to validate the A and AD subtypes of LA-NPC and investigate for germline variants that are associated with them.
We utilized a cohort of 255 patients with biopsy-proven, non-metastatic, T3-4 NPC (AJCC/UICC 8th edition). Association of clinical covariates were tested by Cox regression. Germline profiling was conducted by whole exome sequencing (100x; Illumina NovaSeq) and variants were shortlisted based on known/predicted pathogenicity. The differential prevalence of variants was tested using Fisher’s exact test.
Median follow-up duration of the cohort was 79 (IQR: 66-90) mo; median age was 49.4 (43.2-58.1) y. We identified 108 (42.3%) A- and 147 (57.6%) AD-subtype in our cohort. 55 (50.9%) and 35 (32.4%) of the A-subtype patients compared to 64 (43.5%) and 75 (51.0%) in the AD-subgroup received chemoradiotherapy (CRT) alone and CRT+induction/adjuvant chemotherapy, respectively. High EBV DNA titer of >4000 copies were more frequent in the AD- than A-subgroup (50.0% vs 31.2%, P = 0.0141). 5-y DFS differed between the A and AD subtypes (85.1% [95% CI: 78.2-92.7] vs 67.0% [59.2-75.8%], P <0.001); the AD-subtype was significantly associated with worse DFS (HR 3.10 [1.54-6.23], P = 0.00147) after adjustment for age, EBV DNA and T4-status. Next, we observed germline variants in hallmark-of-cancer genes (FAT1 [N=46; 18.0%] and NOTCH1 [N=13; 5.1%]), DNA repair genes (SRSF6 [N=13; 5.1%] and POLD1 [N=14; 5.5%]) and genes with known association to NPC (MST1R [N=13; 5.1%] and SYNE1[N=50; 19.6%]). Of them, TGFBR2 variants were significantly associated with the unfavorable AD-subtype (OR 3.68 [1.06-15.3], P = 0.041).
We have shown that the AD-subtype in patients with LA-NPC is associated with an inferior DFS. The TGFBR2germline variants may be associated with the susceptibility of this unfavorable phenotype.
Clinical trial identification
CIRB Ref. No.: 2019/2177.
Legal entity responsible for the study
National Medical Research Council.
All authors have declared no conflicts of interest.