Variants at an HLA and an IL Locus Are Associated with NKTCL

Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is known to predominantly affect people of Asian or Latin American descent and has been linked to infection with Epstein-Barr virus (EBV); however, EBV infection is very common in adults, and the genetic basis for the disparity in prevalence among populations is not well established. In one genome-wide association study (GWAS), common variants of HLA-DPB1 were found to be associated with an increased NKTCL risk. In a larger GWAS by the same group involving patients and matched control participants from multiple East Asian populations, Lin, Xu, Chen, Huang, Chen, Song, Chan, Li, and colleagues identified two previously unknown susceptibility loci: IL18RAP and HLA-DRB1. Participants homozygous for all three now-identified risk variants had the greatest risk (18- to 51-fold higher) of developing NKTCL. The fact that both HLA-DPB1 and HLA-DRB1 have now been pinpointed as risk loci for NKTCL implicates the class II histone leukocyte antigen (HLA) in the etiology of NKTCL. Interestingly, IL18RAP, encoding IL18 receptor accessory protein, represents the first known risk locus for NKTCL outside the HLA region. In two NKTCL cell lines, IL18RAP knockdown substantially decreased cell growth and appeared to cause cell-cycle arrest at the G₀–G₁ and G₂–M transitions, suggesting that IL18RAP may mediate proliferation through effects on cell-cycle progression. Although the larger GWAS performed in this study had sufficient statistical power to identify variants with moderate or greater effect sizes, the work has some limitations; specifically, in vivo evidence would add weight to these findings, as would a more detailed molecular characterization of the mechanisms at play in NKTCL pathogenesis potentially driven by these variants. Further, a larger study would be needed to identify risk variants with smaller effect sizes, and research on participants from other populations (e.g., those of European or African descent) is needed. In summary, this study identifies two new susceptibility loci for NKTCL and provides hints about how variants at these loci may promote disease.

Lin GW, Xu C, Chen K, Huang HQ, Chen J, Song B, et al. Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations. Lancet Oncol 2019 Dec 23 [Epub ahead of print].

• ©2020 American Association for Cancer Research.