Abstract 2293: <i>KLRC2</i> gene deletion is associated with active cytomegalovirus infection and risk of head and neck cancer

Abstract Human cytomegalovirus (CMV) is a common infection that can have a profound impact on the immune system which, in turn, has the potential to impact cancer risk. Natural Killer (NK) cells are the front-line defense against viral infection and CMV seropositive individuals develop a specialized subset of NK cells, the adaptive NK (aNK), in response to CMV reactivation. A defining feature of aNK is surface expression of the NKG2C receptor, encoded by the KLRC2 gene. There is a polymorphic 15.5 kb deletion of the KLRC2 gene and approximately 5% of the Caucasian population completely lacks the NKG2C receptor due to this polymorphism. KLRC2 gene copy number has been shown to influence steady-state levels of aNK cells in CMV seropositive individuals, and deletion of the gene is associated with both early life CMV infection and CMV viremia after transplantation. Here, we have evaluated whether the polymorphic KLRC2 gene deletion is associated with active CMV infection and risk of head and neck squamous cell carcinoma (HNSCC) using the resources of the CoHANDS epidemiology study. KLRC2 deletion was measured using PCR with gel visualization in 1, 096 cases and 1, 179 controls. Among a subset of the controls (n=207) we measured CMV DNAemia, the presence of cell free CMV DNA in serum, which is an established biomarker of active CMV infection. KLRC2 deletion was associated with the presence of CMV DNAemia: among those with one copy of KLRC2 the risk of active infection was 2.74 (95% CI 1.30 - 5.78), and among those with homozygous deletion of KLRC2 the risk was 5.17 (95% CI 1.56 - 17.16). These results from a healthy population are consistent with prior reports that the KLRC2 gene is important in the control of CMV reactivation. We then evaluated KLRC2 as a risk factor for HNSCC. Homozygous deletion of the KLRC2 gene was strongly associated with increased risk of HNSCC after adjusting for age and sex (OR 3.99; 95% CI 2.62 - 6.10). Collectively, these data support the hypothesis that active CMV infection may be a risk factor for HNSCC. Citation Format: Heather H. Nelson, DeVon Hunter-Schlichting, Rondi Butler, Anna Prizment, Bharat Thyagarajan, Karl Kelsey. KLRC2 gene deletion is associated with active cytomegalovirus infection and risk of head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2293.