Immunogenetic Determinants of Susceptibility to Head and Neck Cancer in the Million Veteran Program Cohort

Yanhong Liu, Jennifer R. Kramer, Vlad C. Sandulache, Robert Yu, Guojun Li, Liang Chen, Zenab I. Yusuf, Yunling Shi, Saiju Pyarajan, Spyros Tsavachidis, Li Jiao, Michelle L. Mierzwa, Elizabeth Chiao, Yvonne M. Mowery, Andrew Shuman, Sanjay Shete, Andrew G. Sikora, Donna L. White

Research output: Contribution to journalArticlepeer-review


Increasing rates of human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) have largely offset declines in tobacco-associated head and neck squamous cell carcinoma (HNSCC) at non-OPC sites. Host immunity is an important modulator of HPV infection, persistence, and clearance, and also of immune evasion in both virally- and nonvirally-driven cancers. However, the association between collective known cancer-related immune gene variants and HNSCC susceptibility has not been fully characterized. Here, we conducted a genetic association study in the multiethnic Veterans Affairs Million Veteran Program cohort, evaluating 16,050 variants in 1,576 immune genes in 4,012 HNSCC cases (OPC = 1,823; non-OPC = 2,189) and 16,048 matched controls. Significant polymorphisms were further examined in a non-Hispanic white (NHW) validation cohort (OPC = 1,206; non-OPC = 955; controls = 4,507). For overall HNSCC susceptibility in NHWs, we discovered and validated a novel 9q31.1 SMC2 association and replicated the known 6p21.32 HLA-DQ-DR association. Six loci/genes for overall HNSCC susceptibility were selectively enriched in African-Americans (6p21.32 HLA-G, 9q21.33 GAS1, 11q12.2 CD6, 11q23.2 NCAM1/CD56, 17p13.1 CD68, 18q22.2 SOCS6); all 6 genes function in antigen-presenting regulation and T-cell activation. Two additional loci (10q26 DMBT1, 15q22.2 TPM1) were uncovered for non-OPC susceptibility, and three loci (11q24 CRTAM, 16q21 CDH5, 18q12.1 CDH2) were identified for HPV-positive OPC susceptibility. This study underscores the role of immune gene variants in modulating susceptibility for both HPV-driven and non-HPV-driven HNSCC. Additional large studies, particularly in racially diverse populations, are needed to further validate the associations and to help elucidate other potential immune factors and mechanisms that may underlie HNSCC risk. SIGNIFICANCE: Several inherited variations in immune system genes are significantly associated with susceptibility to head and neck cancer, which could help improve personalized cancer risk estimates.

Original languageEnglish
Pages (from-to)386-397
Number of pages12
JournalCancer Research
Issue number3
StatePublished - 3 Feb 2023
Externally publishedYes


Dive into the research topics of 'Immunogenetic Determinants of Susceptibility to Head and Neck Cancer in the Million Veteran Program Cohort'. Together they form a unique fingerprint.

Cite this