GWAS-identified telomere length associated genetic variants predict risk of recurrence of HPV-positive oropharyngeal cancer after definitive radiotherapy

Background: Lymphocyte telomere length (LTL)-related genetic variants may modulate LTL and affect recurrence of squamous cell carcinoma of the oropharynx (SCCOP). Methods: A total of 1013 patients with incident SCCOP were recruited and genotyped for 16 genome-wide association study (GWAS)-identified TL-related polymorphisms. Of these patients, 489 had tumour HPV16 status determination. Univariate and multivariate analyses were performed to evaluate associations. Findings: Of the 16 TL-related polymorphisms, four were significantly associated with LTL: rs1920116, rs3027234, rs6772228, and rs11125529, and the patients with putatively favourable genotypes had approximately 1.5–3 times the likelihood of shorter LTL compared with patients with the corresponding risk genotypes. Moreover, patients with one to four favourable genotypes of the four combined polymorphisms had approximately 3–11 times the likelihood of shorter LTL compared with patients with no favourable genotype. The four LTL-related polymorphisms were significantly associated with approximately 40% reduced risk (for favourable genotypes) or doubled risk (for risk genotypes) of recurrence, and similar but more pronounced associations were observed in patients with tumour HPV16-positive SCCOP. Similarly, patients with one to four risk genotypes had significantly approximately 2.5–4 times increased recurrence risk compared with patients with no risk genotype, and similar but more pronounced associations were observed in patients with tumour HPV16-positive SCCOP. Interpretation: Four LTL-related polymorphisms individually or jointly modify LTL and risk of recurrence of SCCOP, particularly HPV-positive SCCOP. These LTL-related polymorphisms could have potential to further stratify patients with HPV-positive SCCOP for individualized treatment and better survival. Funding: Not applicable.