Genotype and Associated Cancer Risk in Individuals With Telomere Biology Disorders

Importance: Telomere biology disorders (TBDs) are inherited cancer-prone bone marrow failure syndromes with differences in morbidity and mortality based on mode of inheritance. Objective: To quantify cancer risks in TBDs by genetic subgroups. Design, Setting, and Participants: This longitudinal cohort study of TBDs assessed cancer occurrences from 2002 through 2022. Participants were individuals with a TBD-associated pathogenic germline variant recruited across institutions by self-referral. Data were collected and analyzed through June 30, 2022. Exposures: The exposure was TBD genotypes, with subgroups defined by inheritance pattern (autosomal-dominant AD-non-TINF2 vs autosomal-recessive/X-linked AR/XLR vs AD-TINF2). Main Outcomes and Measures: The main outcome was cancer; secondary outcomes included death, or organ transplant. Cumulative cancer incidence was determined considering death or transplant as competing events. Observed:expected (O:E) ratios of cancer before and after any organ transplant were calculated using the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Results: Among 230 individuals with TBD (135 58.7% male; median range age at last follow-up, 34.6 1.4-82.2 years) included, the risk of cancer was 3-fold higher than the general population (O:E, 3.35 95% CI, 2.32-4.68). The highest risk was observed in individuals with AR/XLR (O:E, 19.16 95% CI, 9.19-35.24) with a significantly younger cancer onset than in individuals with AD-non-TINF2 (median range age, 36.7 25.2-53.6 years vs 44.5 32.2-67.5 years; P = .01). The risk of solid tumors was highest in individuals with AR/XLR (O:E = 23.97 95% CI, 10.96-45.50), predominantly head and neck squamous cell carcinomas (O:E, 276.00 95% CI, 75.20-706.67). Hematologic malignant neoplasm risk was highest in individuals with AD-non-TINF2 (O:E, 9.41 95% CI, 4.30-17.86). Solid tumor cumulative incidence increased to 12% for individuals with AR/XLR by age 45 years and to 13% for individuals with AD-non-TINF2 by age 70 years. The cumulative incidence of hematologic malignant neoplasms leveled off at 2% by age 30 years and 19% by age 70 years in individuals with AR/XLR and AD-non-TINF2, respectively. Individuals with AD-TINF2 showed the highest cumulative incidence for transplant or death (49% by age 15 years). Following transplant, individuals with AR/XLR (O:E, 136.11 95% CI, 54.72-280.44) or AD-TINF2 (O:E, 81.07 [95% CI, 16.72-236.92) had the highest cancer risk, predominantly young-onset head and neck squamous cell carcinomas (median range age, 32.2 10.5-35.5 years). Conclusions and Relevance: This cohort study of individuals with TBDs found an increased cancer risk compared with the general population, with the earliest age at onset for individuals with AR/XLR inheritance. Cancer risks increased after organ transplant across all subgroups. These differences in TBD-associated cancer risks by mode of inheritance suggest cancer screening could be tailored by genotype, but additional research is warranted.