Genotype and Associated Cancer Risk in Individuals With Telomere Biology Disorders
Authors: Niewisch Marena R. , Kim Jung , Giri Neelam , Lunger Judith C. , McReynolds Lisa J. , Savage Sharon A. 
Published: December 2024

ImportanceTelomere biology disorders (TBDs) are inherited cancer-prone bone marrow failure syndromes with differences in morbidity and mortality based on mode of inheritance.ObjectiveTo quantify cancer risks in TBDs by genetic subgroups.Design, Setting, and ParticipantsThis 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.ExposuresThe 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 MeasuresThe 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.ResultsAmong 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 RelevanceThis 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.