Report T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers

Patients with short telomere syndromes (STS) are predisposed to developing cancer, believed to stem from chromosome instability in neoplastic cells. We tested this hypothesis in a large cohort assembled over the last 20 years. We found that the only solid cancers to which patients with STS are predisposed are squamous cell carcinomas of the head and neck, anus, or skin, a spectrum reminiscent of cancers seen in patients with immunodeficiency. Whole-genome sequencing showed no increase in chromosome instability, such as translocations or chromothripsis. Moreover, STS-associated cancers acquired telomere maintenance mech-anisms, including telomerase reverse transcriptase (TERT) promoter mutations. A detailed study of the im-mune status of patients with STS revealed a striking T cell immunodeficiency at the time of cancer diagnosis. A similar immunodeficiency that impaired tumor surveillance was documented in mice with short telomeres. We conclude that STS patients' predisposition to solid cancers is due to T cell exhaustion rather than auton-omous defects in the neoplastic cells themselves.

Automated summary

Patients with short telomere syndromes (STS) have a predisposition to certain types of solid cancers, specifically squamous cell carcinomas of the head and neck, anus, or skin. This predisposition is not due to increased chromosome instability but rather acquisition of telomere maintenance mechanisms and T cell immunodeficiency. The findings suggest that the susceptibility to solid cancers in STS patients is driven by T cell exhaustion.