Abstract
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 patients with STS are only predisposed to squamous cell carcinoma 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 mechanisms, including telomerase reverse transcriptase (TERT) promoter mutations. A detailed study of the immune 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 autonomous defects in the neoplastic cells themselves.
Original language | English (US) |
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Pages (from-to) | 807-817.e6 |
Journal | Cancer cell |
Volume | 41 |
Issue number | 4 |
DOIs | |
State | Published - Apr 10 2023 |
Keywords
- T cell aging
- aging
- genome instability
- head and neck cancer
- immune aging
- pulmonary fibrosis
- senescence
- telomerase
ASJC Scopus subject areas
- Oncology
- Cancer Research