Solid malignancies in telomere biology disorders

Telomere biology disorders (TBDs) are caused by pathogenic germline variants in genes essential for telomere maintenance and function, including at least 17 different genes with X-linked recessive (XLR), autosomal dominant (AD) and/or autosomal recessive (AR) inheritance as well as de novo occurrence. Individuals with TBDs have short and/or dysfunctional telomeres and high rates of bone marrow failure, pulmonary fibrosis, liver disease, certain immunodeficiencies, and many other problems. TBDs are cancer predisposition syndromes with an approximately 3-fold increased risk of any cancer and an overall cancer-free survival in the mid-40s. Head/neck squamous cell carcinoma (HNSCC), the most common TBD-associated solid malignancy, is notable for a 43-fold increased risk in AD TBDs and 276-fold in AR/XLR disease compared with the general population. The limited data on cancer treatment in TBDs suggests poor tolerance of standard chemotherapy and radiation regimens and dismal outcomes. Cancer surveillance modalities have not been prospectively studied in TBDs and are currently based on expert opinion. The mechanisms by which cancer develops in TBDs are proposed to include chromosomal instability and DNA damage accumulation due to abnormal telomere function and an underlying T cell immunodeficiency with suboptimal immune surveillance. Clonal hematopoiesis (CH) is relatively common in TBDs, including reversion or compensation of the germline variant and recurrent clonal hematopoiesis mutations modulating the TP53 pathway associated with cancer development. This review highlights recent advances in understanding solid malignancies in TBDs and underscores the urgent need for prospective studies to develop the evidence base for cancer surveillance and treatment in these complex disorders.