The distribution of telomere length in humans is broad, but it has finite upper and lower boundaries. Growing evidence shows that there are disease processes that are caused by both short and long telomere length extremes. The genetic basis of these short and long telomere syndromes may be linked to mutations in the same genes, such as the telomerase reverse transcriptase (TERT), but through differential effects on telomere length. Short telomere syndromes have a predominant degenerative phenotype marked by organ failure that most commonly manifests as pulmonary fibrosis and are associated with a relatively low cancer incidence. In contrast, insights from studies of cancer-prone families as well as genome-wide association studies (GWAS) have identified both rare and common variants that lengthen telomeres as being strongly associated with cancer risk. We have hypothesized that these cancers represent a long telomere syndrome that is associated with a high penetrance of cutaneous melanoma and chronic lymphocytic leukemia. In this Review, we will synthesize the clinical and human genetic observations with data from mouse models to define the role of telomeres in cancer etiology and biology.
Emily J. McNally, Paz J. Luncsford, Mary Armanios
Submitter: Sharon Savage | firstname.lastname@example.org
Authors: Sharon Savage, Neelam Giri, Alison A. Bertuch, Suneet Agarwal, and Blanche P. Alter
Division of Cancer Epidemiology and Genetics, National Cancer Institute
Published November 1, 2019
McNally and colleagues assert that “cancer is relatively rare in short telomere syndromes” and state a “… low cancer incidence…” in such patients. They base this on data showing that 10% of patients with dyskeratosis congenita (DC), a disorder characterized by very short telomeres, develop cancer whereas 90% of Li-Fraumeni syndrome patients develop cancer. These statements are incorrect and warrant clarification.
Cancer has been a well-recognized part of the DC phenotype for more than 80 years. Three of the first reported cases developed oral or skin squamous cell carcinoma (SCC)(1-4). The UK’s DC Registry reported cancer in nearly 9% of index DC cases (5, 6).
However, simply comparing percentages of patients with cancer results in a significant underestimate of risk because they do not account for age, sex, birth cohort, competing risks of adverse events (i.e., pulmonary fibrosis, cirrhosis, or hepatopulmonary syndrome), or provide risk comparisons with the general population.
The National Cancer Institute’s (NCI’s) longitudinal cohort is the first epidemiologic study of DC/TBDs and quantified cancer incidence and risk (7-9). In 2018, the 15-year follow-up reported a 4.2-fold increased risk of cancer in DC compared with the general population (9). For DC patients who have not undergone HCT, the cumulative incidence of any solid cancer is 40% by age 65 years, 10 % for leukemia by age 70, and 40% for myelodysplastic syndrome (MDS) by that age. The solid tumor risk in DC after HCT increases to approximately 60% by 20 years of age.
Head and neck SCC is most common solid cancer in non-HCT patients with DC, occurring in 11 of 197 cases (median age 38 years, range 18-61) (9). MDS was reported in 18 of 197 patients (median age 31 years, range 4-73). These data are not consistent the statement of McNally et al: “The short telomere cancer spectrum is also restricted to mostly hematologic cancers...”
Fifteen of 20 patients with DC and cancer in the 2018 report had pathogenic germline variants in DKC1, TERT, TERC, TINF2, or WRAP53 (9), in notable contrast with the statement “Two of these genes are also mutated in cancer-prone families” (page 3475).
DC/TBDs are cancer predisposition syndromes with cancer onset at much younger ages than the general population. Clarification of these data in the Review are essential in order for patients and providers to understand risks and facilitate early detection and management (10).
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