Cancer spectrum and outcomes in the Mendelian short telomere syndromes.

Short telomeres have been linked to cancer risk, yet other evidence supports they are tumor suppressive. Here, we report cancer outcomes in individuals with germline mutations in telomerase and other telomere maintenance genes. Among 180 individuals evaluated in a hospital-based setting, 12.8% had cancer. Solid tumors were rare (2.8%); nearly all were young male DKC1 mutation carriers, and they were generally resectable with good outcomes. Myelodysplastic syndrome (MDS) was most common, followed by acute myeloid leukemia (AML); they accounted for 75% of cancers. Age over 50 was the biggest risk factor, and MDS/AML manifested usually with marrow hypoplasia, monosomy 7, but the somatic mutation landscape was indistinct from unselected patients. One- and two-year survival were 61% and 39%, respectively, and two-thirds of MDS/AML patients died from pulmonary fibrosis and/or hepatopulmonary syndrome. In half the cases, MDS/AML patients showed a recurrent peripheral blood pattern of acquired, granulocyte-specific telomere shortening. This attrition was absent in age-matched mutation carriers who did not have MDS/AML. We tested if adult short telomere patients without MDS/AML also had evidence of clonal hematopoiesis of indeterminate potential (CHIP)-related mutations and found 30% were affected. These patients also primarily suffered morbidity from pulmonary fibrosis during followup. Our data show the Mendelian short telomere syndromes are associated with a relatively narrow cancer spectrum, primarily MDS and AML. They suggest short telomere length is sufficient to drive premature age-related clonal hematopoiesis in these inherited disorders.