Cancer spectrum and outcomes in the Mendelian short telomere syndromes

• Published in: Blood 2020-05, Vol.135 (22), p.1946-1956
• Main Authors: Schratz, Kristen E., Haley, Lisa, Danoff, Sonye K., Blackford, Amanda L., DeZern, Amy E., Gocke, Christopher D., Duffield, Amy S., Armanios, Mary
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Cell Cycle Proteins - genetics; Child; Female; Germ-Line Mutation; Hematopoiesis - genetics; Humans; Leukemia, Myeloid, Acute - diagnosis; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - therapy; Male; Middle Aged; Myelodysplastic Syndromes - diagnosis; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - therapy; Myeloid Neoplasia; Neoplasms - diagnosis; Neoplasms - genetics; Neoplasms - therapy; Nuclear Proteins - genetics; Prognosis; Registries; Risk Factors; Syndrome; Telomere - genetics; Telomere Shortening - genetics; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2019003264

Short telomeres have been linked to cancer risk, yet other evidence supports them being 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 short-term outcomes. Myelodysplastic syndrome (MDS) was most common, followed by acute myeloid leukemia (AML); they accounted for 75% of cancers. Age over 50 years was the biggest risk factor, and MDS/AML usually manifested with marrow hypoplasia and monosomy 7, but the somatic mutation landscape was indistinct from unselected patients. One- and 2-year survival were 61% and 39%, respectively, and two-thirds of MDS/AML patients died of pulmonary fibrosis and/or hepatopulmonary syndrome. In one-half of 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 whether adult short telomere patients without MDS/AML also had evidence of clonal hematopoiesis of indeterminate potential–related mutations and found that 30% were affected. These patients also primarily suffered morbidity from pulmonary fibrosis during follow-up. Our data show that the Mendelian short telomere syndromes are associated with a relatively narrow cancer spectrum, primarily MDS and AML. They suggest that short telomere length is sufficient to drive premature age-related clonal hematopoiesis in these inherited disorders. •MDS/AML are the most common short telomere malignancies; their natural history is complicated by extra-hematopoietic disease.•Adults with short telomeres who have no MDS/AML have premature age-related clonal hematopoiesis. [Display omitted]