端粒
癌症
内科学
医学
端粒酶
肿瘤科
髓系白血病
细胞减少
三体8
先天性角化不良
种系突变
骨髓
免疫学
突变
生物
遗传学
细胞遗传学
染色体
DNA
基因
作者
Kristen E. Schratz,Lisa Haley,Sonye K. Danoff,Amanda L. Blackford,Amy E. DeZern,Christopher D. Gocke,Amy S. Duffield,Mary Armanios
出处
期刊:Blood
[American Society of Hematology]
日期:2020-05-28
卷期号:135 (22): 1946-1956
被引量:80
标识
DOI:10.1182/blood.2019003264
摘要
Abstract 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.
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