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.

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孟德尔短端粒综合征的癌症谱和结果

短端粒与癌症风险有关，但其他证据支持它们具有肿瘤抑制作用。在这里，我们报告了在端粒酶和其他端粒维持基因中有种系突变的个体的癌症结果。在医院环境中评估的 180 人中，12.8% 患有癌症。实体瘤罕见（2.8%）；几乎所有人都是年轻的男性 DKC1 突变携带者，他们通常可以切除并获得良好的结果。骨髓增生异常综合征（MDS）最常见，其次是急性髓系白血病（AML）；它们占癌症的75%。年龄超过 50 岁是最大的危险因素，MDS/AML 通常表现为骨髓发育不全、7 号单体，但体细胞突变情况与未选择的患者不同。一年和两年的生存率分别为 61% 和 39%，三分之二的 MDS/AML 患者死于肺纤维化和/或肝肺综合征。在一半的病例中，MDS/AML 患者表现出获得性粒细胞特异性端粒缩短的复发性外周血模式。在没有 MDS/AML 的年龄匹配的突变携带者中不存在这种损耗。我们测试了没有 MDS/AML 的成年短端粒患者是否也有不确定潜能 (CHIP) 相关突变的克隆造血证据，发现 30% 受到影响。这些患者在随访期间也主要患有肺纤维化。我们的数据显示孟德尔短端粒综合征与相对狭窄的癌症谱相关，主要是 MDS 和 AML。他们认为，在这些遗传性疾病中，较短的端粒长度足以驱动与年龄相关的过早克隆造血。