Cancer spectrum and outcomes in the Mendelian short telomere syndromes
Cancer spectrum and outcomes in the Mendelian short telomere syndromes
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DOI：
10.1182/blood.2019003264
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发表时间：
2020-05-28
期刊：
影响因子：
20.3
通讯作者：
Armanios, Mary
中科院分区：
文献类型：
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作者：
Schratz, Kristen E.;Haley, Lisa;Armanios, Mary
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，我们报告了端粒酶和其他端粒维持基因发生种系突变的个体的癌症结局。在医院接受评估的180人中，12.8%患有癌症。实体瘤是罕见的（2.8%），几乎所有的年轻男性DKC 1突变携带者，他们通常是切除良好的短期结果。骨髓增生异常综合征（MDS）最常见，其次是急性髓细胞白血病（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和7号单体性，但体细胞突变情况与未选择的患者不明显。1年和2年生存率分别为61%和39%，三分之二的MDS/AML患者死于肺纤维化和/或肝硬化综合征。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。这种损耗在年龄匹配的突变携带者中不存在，他们没有MDS/AML。我们测试了没有MDS/AML的成年短端粒患者是否也有不确定的潜在相关突变的克隆造血的证据，发现30%受到影响。这些患者在随访期间也主要因肺纤维化而发病。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，短端粒长度足以驱动这些遗传性疾病中与年龄相关的过早克隆性造血。
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.