长端粒综合征中的家族性克隆性造血
Familial Clonal Hematopoiesis in a Long Telomere Syndrome.
机构信息
From the Departments of Oncology (E.A.D., K.E.S., Z.L.C., E.J.M., Z.X., E.S.A., C.D.G., M.A.), Pathology (C.D.G., M.A.), and Genetic Medicine (M.A.), the Medical Scientist Training Program (E.A.D.), the Telomere Center (E.A.D., K.E.S., Z.L.C., E.J.M., Z.X., M.A.), and Sidney Kimmel Comprehensive Cancer Center (K.E.S., E.S.A., C.D.G., M.A.), Johns Hopkins University School of Medicine, and the Department of Biology, Krieger School of Arts and Sciences, Johns Hopkins University (M.G.T., S.M.Y., R.C.M.) - both in Baltimore; the Child Neurology Residency Program, Boston Children's Hospital, Boston (D.L.G.); the Department of Pathology and Laboratory Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami (D.B.L.); and the Division of Hematology, Oncology, and Transplantation, University of Minnesota Masonic Cancer Center, Minneapolis (E.S.A.).
出版信息
N Engl J Med. 2023 Jun 29;388(26):2422-2433. doi: 10.1056/NEJMoa2300503. Epub 2023 May 4.
BACKGROUND
Telomere shortening is a well-characterized cellular aging mechanism, and short telomere syndromes cause age-related disease. However, whether long telomere length is advantageous is poorly understood.
METHODS
We examined the clinical and molecular features of aging and cancer in persons carrying heterozygous loss-of-function mutations in the telomere-related gene and noncarrier relatives.
RESULTS
A total of 17 mutation carriers and 21 noncarrier relatives were initially included in the study, and a validation cohort of 6 additional mutation carriers was subsequently recruited. A majority of the mutation carriers with telomere length evaluated (9 of 13) had long telomeres (>99th percentile). mutation carriers had a range of benign and malignant neoplasms involving epithelial, mesenchymal, and neuronal tissues in addition to B- and T-cell lymphoma and myeloid cancers. Five of 18 mutation carriers (28%) had T-cell clonality, and 8 of 12 (67%) had clonal hematopoiesis of indeterminate potential. A predisposition to clonal hematopoiesis had an autosomal dominant pattern of inheritance, as well as penetrance that increased with age; somatic and hotspot mutations were common. These and other somatic driver mutations probably arose in the first decades of life, and their lineages secondarily accumulated a higher mutation burden characterized by a clocklike signature. Successive generations showed genetic anticipation (i.e., an increasingly early onset of disease). In contrast to noncarrier relatives, who had the typical telomere shortening with age, mutation carriers maintained telomere length over the course of 2 years.
CONCLUSIONS
mutations associated with long telomere length conferred a predisposition to a familial clonal hematopoiesis syndrome that was associated with a range of benign and malignant solid neoplasms. The risk of these phenotypes was mediated by extended cellular longevity and by the capacity to maintain telomeres over time. (Funded by the National Institutes of Health and others.).
背景
端粒缩短是一种特征明确的细胞衰老机制，短端粒综合征会导致与年龄相关的疾病。然而，长端粒长度是否有利尚不清楚。
方法
我们研究了携带端粒相关基因 杂合失活突变的个体以及非携带者亲属的衰老和癌症的临床和分子特征。
结果
最初纳入研究的共有 17 名突变携带者和 21 名非携带者亲属，随后招募了另外 6 名突变携带者的验证队列。在评估端粒长度的 13 名 突变携带者中，大多数（9 名，占 9 名）的端粒较长（超过第 99 个百分位数）。除了 B 细胞和 T 细胞淋巴瘤和髓系癌症外，18 名 突变携带者中有多种良性和恶性肿瘤，涉及上皮、间充质和神经元组织。在 18 名 突变携带者中有 5 名（28%）有 T 细胞克隆性，在 12 名中有 8 名（67%）有不确定潜能的克隆性造血。克隆性造血倾向呈常染色体显性遗传模式，且随着年龄的增长而增加，具有较高的外显率；体细胞 和 热点突变很常见。这些和其他体细胞驱动突变可能发生在生命的头几十年，其谱系随后积累了具有时钟特征的更高突变负担。后代显示出遗传预期（即疾病的发病时间越来越早）。与非携带者亲属随着年龄增长而出现典型的端粒缩短不同， 突变携带者在 2 年内维持端粒长度。
结论
与长端粒长度相关的突变赋予了一种易患家族性克隆性造血综合征的倾向，这种综合征与一系列良性和恶性实体肿瘤有关。这些表型的风险是由细胞寿命延长和随着时间推移维持端粒的能力介导的。（由美国国立卫生研究院等资助）。
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