骨髓增生异常综合征患者常染色体单体缺失的细胞遗传学研究

Cytogenetic Study of Autosomal Monosomies amomg Myelodysplastic Syndrome Patients

单体核型(MK)目前被认为与骨髓增生异常综合征(MDS)的不良预后相关。本研究的目的是调查我院连续成功实施染色体核型分析的初发MDS患者中常染色体单体缺失累及的染色体谱系并分析与其相应的临床病理表型。采用回顾性分析方法收集了我院血液科细胞遗传室自2004年2月至2012年5月连续成功实施染色体核型分析的初发MDS患者细胞遗传学结果,并根据外周血分类计数、骨髓抽吸液涂片、骨髓活检及细胞遗传学分析结果按WHO分类标准进行分型。结果表明,初发MDS患者1 532例中异常核型者538例(35.1%),其中包括证实至少存在1条常染色体单体缺失患者202例。在202例中47例(23.3%)仅表现为单独具有单体异常,其余155例常染色体单体异常并发于2种异常(n=33,21.3%)或3种及以上异常即复杂核型(n=112,78.7%)。单体核型异常几乎累及所有22条常染色体,但7号染色体单体累及频率最高,在所有单独常染色体单体缺失病例中约达66.0%,其并发于2种异常或复杂核型中检出率也是最高的,其余并发于2种异常或复杂核型可重现的单体异常依次累及13号(12.5%),18号(8.3%),20号(6.3%),17号(7.3%),21号(5.2%),12号(5.2%)和5号(5.2%)。单独常染色体单体缺失病例的临床病理表型分析中RCMD(n=20,13例为-7),RAEB(n=12,11例为-7),RA(n=9,3例为-7),CMML(n=6,4例为-7)。单独20单体(n=7,3例RA,4例RCMD),单独20单体未见于RAEB或CMML病例。结论:常染色体单体缺失的高比例提示其对MDS发病的潜在影响。缺失主要累及7号染色体,提示7号染色体相关基因单倍体数量不足可能是MDS发病机制之一。累及其他整条染色体的单倍体数量不足可能不利于恶性克隆存活,除非其有害效应能被其他遗传学畸变效应抵消,这表明并发于2种异常或复杂核型可重现的单体异常累及的染色体谱系更为广泛。20号染色体单体缺失是相对良好的预后特征。

Monosomal karyotype （MK） has recently been associated with poor prognosis of myelodysplastic syndromes （MDS）. The objective of the current study was to investigate the prevalence and spectrum of autosomal monosomies in an unselected cohort of patients with known or suspected MDS by using retrospective analysis. The results showed that bone marrow cytogenetic studies （1532 cases） were performed between 2004 and 2012, and an abnormal karyotype was found in 538 cases （35. 1% ）. In the 538 cases, 202 （37. 5% ） cases had autosomal monosomies including sole （ n = 47, 23.3% ）, part of two （ n = 33, 21.3% ） or more （ n = 122, 78.7% ） anomalies. Almost all 22 autosomes were involved, but monosomy 7 was by far the most frequent, constituting 66. 1% of all isolated monosomies and the highest fraction of those with two or more abnormalities. Other recurrent sole monosomies included chromosomes 20 （ 15.0% ） and 13 （ 8.5 % ）. Monosomy 13 （ 12.5 % ）, 18 （8.3 % ）, 20 （6.3 % ）, 17 （7.3 % ）, 21 （5.2%）, 5 （5.2%） and 12 （5.2%） were also recurrent in the setting of 3 abnormalities. Bone marrow histology and clinical information were reviewed in all cases with isolated monosomy; associated clinical phenotypes were found in RCMD （n =20, 13 were -7）, RAEB （n = 12, 11 were -7）, RA （n =9, 3 were -7） and chronic myelomonocytic leukemia （CMML, n =6, 4 were -7） cases. Sole monosomy 20 （n =7, RA 3 case and RCMD 4 cases） was notdetected in RAEB or CMML cases. It is concluded that the presence of at least 1 autosomal monosomy was documented in approximately 37.5 % of all abnormal cases, which has potential impact on a more than trivial fraction of patients with MDS. The preponderance of monosomy 7 implicates a pathogenetic role for haploinsufficiency of genes associated with chromosome 7. The rarity of sole monosomy involving other chromosomes other than 7, 20, and 13 suggests that haploinsufficiency involving entire chromosomes is detrimental to cell survival, unless their effect is overcome by the presence of other genetic changes that are often associated with additional chromosomal abnormalities. The observation is consistent with the usually favorable prognostic profile associated with sole monosomy 20.