Background:KMT2Arearrangements are major genetic entities in the classification of acute myeloid leukemias (AMLs), but their diverse and frequently cryptic nature makes their detection and characterization challenging. Karyotypic anomalies at theKMT2Alocus and/or abnormalKMT2AFluorescence in situ hybridization (FISH) results strongly indicate aKMT2Afusion, but the identification of the translocation partner gene often requires further investigation.KMT2Apartial tandem duplications (PTDs), on the other hand, are undetectable by standard cytogenetics methods.Methods:We herein report the optical genome mapping (OGM) analysis of 38 AML samples: 12 cryptic/hard-to-characterizeKMT2Afusions, 20KMT2A-PTDs and 6 cases with noKMT2Aanomaly.Results:In all the fusion cases, the rearrangement between 5’KMT2Aand the 3’partner gene was identified as a translocation t(v;11q23.3)(v;118479068), and the analysis of co-occurring variants elucidated the formation of the rearrangement. TheKMT2Avariants detected in theKMT2A-PTD cases were surprisingly diverse. Combined with RNAseq data, OGM analysis identified 9 distinct in-frameKMT2A-PTD variants among the 20 cases analyzed.Conclusions:With the clinical development of menin inhibitors for the treatment of patients withKMT2A-rearranged acute leukemias, the characterization of these rearrangements is of utmost importance. Our results suggest that OGM is a promising tool for accurate genetic diagnosis in this context.
背景：KMT2A重排是急性髓系白血病（AML）分类中的主要遗传实体，但其多样且常为隐匿的特性使其检测与表征极具挑战。KMT2A位点的核型异常和/或异常的KMT2A荧光原位杂交（FISH）结果强烈提示存在KMT2A融合，但易位伙伴基因的识别通常需要进一步研究。另一方面，KMT2A部分串联重复（PTD）无法通过标准细胞遗传学方法检测。 方法：本文报告了38例AML样本的光学基因组图谱（OGM）分析结果：包括12例隐匿/难以表征的KMT2A融合、20例KMT2A-PTD以及6例无KMT2A异常的病例。 结果：在所有融合病例中，5'端KMT2A与3'端伙伴基因之间的重排均被鉴定为t(v;11q23.3)(v;118479068)易位，对共存变异的分析阐明了该重排的形成机制。在KMT2A-PTD病例中检测到的KMT2A变异呈现出惊人的多样性。结合RNA测序数据，OGM分析在20例病例中识别出9种不同的框内KMT2A-PTD变异类型。 结论：随着menin抑制剂用于治疗KMT2A重排急性白血病患者的临床进展，明确这些重排的特征至关重要。我们的研究结果表明，OGM在此背景下是一种实现精准遗传诊断的有力工具。
肿瘤(癌症)患者之家