Background: TheKMT2A(MLL1) gene is altered in a variety of hematological malignancies and solid tumors.KMT2A-rearranged (KMT2Ar) AML represents a distinct subtype associated with poor outcomes and high relapse rate despite initial responsiveness to chemotherapy.Methods: A total of 3863 cases of AML peripheral blood samples were analyzed using the FoundationOne Heme combined comprehensive hybrid capture-based DNA and RNA sequencing assay.Results: Of the 3863 AML cases, 521 (13.4%) featured genomic alterations (GAs) in theKMT2Agene, 99.1% of which were large rearrangements (KMT2Ar). A total of 56.9% were males with a median age of 62 years. Of theKMT2Arcases, there were 43.1%KMT2Aduplications, 52.7% fusions, and 4.2% not otherwise specified rearrangements. A total of 0.9% of theKMT2A-altered AML cases were short variant mutations. There were noKMT2A(0%) amplifications or deletions.KMT2Arcases were associated with increased GA frequencies inFLT3(27.3% vs. 19.8%;p= 0.0002),KRAS(17.2% vs. 7.8%;p< 0.0001) (overall; 1.1%KRASG12C), andIDH2(16.0% vs. 10.4%;p< 0.0001), whileKMT2Awild-type AML (KMT2Awt)had significantly increased GA frequencies inRUNX1(20.7% vs. 15.8%;p= 0.0081),ASXL1(16.6% vs. 10.5%;p= 0.0003), andTET2(16.4% vs. 10.1%;p= 0.0002),NPM1(17.5% vs. 0.2%;p< 0.0001), andTP53(17.8% vs. 7.9%;p< 0.0001).Conclusions:KMT2Arearrangements are common in AML (13.4% of cases featuredKMT2Ar). A total of 99.1% of alterations inKMT2Aare large rearrangements, with fusions being the most commonly observed alteration (52.7% of total rearrangements). No amplifications or deletions were seen. This genomic landscape study highlights significant genomic differences betweenKMT2ArandKMT2AwtAML patients, which may enrich our understanding of the molecular profile and clusters of mutations in AML.
背景：KMT2A（MLL1）基因在多种血液系统恶性肿瘤和实体瘤中发生改变。KMT2A重排（KMT2Ar）急性髓系白血病（AML）代表了一种独特的亚型，尽管对初始化疗有反应，但其预后不良且复发率高。 方法：使用FoundationOne Heme综合混合捕获DNA和RNA测序检测方法，共分析了3863例AML外周血样本。 结果：在3863例AML病例中，521例（13.4%）存在KMT2A基因的基因组改变（GAs），其中99.1%为大规模重排（KMT2Ar）。患者中56.9%为男性，中位年龄62岁。在KMT2Ar病例中，43.1%为KMT2A重复，52.7%为融合，4.2%为未另行指定的重排。在KMT2A改变的AML病例中，0.9%为短变异突变。未观察到KMT2A扩增或缺失（0%）。KMT2Ar病例与FLT3（27.3% vs. 19.8%；p=0.0002）、KRAS（17.2% vs. 7.8%；p<0.0001）（总体；其中1.1%为KRAS G12C）和IDH2（16.0% vs. 10.4%；p<0.0001）的GA频率增加相关，而KMT2A野生型AML（KMT2Awt）则在RUNX1（20.7% vs. 15.8%；p=0.0081）、ASXL1（16.6% vs. 10.5%；p=0.0003）、TET2（16.4% vs. 10.1%；p=0.0002）、NPM1（17.5% vs. 0.2%；p<0.0001）和TP53（17.8% vs. 7.9%；p<0.0001）的GA频率显著增加。 结论：KMT2A重排在AML中较为常见（13.4%的病例存在KMT2Ar）。KMT2A的改变中99.1%为大规模重排，其中融合是最常见的改变类型（占重排总数的52.7%）。未观察到扩增或缺失。这项基因组景观研究强调了KMT2Ar与KMT2Awt AML患者之间存在显著的基因组差异，这可能丰富我们对AML分子特征和突变簇的理解。
CharacterizingKMT2ARearrangement in Acute Myeloid Leukemia: A Comprehensive Genomic Study
肿瘤(癌症)患者之家