The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
Alliance Statistics and Data Center, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
Clin Cancer Res. 2019 Nov 1;25(21):6524-6531. doi: 10.1158/1078-0432.CCR-19-0725. Epub 2019 Aug 2.
Uniparental disomy (UPD) is a way cancer cells duplicate a mutated gene, causing loss of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We examined the prognostic significance of UPDs and frequency of LOH in patients with CN-AML. We examined the frequency and prognostic significance of UPDs in a set of 425 adult patients with CN-AML who were previously sequenced for 81 genes typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 patients with CN-AML younger than 60 years.
We detected 127 UPDs in 109 patients. Most UPDs were large and typically encompassed all or most of the affected chromosome arm. The most common UPDs occurred on chromosome arms 13q (7.5% of patients), 6p (2.8%), and 11p (2.8%). Many UPDs significantly cooccurred with mutations in genes they encompassed, including 13q UPD with -internal tandem duplication (-ITD; < 0.001), and 11p UPD with mutations ( = 0.02). Among patients younger than 60 years, UPD of 11p was associated with longer overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In multivariable models that accounted for known prognostic markers, including -ITD and mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained association with longer OS.
LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 13q and 11p might be useful for genetic risk stratification of patients with CN-AML.
单亲二倍体（UPD）是癌细胞复制突变基因的一种方式，导致杂合性丢失（LOH）。核型正常的急性髓系白血病（CN-AML）患者没有显微镜下可检测到的染色体异常，但可能存在 UPDs。我们研究了 UPDs 在 CN-AML 患者中的预后意义和 LOH 的频率。我们检查了一组 425 例先前对 81 个通常在癌症中发生突变的基因进行测序的成人 CN-AML 患者中 UPDs 的频率和预后意义。在 315 例年龄小于 60 岁的 CN-AML 患者中分析了 UPDs 与结局的关系。
我们在 109 例患者中检测到 127 例 UPDs。大多数 UPDs 较大，通常包含受影响的整条或大部分染色体臂。最常见的 UPDs 发生在 13q（7.5%的患者）、6p（2.8%）和 11p（2.8%）染色体臂上。许多 UPDs 与它们包含的基因的突变显著相关，包括 13q UPD 与内部串联重复（-ITD；<0.001）和 11p UPD 与 突变（=0.02）。在年龄小于 60 岁的患者中，11p 的 UPD 与总生存期（OS）延长相关，而 13q 的 UPD 与无病生存期（DFS）和 OS 缩短相关。在考虑已知预后标志物（包括-ITD 和 突变）的多变量模型中，13q 的 UPD 与 DFS 缩短相关，而 11p 的 UPD 与 OS 延长相关。
CN-AML 中经常发生由 UPD 介导的 LOH。检测 13q 和 11p 的 UPD 可能有助于对 CN-AML 患者进行遗传风险分层。
