Background

High-resolution genome-wide SNP-arrays detect large chromosomal aberrations including copy-neutral loss of heterozygosity (CNLOH), which is not captured in conventional cytogenetics.

Methods

We used SNP-array genotyping data generated by the DISCOVeRY-BMT study to detect chromosomal aberrations in pre-HCT blood samples from 1,974 acute myeloid leukemia (AML) patients. Clinical data and blood samples were available through the Center for International Blood and Marrow Transplant Research. We used Cox proportional hazard model for statistical analyses.

Results

AML patients in this study received unrelated donor HCT between 2000-2011 at a median age of 48.2 (range=0.6-78.0) years. About 53% of the patients were males, 7.4% had therapy-related disease, and 73% were in complete remission. Chromosomal aberrations were detected in 14.4% of the patients (Figure 1). Most common aberrations in patients with advanced disease at HCT (n=536) were copy losses in chr7 (5.8%), chr5 (4.5%), CNLOH in the following: chr13 (4.7%), chr11 (3.9%), or chr17 (3.5%), and copy gain in chr8 (3.5%). Common aberrations in patients in complete remission (n=1438) were copy-loss in chr7 (1.0%), chr5 (0.7%), and CNLOH in chr9 (0.9%) or in chr17 (0.8%) (Figure 2). Among patients with normal cytogenetics at diagnosis (n=572), 27.5% received HCT in advanced disease (of them 8.3% had chr13-CNLOH).

In multivariable models including commonly detected aberrations and adjusted for important factors (footnote Figure 3), chr13-CNLOH was associated with an approximately 3-fold increased risk of leukemia relapse and post-HCT mortality in patients with advanced disease (relapse: HR=2.67, 95% CI=1.67-4.26; mortality: HR=2.79, 95% CI=1.81-4.28, p<0.0001). In contrast, chr17-CNLOH was associated with a statistically significant risk of post-HCT mortality in patients with remission (HR=2.85, 95% CI=1.51-5.37, p=0.001); the association with relapse was not statistically significant (HR=1.84, p=0.21). Having aberrations in ≥3 chromosomes was associated with a statistically significant excess risk of mortality in patients with advanced disease (HR=1.59, 95% CI=1.07-2.36, p=0.02) (Figure 3). In patients with normal cytogenetics at diagnosis, chr13-CNLOH pre-HCT refined risk stratification of patients with advanced disease; compared to patients in remission, the HR for OS in patients with advanced disease in the presence or absence of chr13-CNLOH= 5.7 vs. 1.7, respectively, p<0.0001 for both; HR=3.6, p=0.0004 when comparing presence or absence of chr13-CNLOH in patients with advanced disease.

Conclusion

Pre-HCT CNLOH in chr13 or chr17 are associated with inferior post-HCT survival in AML; possibly as a consequence of high risk of post-HCT leukemia relapse. CNLOH in chr13 or chr17 may provide new genomic prognostic markers that guide patient risk stratification and possibly therapeutic options.

中文翻译：

---

SNP阵列检测的移植前染色体畸变对接受无关供体造血细胞移植治疗急性髓样白血病的患者的预后影响。

背景

高分辨率全基因组SNP阵列可检测到大的染色体畸变，包括杂合子的复制中性丢失​​（CNLOH），这在常规细胞遗传学中无法捕获。

方法

我们使用DISCOVeRY-BMT研究生成的SNP阵列基因分型数据来检测来自1,974例急性髓样白血病（AML）患者的HCT前血样中的染色体畸变。临床数据和血样可通过国际血液和骨髓移植研究中心获得。我们使用Cox比例风险模型进行统计分析。

结果

这项研究中的AML患者在2000年至2011年之间接受了无关的供体HCT，中位年龄为48.2岁（范围= 0.6-78.0）。大约53％的患者为男性，7.4％患有与治疗有关的疾病，73％的患者完全缓解。在14.4％的患者中检测到染色体畸变（图1）。在HCT（n = 536）的晚期疾病患者中，最常见的像差是chr7（5.8％），chr5（4.5％），以下情况的CNLOH的复制丢失：chr13（4.7％），chr11（3.9％）或chr17 （3.5％），并以chr8（3.5％）复制。完全缓解患者（n = 1438）的常见像差是chr7（1.0％），chr5（0.7％）和chl9（0.9％）或chr17（0.8％）的CNLOH丢失（图2）。在诊断时具有细胞遗传学正常的患者（n = 572）中，有27.5％的患者接受了HCT治疗（其中8.3％的患者患有chr13-CNLOH）。

在包括通常检测到的像差并针对重要因素进行调整的多变量模型中（脚注图3），chr13-CNLOH与晚期疾病患者的白血病复发和HCT术后死亡率增加约3倍相关（复发：HR = 2.67） ，95％CI = 1.67-4.26；死亡率：HR = 2.79，95％CI = 1.81-4.28，p <0.0001）。相反，在缓解患者中，hr17-CNLOH与HCT后死亡的统计学显着风险相关（HR = 2.85，95％CI = 1.51-5.37，p = 0.001）；与复发的相关性无统计学意义（HR = 1.84，p = 0.21）。≥3个染色体上的畸变与晚期疾病患者的死亡具有统计学上的显着过高风险（HR = 1.59，95％CI = 1.07-2.36，p = 0.02）（图3）。在诊断时具有正常细胞遗传学的患者中，chr13-CNLOH HCT前改善了晚期疾病患者的风险分层；与缓解患者相比，在存在或不存在chr13-CNLOH的情况下，晚期疾病患者的OS HR分别为5.7和1.7，两者均为p <0.0001；比较晚期疾病患者中chr13-CNLOH的存在与否，HR = 3.6，p = 0.0004。

结论

chr13或chr17中的HCT之前的CNLOH与AML中HCT的后生存期较差有关；可能是HCT后白血病复发的高风险的结果。chr13或chr17中的CNLOH可提供新的基因组预后标志物，指导患者风险分层以及可能的治疗选择。