Supplementary Material for: Comprehensive study of chromosomal CNVs and genomic variations predicting overall survival in Myelodysplastic syndromes

Introduction: Myelodysplastic syndrome (MDS) is a heterogeneous disease characterized by cytopenia, marrow dysplasia and has a propensity to develop into acute myeloid leukemia (AML). The disease progression is majorly affected by genetic defects. However, about 40% - 50% of patients with MDS present with a normal karyotype and develop different courses of disease. Hence there remains a room to advance the biological understanding and to find molecular prognostic markers for cytogenetically normal (CN) MDS.
Methods: We performed a high-resolution CGH + SNP array along with NGS of 77 primary diagnosed MDS patients and also they were clinically followed up.
Results: Our study revealed 82 clinically significant genomic lesions (losses/gains) in 49% of MDS patients. CGH + SNP array reduced the proportion of normal karyotype by 30%. SNP array in combination with NGS confirmed the biallelic loss of function of the TP53 gene (2/6), which is a clinically relevant biomarker and new genetic-based MDS entity i.e. MDS-biTP53 as per the new WHO classification 2022. Genomic region 2p22.3 presented with frequent lesions and also with a more hazard ratio (2.7, 95% CI 0.37 – 21) when analyzed by Kaplan Meier survival analysis.
Conclusion: CGH + SNP array changed the cytogenetic and IPSS-R risk group in 18% and 13% of patients respectively with an improved prediction of prognosis. This study emphasizes the cytogenetic heterogeneity of MDS and highlights that abnormality with chromosome 2 may have a diagnostic and prognostic impact.

引言：骨髓增生异常综合征（Myelodysplastic syndrome, MDS）是一类异质性疾病，以血细胞减少、骨髓发育异常为特征，且具有进展为急性髓系白血病（acute myeloid leukemia, AML）的倾向。该病的疾病进展主要受遗传缺陷调控。然而，约40%~50%的MDS患者核型正常，且疾病进程存在显著异质性。因此，目前仍需深化对其生物学机制的认知，并为细胞遗传学正常（cytogenetically normal, CN）的MDS患者筛选分子预后标志物。

方法：本研究对77例初诊MDS患者开展高分辨率比较基因组杂交（comparative genomic hybridization, CGH）联合单核苷酸多态性（single nucleotide polymorphism, SNP）阵列检测，同时结合二代测序（next-generation sequencing, NGS）技术，并对所有患者进行了临床随访。

结果：本研究在49%的MDS患者中检出82处具有临床意义的基因组病变（缺失/扩增）。CGH+SNP阵列检测使正常核型的检出比例降低了30%。联合应用SNP阵列与NGS技术，证实了TP53基因的双等位基因功能缺失（2/6例）；该基因是一项具有临床相关性的生物标志物，且符合2022年世界卫生组织（World Health Organization, WHO）新分类中基于遗传学定义的MDS亚型——MDS-biTP53。通过卡普兰-迈耶（Kaplan-Meier）生存分析发现，基因组区域2p22.3存在高频病变，且该区域异常患者的风险比（hazard ratio, HR）更高（HR=2.7，95%置信区间：0.37~21）。

结论：CGH+SNP阵列检测分别使18%和13%的患者的细胞遗传学分组与国际预后评分系统修订版（Revised International Prognostic Scoring System, IPSS-R）风险分组发生改变，同时提升了预后预测效能。本研究证实了MDS的细胞遗传学异质性，并强调2号染色体异常可能具有诊断与预后评估价值。