DataSheet_3_MYBL2-Driven Transcriptional Programs Link Replication Stress and Error-prone DNA Repair With Genomic Instability in Lung Adenocarcinoma.xlsx

It has long been recognized that defects in cell cycle checkpoint and DNA repair pathways give rise to genomic instability, tumor heterogeneity, and metastasis. Despite this knowledge, the transcription factor-mediated gene expression programs that enable survival and proliferation in the face of enormous replication stress and DNA damage have remained elusive. Using robust omics data from two independent studies, we provide evidence that a large cohort of lung adenocarcinomas exhibit significant genome instability and overexpress the DNA damage responsive transcription factor MYB proto-oncogene like 2 (MYBL2). Across two studies, elevated MYBL2 expression was a robust marker of poor overall survival and disease-free survival outcomes, regardless of disease stage. Clinically, elevated MYBL2 expression identified patients with aggressive early onset disease, increased lymph node involvement, and increased incidence of distant metastases. Analysis of genomic sequencing data demonstrated that MYBL2 High lung adenocarcinomas had elevated somatic mutation burden, widespread chromosomal alterations, and alterations in single-strand DNA break repair pathways. In this study, we provide evidence that impaired single-strand break repair, combined with a loss of cell cycle regulators TP53 and RB1, give rise to MYBL2-mediated transcriptional programs. Omics data supports a model wherein tumors with significant genomic instability upregulate MYBL2 to drive genes that control replication stress responses, promote error-prone DNA repair, and antagonize faithful homologous recombination repair. Our study supports the use of checkpoint kinase 1 (CHK1) pharmacological inhibitors, in targeted MYBL2 High patient cohorts, as a future therapy to improve lung adenocarcinoma patient outcomes.

长期以来学界已达成共识：细胞周期检验点（cell cycle checkpoint）与DNA修复通路的缺陷会引发基因组不稳定、肿瘤异质性及肿瘤转移。尽管已有此类认知，但能够使肿瘤细胞在极强复制应激与DNA损伤压力下存活并增殖的、由转录因子介导的基因表达程序，至今仍未被完全阐明。本研究借助两项独立研究中的可靠多组学（omics）数据，证实大量肺腺癌队列呈现显著基因组不稳定特征，且高表达DNA损伤应答转录因子MYB原癌基因样2（MYBL2）。在两项研究中，MYBL2表达升高均是不良总生存期与无病生存期的可靠预测标志物，且与疾病分期无关。临床层面，MYBL2高表达可甄别出具有侵袭性早发性疾病、淋巴结受累程度加重及远处转移发生率增高的患者。基因组测序数据分析显示，MYBL2高表达肺腺癌具有更高的体细胞突变负荷、广泛的染色体改变以及单链DNA断裂修复通路异常。本研究证实，单链DNA断裂修复功能受损，联合细胞周期调控因子TP53与RB1缺失，可诱发MYBL2介导的转录程序。多组学数据支持如下模型：基因组不稳定程度显著的肿瘤会上调MYBL2表达，以驱动调控复制应激应答、促进易错DNA修复并拮抗精准同源重组修复的基因表达。本研究支持在MYBL2高表达的目标患者队列中使用检验点激酶1（CHK1）药理学抑制剂，作为未来改善肺腺癌患者预后的治疗方案。