B‐cell Lymphoma 2 Family Genes Show a Molecular Pattern of Spatiotemporal Heterogeneity in Gynaecologic and Breast Cancer

OBJECTIVES:BCL2 family proteins have been widely studied over the past decade due to their essential roles in apoptosis, oncogenesis and anti-cancer therapy. However, the similarities and differences in the spatial pattern of the BCL2 gene family within the context of chromatin have not been well characterized. We sought to fill this knowledge gap by assessing correlations between gene alteration, gene expression, chromatin accessibility, and clinical outcomes in gynaecologic and breast cancer.MATERIALS AND METHODS:In this study, the molecular characteristics of the BCL2 gene family in gynaecologic cancer were systematically analysed by integrating multi-omics datasets, including transcriptomics, chromatin accessibility, copy number variation, methylomics and clinical outcome.RESULTS:We evaluated spatiotemporal associations between long-range regulation peaks and tumour heterogeneity. Differential expression of the BCL2 family was coupled with widespread chromatin accessibility changes in gynaecologic cancer, accompanied by highly heterogeneous distal non-coding accessibility surrounding the BCL2L1 gene loci. A relationship was also identified between gene expression, gene amplification, enhancer signatures, DNA methylation and overall patient survival. Prognostic analysis implied clinical correlations with BAD, BIK and BAK1. A shared protein regulatory network was established in which the co-mutation signature of TP53 and PIK3CA was linked to the BCL2L1 gene.CONCLUSIONS:Our results provide the first systematic identification of the molecular features of the BCL2 family under the spatial pattern of chromatin in gynaecologic and breast cancer. These findings broaden the therapeutic scope of the BCL2 family to the non-coding region by including a significantly conserved distal region overlaying an enhancer.