Summary of the PCHiC CHiCAGO-scored interactions.

Hormone-dependent cancers (HDCs) share several risk factors, suggesting a common aetiology. Using data from genome-wide association studies, we showed spatial clustering of risk variants across four HDCs (breast, endometrial, ovarian and prostate cancers), contrasting with genetically uncorrelated traits. We identified 44 multi-HDC risk regions across the genome, defined as overlapping risk regions for at least two HDCs: two regions contained risk variants for all four HDCs, 13 for three HDCs and 28 for two HDCs. Integrating GWAS data, epigenomic profiling and promoter capture HiC maps from diverse cell line models, we annotated 53 candidate risk genes at 22 multi-HDC risk regions. These targets were enriched for established genes from the COSMIC Cancer Gene Census, but many had no previously reported pleiotropic roles. Additionally, we pinpointed lncRNAs as potential HDC targets and identified risk alleles in several regions that altered transcription factors motifs, suggesting regulatory mechanisms. Known drug targets were over-represented among the candidate multi-HDC risk genes, implying that some may serve as targets for therapeutic development or facilitate the repurposing of existing treatments for HDC. Our approach provides a framework for identifying common target genes driving complex traits and enhances understanding of HDC susceptibility.

激素依赖性癌症（Hormone-dependent cancers, HDCs）共享多种风险因素，提示其存在共同的致病机制。本研究借助全基因组关联研究（genome-wide association studies, GWAS）数据，揭示了四种HDCs（乳腺癌、子宫内膜癌、卵巢癌与前列腺癌）的风险变异存在空间聚集特征，这与遗传上不相关的性状形成鲜明对比。本研究在全基因组范围内鉴定出44个多激素依赖性癌症风险区域，其定义为至少覆盖两种激素依赖性癌症的重叠风险区域：其中2个区域包含四种癌症共有的风险变异，13个区域覆盖三种癌症的风险变异，剩余28个区域则覆盖两种癌症的风险变异。通过整合全基因组关联研究数据、表观基因组谱分析结果以及多种细胞系模型的启动子捕获Hi-C（promoter capture Hi-C）图谱，本研究为22个多激素依赖性癌症风险区域注释了53个候选风险基因。这些候选靶基因显著富集于COSMIC癌症基因普查（COSMIC Cancer Gene Census）收录的已知癌症基因，但其中多数此前未被报道存在多效性功能。此外，本研究明确了长链非编码RNA（long non-coding RNAs, lncRNAs）作为潜在激素依赖性癌症靶标的可能性，并在多个风险区域中鉴定出可改变转录因子结合基序的风险等位基因，提示了相关调控机制的存在。候选多激素依赖性癌症风险基因中显著富集已知药物靶标，这意味着部分候选基因可作为癌症治疗开发的新靶标，或有助于推动现有疗法在激素依赖性癌症中的重定位应用。本研究的分析框架可为鉴定驱动复杂性状的共同靶基因提供范式，并加深人们对激素依赖性癌症易感性的理解。