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.激素依赖性肿瘤（Hormone-dependent cancers, HDCs）存在多项共同风险因素，提示其具有共同的致病机制。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、子宫内膜、卵巢及前列腺癌——的风险变异呈现空间聚集特征，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HDCs风险区域，该类区域被定义为至少覆盖两种激素依赖性肿瘤的重叠风险区域：其中2个区域涵盖四种肿瘤共有的风险变异，13个区域覆盖三种肿瘤的风险变异，剩余28个区域覆盖两种肿瘤的风险变异。本研究整合GWAS数据、表观基因组谱（epigenomic profiling）及多种细胞系模型的启动子捕获Hi-C（promoter capture Hi-C）图谱，在22个多HDCs风险区域内注释得到53个候选风险基因。这些候选靶基因显著富集于癌症体细胞突变目录（COSMIC）癌症基因普查（Cancer Gene Census）收录的已确立致癌基因，但其中多数此前未被报道具有多效性功能。此外，本研究明确了长链非编码RNA（long non-coding RNAs, lncRNAs）作为HDCs潜在治疗靶标的潜力，并在多个区域中鉴定出可改变转录因子结合基序的风险等位基因，提示其存在调控机制。已知药物靶点在候选多HDCs风险基因中显著富集，这提示部分候选基因可作为治疗开发的靶标，或有助于现有疗法在激素依赖性肿瘤中的重定位应用。本研究方法为鉴定驱动复杂性状的共同靶基因提供了一套研究框架，并加深了我们对HDCs易感性的认知。