Why are Some Tissues More Vulnerable? Revisiting Tissue Specificity in Hereditary Cancer Syndromes.

The genomic era revolution has significantly enhanced our understanding of hereditary cancer predisposition syndromes (HCPSs). However, despite the identification of pathogenic variants in cancer predisposition genes such as RB1, TP53, BRCA1, and BRCA2 and mismatch repair genes as the molecular explanations for familial clustering of specific cancer types, the biological basis behind the striking tissue preference for cancer development in these conditions remains unclear. Although the cancer spectra for each HCPS are widely recognized and routinely used to inform clinical strategies, most cancer predisposition genes are ubiquitously expressed and have DNA damage repair functions that would be expected to impact any tissue involved by loss (or gain, for oncogenes) of function. This narrative review aims to provide a comprehensive overview of the literature on the tissue specificity of HCPSs, integrating insights from molecular biology and epigenetics and discussing the evolving landscape of multi-omics. A structured literature search was conducted in PubMed (March 2023-September 2025) using predefined keywords related to tissue specificity and hereditary cancer, with additional screening of reference lists to identify relevant studies. While isolated mechanisms, including higher proliferation rates and organ-specific sequential patterns of mutation acquisition during carcinogenesis, have been proposed, the marked heterogeneity in tumor spectra across syndromes, together with their intrinsic complexity, suggest that no single mechanism is likely to fully explain tissue specificity. In support of this view, recent literature proposes that germline defects interact with the distinct epigenetic landscape of each cell type, which is inherently multifactorial. The epigenetic "hardwiring" prior to malignant transformation would include differential expression of genes that interact with the causal gene, and the presence of redundant compensatory pathways in unaffected organs. In parallel, the combined effects of inherited DNA repair defects and tissue-specific endogenous or exogenous genotoxic exposures, including hormone-mediated oxidative stress or ultraviolet radiation, further shape organ vulnerability. Experimental models reinforce the complexity, demonstrating that loss of tumor suppressor function is tolerated in certain cellular contexts but triggers cell death in others, suggesting that differential thresholds for genomic instability-induced apoptosis versus malignant transformation can delineate target tissues. Additionally, emerging evidence implicates microRNAs and regulatory variants in modifying cancer risk and organ tropism within hereditary syndromes. Collectively, the tissue specificity in HCPSs likely reflects the convergence of the germline defect with tissue-specific epigenetic architecture, regulatory networks, and environmental exposures, rather than a single causative mechanism. A better understanding of these factors could provide insights into tailored surveillance strategies and guide future research directions.