Revisiting familial aggregation of prostate cancer within the 3D framework of genetics-epigenetics-environment

Prostate cancer (PCa) is one of the most heritable cancers, exhibiting significant familial aggregation, however, its underlying mechanisms remain incompletely understood. This review proposes a Genetics-Epigenetics-Environment (G-E-E) 3D framework, which not only integrates genetic factors frequently addressed in previous reviews but also incorporates overlooked intergenerational/transgenerational epigenetic inheritance (IEI/TEI) and family-shared environment (FSE). Regarding genetic factors, germline mutations (e.g. BRCA1/2, MLH1, HOXB13), single nucleotide polymorphisms (SNPs), germline copy number variations (GCNVs), and Y-chromosome haplotypes have been extensively documented in PCa familial aggregation research. Adverse parental environmental exposures can induce epigenomic abnormalities in germ cells (including DNA methylation, histone modifications, and non-coding RNAs), which can be transmitted intergenerationally or transgenerationally to drive the initiation and progression of PCa in offspring. Finally, we note that family-shared environments collectively influence all family members, thereby contributing to PCa familial aggregation. Together, these three classes of factors-genetic, epigenetic, and environmental-provide a more comprehensive perspective for explaining the familial aggregation of PCa, offering new insights into predicting its occurrence within families.