Hereditary Decreased Cancer Risk: Reality or Mirage? A Review

Most of the knowledge about germline related cancer risks emerged from pioneering studies of families with increased cancer incidence. This led to the discovery of the chapter of hereditary cancer predisposing syndromes. More than 50 syndromes have been identified and most of them have been thoroughly studied. While most germline studies focused on pathogenic variants that increase cancer risk (e.g. BRCA1/2, CHEK2 with odds ratio up to 8.6), little research has been dedicated to the opposite situation, that is germline mutations or variants that decrease the risk of cancer. The methods employed in these cancer risk reduction studies were not centered on family history of cancer but rather on genome wide association studies (GWAS). A body of knowledge has been accumulating in this regard slowly but steadily. No single genes fully prevent cancer in humans, but specific genetic variants and highly conserved genes across species have been proposed as inducers of reduced risk by enhancing DNA repair, apoptosis, or immune surveillance. Research identified some protective alleles that limit tumor initiation or progression, often acting dominantly at tissue levels. However, most of the publications show controversial results. It is not possible to construct a list of germline variants that confer reduced overall cancer risk, as most identified associations are context-specific (e.g., for certain cancer types, or specific populations) and based on statistical correlations rather than causal mechanisms. Research has uncovered rare protective variants and common polymorphisms with modest effects, often in immune or tumor suppressor pathways. These mechanisms do not fully explain why two-thirds of people, including most heavy smokers, remain cancer-free. The aim of this review is to summarize the main genetic features that can reduce the risk of developing cancer in general and in some specific cancers as well.