Genetic and epigenetic risk of cancer as a complex hereditary disease

Cancer is a genetic disease that in its deadly form includes 10 functionally linked groups of mutated or modified genes that describe hallmarks like: 1) independence of growth, 2) (multi-drug) resistance to growth inhibitors, 3) apoptosis escape, 4) replicative immortalization ("telomerization"), 5) promotion of angiogenesis, and 6) invasive spreading with metastasis, 7) deregulation of carbohydrate metabolism, 8) escaping the destruction by the immune system, 9) increased genetic instability and 10) inflammation (as a growth stimulating factor). The last two are the accelerating features. Cancer forms a special tissue microenvironment, in which cancer stem cells further divide, develop, mutate and spread. Theoretically, all genes coding for the proteins that characterize, shape of modify 10 hallmarks of cancer are risk factors for cancer. They need to be proven, and hence our first part of the research proposal, in which we focus on the two immunologically related ones. The avoidance of destruction by the immune system and inflammation are two cancer hallmarks that do not necessitate a change (mutation) in cancer cell per se. For example, a mutation (or epigenetic modification) in the host can make individuals more susceptible to cancer by diminishing their immune surveillance capability. Most cancer research literature reported mutations in the cancer-tissue DNA, but little is known about the associations between cancer and polymorphisms of the immune response- and inflammation-linked genes in affected individuals. We know very little about such factors, and it would help to find them through association analyses by genetic-epidemiologic (and hereditary) research.