Modification of cancer risks in offspring by sibling and parental cancers from 2,112,616 nuclear families.

Comparisons of cancer risks in persons by sibling cancers and those by parental cancers are informative of elucidating the potential genetic modes in the etiology of the cancers. The Swedish Family-Cancer Database was used to systematically estimate the effects of parental and sibling cancers on the cancer risks in the individuals born after 1934 (offspring). The study population included 5,520,756 offspring and their parents from 2,112,616 nuclear families. Standardized incidence ratios (SIRs) were calculated to analyze the risks for cancers in offspring by parental cancers (offspring risk) and by sibling cancers (sibling risk). For 20 concordant sites, all offspring and sibling risks were significantly increased except for sibling risks for squamous cell carcinoma of the skin and myeloma. Apart from breast cancer, the SIRs were more than 10 when offspring had both an affected parent and an affected sib at the concordant site. The ratio for the sibling to offspring risk was around 2.0 or more for gastric, renal, non-thyroid endocrine, urinary bladder, colon, testicular and prostate cancers and leukemia. For discordant sites, many reported across-site associations were confirmed and several consistent novel associations (rectum-skin, breast-endocrine and lung-endocrine) were found only among sibs. Our findings suggested that low-penetrance polygenic dominant effects or dominant genes of high penetrance but low mutant allele frequency in the population may be involved in the observed familial cancers at many sites. Recessive or X-linked effects may contribute particularly to gastric, renal, non-thyroid endocrine, bladder, colon, testicular and prostate cancers and leukemia. The search for pleiotropic recessive/X-linked susceptibility genes should be well motivated based on our results.