PubMed · 6641330
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L Lipton. Family resource programs.. https://pubmed.ncbi.nlm.nih.gov/6641330/
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Much of the familial aggregation of common cancer results from inherited susceptibility, but highly penetrant mutations in known genes cannot account for most of the excess. Some of the unexplained familial risk is presumably due to high-penetrance mutations in as yet unidentified genes, but polygenic mechanisms are likely to account for a greater proportion, particularly in breast cancer. This inference, coupled with technological developments, has led to a renaissance in association studies. Most such studies have evaluated small numbers of single-nucleotide polymorphisms (SNPs) in a few candidate genes, but reliable high-density oligonucleotide arrays and other novel techniques will allow genome-wide allelic association studies to be conducted. High-density genome-wide SNP analysis will include targets identified by structural considerations, as well as the growing list of candidate genes. In the longer term, high-throughput re-sequencing will be required to identify the rare pathogenic variants that may constitute the majority of low-penetrance alleles. The detection of low-penetrance cancer susceptibility genes will then be restricted mainly by the availability of large numbers of well-characterized cases and controls. Cancer patients with affected relatives are considerably more informative than unselected cases for such studies.
Occurrence of cancer in parents and offspring may be due to dominant causes, whereas cancer affecting only siblings may indicate a recessive causation. Systematic comparisons of mode of inheritance have not been available for most types of cancer. Using the Swedish Family-Cancer Database, standardized incidence ratios (SIR) were calculated for offspring whose parents or siblings were diagnosed with the same cancer. The degree of environmental causation was assessed by spouse correlation and by comparing risks among siblings of different ages. We identified reliable familial risks for all common neoplasms, SIRs ranging from 1.6 to 4.3 when only a parent was affected and up to 8.5 when only a sibling was effected. Risks between siblings were particularly high for renal cancer. Spouse correlation was found only for lung and stomach cancer, but the analysis of sibling risks by their age difference suggested that even for some other cancers environmental effects in childhood may contribute to familial aggregation. The results from these analysis suggest that familial cluster of cancer at most sites is heritable, caused by dominant effects; for renal cancer recessive effects may be most important.