Abstract
Simple SummaryFamilial clustering of cancer and identification of high- and low-risk cancer predisposition gene variants implicate that there are families that are at a high to moderate excess risk of cancer. We wanted to test genetically whether there are families protected from cancer. We whole-genome sequenced 51 elderly individuals without any personal or family history of cancer. We identified less high-risk loss-of-function variants in known and suggested cancer predisposition genes in these cancer-free individuals than in the general population. However, our results for low-risk variants were not conclusive. Our study suggests that random environmental causes of cancer are so dominant that a clear demarcation of cancer-free populations using genetic data may not be feasible. However, carrier identification of and counseling about prevalent high-risk cancer predisposition genes is useful. Familial clustering, twin concordance, and identification of high- and low-penetrance cancer predisposition variants support the idea that there are families that are at a high to moderate excess risk of cancer. To what extent there may be families that are protected from cancer is unknown. We wanted to test genetically whether cancer-free families share fewer breast, colorectal, and prostate cancer risk alleles than the population at large. We addressed this question by whole-genome sequencing (WGS) of 51 elderly cancer-free individuals whose numerous (ca. 1000) family members were found to be cancer-free (‘cancer-free families’, CFFs) based on face-to-face interviews. The average coverage of the 51 samples in the WGS was 42x. We compared cancer risk allele frequencies in cancer-free individuals with those in the general population available in public databases. The CFF members had fewer loss-of-function variants in suggested cancer predisposition genes compared to the ExAC data, and for high-risk cancer predisposition genes, no pathogenic variants were found in CFFs. For common low-penetrance breast, colorectal, and prostate cancer risk alleles, the results were not conclusive. The results suggest that, in line with twin and family studies, random environmental causes are so dominant that a clear demarcation of cancer-free populations using genetic data may not be feasible.
Highlights
IntroductionFamilial cancer (i.e., two or more first-degree relatives diagnosed with the same cancer) accounts for 25% of prostate cancer, 16% of breast cancer, and 15% of colorectal cancer [1]
Familial cancer accounts for 25% of prostate cancer, 16% of breast cancer, and 15% of colorectal cancer [1]
The analysis of the low-risk alleles included a total of 106 single-nucleotide polymorphisms (SNPs) for breast cancer, 81 SNPs for colorectal cancer, and 105 SNPs for prostate cancer identified in five large
Summary
Familial cancer (i.e., two or more first-degree relatives diagnosed with the same cancer) accounts for 25% of prostate cancer, 16% of breast cancer, and 15% of colorectal cancer [1]. These proportions are much lower than twin estimates on the heritability of various cancers [2,3] This may imply, among various explanations, that population genetics is characterized by common genes and polygenes of low penetrance, which would rarely aggregate in families [1,4,5]. As presently known, depends on the type of cancer For common cancers, such as breast and colorectal cancers, mutations in high-risk predisposition genes BRCA1/2 and mismatch repair genes are rare, accounting for a small proportion of the particular cancers (depending on population, approximately 1%) [6,7,8]. The high and low-risk variants explain a small proportion of the known familial risk and even less about the heritability estimated on twins
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