Article

An Evolutionary Perspective on Single-Nucleotide Polymorphism Screening in Molecular Cancer Epidemiology

Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Cancer Research (Impact Factor: 9.33). 04/2004; 64(6):2251-7. DOI: 10.1158/0008-5472.CAN-03-2800
Source: PubMed

ABSTRACT

Given that there are millions of single-nucleotide polymorphisms (SNPs) in the entire human genome, a major difficulty faced by scientists in planning costly population-based genotyping is to choose target SNPs that are most likely to affect phenotypic functions and ultimately contribute to disease development. Although it is widely accepted that sequences with important functionality tend to be less variable across species because of selective pressure, to what extent evolutionary conservation is mirrored by epidemiological outcome has never been demonstrated. In this study, we surveyed odds ratios detected for 46 SNPs in 39 different cancer-related genes from 166 molecular epidemiological studies. The conservation levels of amino acid that these SNPs affected were calculated as a tolerance index by comparing sequences from different species. Our results provide evidence of a significant relationship between the detected odds ratios associated with cancer risk and the conservation levels of the SNP-affected amino acids (P = 0.002; R(2) = 0.06). Tolerance indices were further calculated for 355 nonsynonymous SNPs identified in 90 human DNA repair genes, of which 103 caused amino acid changes in very conserved positions. Our findings support the concept that SNPs altering the conserved amino acids are more likely to be associated with cancer susceptibility. Using such a molecular evolutionary approach may hold great promise for prioritizing SNPs to be genotyped in future molecular epidemiological studies.

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Available from: Matthew B. Schabath, Apr 30, 2015
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    • "There is an increasing evidence that reduced DNA repair capacity, resulting from genetic polymorphisms of various DNA repair genes, is associated with increased risk and susceptibility to various types of human cancers (Shen et al 2000, David-Beabes et al., 2001, Ratnasinghe et al., 2001, Hao et al., 2004, Zhi, et al., 2004, Zhang et al., 2005). The polymorphism in DNA repair genes has been extensively investigated for its associations with cancer risk and the results were conflicting in different types of cancer or different populations (Hu et al., 2005, Zeng et al., 2009, Wei et al., 2010, Saadat, 2010). "
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    • "Deleterious alleles may play an important functional role in affecting the phenotype of traits of interest, and complementation between haplotypes carrying different deleterious alleles may explain much of the observation of hybrid vigor or heterosis (Charlesworth and Willis 2009). In studies of human disease, a significant correlation was observed between the deleterious predictions of single-nucleotide polymorphisms (SNPs) and their association with cancer (Zhu et al. 2004); predicted rare, deleterious SNPs also were shown to be involved in common diseases (Cohen et al. 2004; Smigrodzki et al. 2004). Furthermore, rare, deleterious SNPs have gained interest as the result of their potential role in explaining quantitative trait variation (Gibson 2012), especially in populations that have experienced recent growth (Lohmueller 2013). "
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