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


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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    • "This indicates that not all variant SNPs are risky. From an evolutionary perspective, it is possible that the substitutions observed frequently are likely to be neutral or favorable, whereas those observed rarely are likely to be deleterious (Zhu et al. 2004). More importantly, group comparison between cases and controls showed statistically significant difference in the median number of risk alleles (P \ 0.001) with the radiosensitive group (G3–4) harboring higher number of risk alleles (Fig. 3). "
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    ABSTRACT: Due to individual variations in radiosensitivity, biomarkers are needed to tailor radiation treatment to cancer patients. Since single nucleotide polymorphisms (SNPs) are frequent in human, we hypothesized that SNPs in genes that mitigate the radiation response are associated with radiotoxicity, in particular late complications to radiotherapy and could be used as genetic biomarkers for radiation sensitivity. A total of 155 patients with nasopharyngeal cancer were included in the study. Normal tissue fibrosis was scored using RTOG/EORTC grading system. Eleven candidate genes (ATM, XRCC1, XRCC3, XRCC4, XRCC5, PRKDC, LIG4, TP53, HDM2, CDKN1A, TGFB1) were selected for their presumed influence on radiosensitivity. Forty-five SNPs (12 primary and 33 neighboring) were genotyped by direct sequencing of genomic DNA. Patients with severe fibrosis (cases, G3–4, n = 48) were compared to controls (G0–2, n = 107). Results showed statistically significant (P < 0.05) association with radiation complications for six SNPs (ATM G/A rs1801516, HDM2 promoter T/G rs2279744 and T/A rs1196333, XRCC1 G/A rs25487, XRCC5 T/C rs1051677 and TGFB1 C/T rs1800469). We conclude that these six SNPs are candidate genetic biomarkers for radiosensitivity in our patients that have cumulative effects as patients with severe fibrosis harbored significantly higher number of risk alleles than the controls (P < 0.001). Larger cohort, independent replication of these findings and genome-wide association studies are required to confirm these results in order for SNPs to be used as biomarkers to individualize radiotherapy on genetic basis.
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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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    ABSTRACT: Most non-synonymous mutations are thought to be deleterious because of their effect on protein sequence, and are expected to be removed or kept at low frequency by the action of natural selection. Nonetheless, the effect of positive selection on linked sites or drift in small or inbred populations may also impact the evolution of deleterious alleles. In spite of their potential to affect complex trait phenotypes, deleterious alleles are difficult to study precisely because they are often at low frequency. Here, we made use of genome-wide genotyping data to characterize deleterious variants in a large panel of maize inbred lines. We show that, in spite of small effective population sizes and inbreeding, most putatively deleterious SNPs are indeed at low frequencies within individual genetic groups. We find that genes associated with a number of complex traits are enriched for deleterious variants. Together these data are consistent with the dominance model of heterosis, in which complementation of numerous low frequency, weak deleterious variants contribute to hybrid vigor.
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