Dataset Information

Biological processes, properties and molecular wiring diagrams of candidate low-penetrance breast cancer susceptibility genes.

ABSTRACT:

Background

Recent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined.

Methods

We applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence.

Results

First, examination of the distribution of Gene Ontology terms in ordered WGAS results identified asymmetrical distribution of Cell Communication and Cell Death processes linked to risk. Second, analysis of 11 different types of molecular or functional relationships in genomic and proteomic data sets defined the "omic" properties of candidate genes: i/ differential expression in tumors relative to normal tissue; ii/ somatic genomic copy number changes correlating with gene expression levels; iii/ differentially expressed across age at diagnosis; and iv/ expression changes after BRCA1 perturbation. Finally, network modeling of the effects of variants on germline gene expression showed higher connectivity than expected by chance between novel candidates and with known susceptibility genes, which supports functional relationships and provides mechanistic hypotheses of risk.

Conclusion

This study proposes that cell communication and cell death are major biological processes perturbed in risk of breast cancer conferred by low-penetrance variants, and defines the common omic properties, molecular interactions and possible functional effects of candidate genes and proteins.

SUBMITTER: Bonifaci N

PROVIDER: S-EPMC2628924 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Breast cancer is the most common type of cancer and the second leading cause of cancer-death among women in Poland. The known high-risk mutations account for 25% of familial aggregation cases and 5% of total breast cancer predisposition. Genome-wide association studies have identified a number of common low-penetrance genetic variants, but their contribution to disease risk differs between populations. METHODS: To verify selected associations with breast cancer susceptibility among Polish women, the replication study was performed, included 1424 women with breast cancer and 1788 healthy persons. Sixteen single-nucleotide polymorphisms (SNPs) were analyzed using TaqMan SNP Genotyping Assays. Allele frequency differences were tested using chi2-test implemented in PLINK v1.07 and Cochran-Armitage trend test was performed using R software. RESULTS: Significant differences (Bonferroni corrected p-valuecor ? 0.0197) in the frequency of alleles distribution between all cancer and control subjects were observed for four (rs2736098, rs13281615, rs1219648, rs2981582) out of 16 SNPs. The same result was obtained for group of patients without high-risk BRCA1/2 mutations. The rs1219648 (p-valuecor ? 6.73E-03) and rs2981582 (p-valuecor ? 6.48E-03) SNPs showed significant association with both familial and sporadic cancers. Additionally, rs2736098 (p-valuecor ? 0.0234) was associated with only sporadic cancers; also in group without carriers of high-risk mutation. All these associations revealed their significance also in Cochran-Armitage trend test. Opposite to other SNPs, rs2736098 was associated with a decreased risk of breast cancer. CONCLUSION: The association of four known susceptibility SNPs, representing three individual loci, with breast cancer risk in Polish women was confirmed. One of them (rs2736098) seems to be specific for the Polish population. Due to the population differences in allele frequencies, identification of general genetic risk factors requires sets of association studies conducted on different populations.