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Six low-penetrance SNPs for the estimation of breast cancer heritability: A family-based study in Caucasian Italian patients.

ABSTRACT: Breast cancer is a malignancy with a strong heritable component. Genetic counseling has been principally focused on families carrying high-penetrance breast cancer 1/2, early onset genes. Current modeling suggests that the majority of the unexplained fraction of familial risk is likely to be explained by a polygenic model. The aim of the present study was to estimate the heritability (h2) of breast cancer susceptibility through the analysis of 6 single nucleotide polymorphisms (SNPs), nuclear mitotic apparatus protein 1, cyclin D1, cytochrome C oxidase copper chaperone, fibroblast growth factor receptor 2, TOX high mobility group box family member 3 and solute carrier family 4 member 7. These 6 SNPs, previously identified by genome-wide association studies, were considered to evaluate the additive and common environmental components that contribute to the development of breast cancer in nuclear (pedigrees including only first degree relationships) and in extended families (with at most third degree relationships). A total of 22 extended pedigrees, subsequently split into 52 nuclear pedigrees were analyzed. An example of splitting process from extended to nuclear pedigree is shown in Fig. 1. Firstly, an underline latent continuous trait (Y*) using breast cancer status and information of 6 breast cancer-associated SNPs was calculated. This novel trait summarized the susceptibility of breast cancer in each individual. Secondly, the h2 of Y* was estimated using an additive polygenic-common environment-unique error model. h2 was evaluated in extended and immediate pedigrees, obtaining comparable results. h2 accounts for ~40% of the total phenotypic variance, indicating a fairly strong additive genetic effect of breast cancer susceptibility. The present study indicated the importance of the evaluation and consideration of these six SNPs, which can be used as instrumental variables in order to obtain improved genetic models that are useful for h2 analysis.

SUBMITTER: De Summa S

PROVIDER: S-EPMC5592885 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Six low-penetrance SNPs for the estimation of breast cancer heritability: A family-based study in Caucasian Italian patients.

De Summa Simona S Graziano Francesca F Pilato Brunella B Pinto Rosamaria R Danza Katia K Lacalamita Rosanna R Serratì Simona S Sambiasi Domenico D Grassi Mario M Tommasi Stefania S

Oncology letters 20170804 4

Breast cancer is a malignancy with a strong heritable component. Genetic counseling has been principally focused on families carrying high-penetrance <i>breast cancer 1/2, early onset</i> genes. Current modeling suggests that the majority of the unexplained fraction of familial risk is likely to be explained by a polygenic model. The aim of the present study was to estimate the heritability (h<sup>2</sup>) of breast cancer susceptibility through the analysis of 6 single nucleotide polymorphisms ...[more]

PMID: 28943953

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Project description:BACKGROUND:Genome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with small increases in breast cancer risk. Studies to date suggest that some SNPs alter the expression of the associated genes, which potentially mediates risk modification. On this basis, we hypothesised that some of these genes may be enriched for rare coding variants associated with a higher breast cancer risk. METHODS:The coding regions and exon-intron boundaries of 56 genes that have either been proposed by GWASs to be the regulatory targets of the SNPs and/or located?<?500 kb from the risk SNPs were sequenced in index cases from 1043 familial breast cancer families that previously had negative test results for BRCA1 and BRCA2 mutations and 944 population-matched cancer-free control participants from an Australian population. Rare (minor allele frequency???0.001 in the Exome Aggregation Consortium and Exome Variant Server databases) loss-of-function (LoF) and missense variants were studied. RESULTS:LoF variants were rare in both the cases and control participants across all the candidate genes, with only 38 different LoF variants observed in a total of 39 carriers. For the majority of genes (n?=?36), no LoF variants were detected in either the case or control cohorts. No individual gene showed a significant excess of LoF or missense variants in the cases compared with control participants. Among all candidate genes as a group, the total number of carriers with LoF variants was higher in the cases than in the control participants (26 cases and 13 control participants), as was the total number of carriers with missense variants (406 versus 353), but neither reached statistical significance (p?=?0.077 and p?=?0.512, respectively). The genes contributing most of the excess of LoF variants in the cases included TET2, NRIP1, RAD51B and SNX32 (12 cases versus 2 control participants), whereas ZNF283 and CASP8 contributed largely to the excess of missense variants (25 cases versus 8 control participants). CONCLUSIONS:Our data suggest that rare LoF and missense variants in genes associated with low-penetrance breast cancer risk SNPs may contribute some additional risk, but as a group these genes are unlikely to be major contributors to breast cancer heritability.

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.

Dataset Information

Six low-penetrance SNPs for the estimation of breast cancer heritability: A family-based study in Caucasian Italian patients.

Publications

Six low-penetrance SNPs for the estimation of breast cancer heritability: A family-based study in Caucasian Italian patients.

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