Significant overlap between human genome-wide association-study nominated breast cancer risk alleles and rat mammary cancer susceptibility lociReport as inadecuate




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Breast Cancer Research

, 16:R14

First Online: 27 January 2014Received: 08 July 2013Accepted: 10 January 2014DOI: 10.1186-bcr3607

Cite this article as: Sanders, J. & Samuelson, D.J. Breast Cancer Res 2014 16: R14. doi:10.1186-bcr3607

Abstract

IntroductionHuman population-based genome-wide association GWA studies identify low penetrance breast cancer risk alleles; however, GWA studies alone do not definitively determine causative genes or mechanisms. Stringent genome- wide statistical significance level requirements, set to avoid false-positive associations, yield many false-negative associations. Laboratory rats Rattus norvegicus are useful to study many aspects of breast cancer, including genetic susceptibility. Several rat mammary cancer associated loci have been identified using genetic linkage and congenic strain based-approaches. Here, we sought to determine the amount of overlap between GWA study nominated human breast and rat mammary cancer susceptibility loci.

MethodsWe queried published GWA studies to identify two groups of SNPs, one that reached genome-wide significance and one comprised of SNPs failing a validation step and not reaching genome- wide significance. Human genome locations of these SNPs were compared to known rat mammary carcinoma susceptibility loci to determine if risk alleles existed in both species. Rat genome regions not known to associate with mammary cancer risk were randomly selected as control regions.

ResultsSignificantly more human breast cancer risk GWA study nominated SNPs mapped at orthologs of rat mammary cancer loci than to regions not known to contain rat mammary cancer loci. The rat genome was useful to predict associations that had met human genome-wide significance criteria and weaker associations that had not.

ConclusionsIntegration of human and rat comparative genomics may be useful to parse out false-negative associations in GWA studies of breast cancer risk.

AbbreviationsACIAugust Copenhagen Irish

BNBrown Norway

bpbase pair

BRCA 1 or 2breast cancer 1 or 2

COPCopenhagen

DMBA7,12-dimethylbenzaanthracene

EMCAestrogen- induced mammary cancer

GWA studygenome-wide association study

Mcsmammary carcinoma susceptibility

Mcsmmammary carcinoma susceptibility modifier

Mcstamammary cancer susceptibility tumor aggressiveness

Mcstmmammary cancer susceptibility tumor multiplicity

NMUN-nitroso-N-methylurea

PALB 2partner and localizer of BRCA2

QTLquantitative trait locus

SNPsingle nucleotide polymorphism

WFWistar-Furth

WKYWistar-Kyoto.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr3607 contains supplementary material, which is available to authorized users.

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Author: Jennifer Sanders - David J Samuelson

Source: https://link.springer.com/







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