Dataset Information

Mcs5c: a mammary carcinoma susceptibility locus located in a gene desert that associates with tenascin C expression.

ABSTRACT: Genetic factors have been estimated to account for at least 30% of a woman's risk to develop breast cancer. We have developed a rat model using Wistar Furth (WF) and Wistar Kyoto (WKy) strains to genetically identify mammary cancer susceptibility loci. The WKy allele of the mammary carcinogenesis susceptibility locus Mcs5c, was previously shown to reduce carcinoma multiplicity after 7,12-dimethylbenz-[a]anthracene (DMBA) exposure. In this study, Mcs5c was fine-mapped using WF.WKy congenic lines. Mcs5c was located to a region of approximately 176 kb on rat chromosome 5. One of the Mcs5c congenic lines containing a narrow Mcs5c WKy interval displayed a 40% decrease in average carcinoma number compared with WF-homozygous congenic controls after mammary carcinogenesis induction using two different models. As genetically mapped, the Mcs5c locus is located in a gene desert and thus is devoid of genes and annotated RNAs; thus, a genetic element in Mcs5c was hypothesized to regulate the expression of genes outside the locus. Tenascin c (Tnc) was identified as a candidate gene due to its reduced expression in thymus and ovarian tissues of Mcs5c WKy-homozygous congenic females compared with WF-homozygous congenic controls. This allele-specific differential expression is environmentally controlled.

SUBMITTER: Veillet AL

PROVIDER: S-EPMC3447625 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Mcs5c: a mammary carcinoma susceptibility locus located in a gene desert that associates with tenascin C expression.

Veillet Adeline L AL Haag Jill D JD Remfert Jane L JL Meilahn Amanda L AL Samuelson David J DJ Gould Michael N MN

Cancer prevention research (Philadelphia, Pa.) 20110101 1

Genetic factors have been estimated to account for at least 30% of a woman's risk to develop breast cancer. We have developed a rat model using Wistar Furth (WF) and Wistar Kyoto (WKy) strains to genetically identify mammary cancer susceptibility loci. The WKy allele of the mammary carcinogenesis susceptibility locus Mcs5c, was previously shown to reduce carcinoma multiplicity after 7,12-dimethylbenz-[a]anthracene (DMBA) exposure. In this study, Mcs5c was fine-mapped using WF.WKy congenic lines. ...[more]

PMID: 21205740

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Project description:Genome-wide association studies have revealed that many low-penetrance breast cancer susceptibility loci are located in non-protein coding genomic regions; however, few have been characterized. In a comparative genetics approach to model such loci in a rat breast cancer model, we previously identified the mammary carcinoma susceptibility locus Mcs1a. We now localize Mcs1a to a critical interval (277 Kb) within a gene desert. Mcs1a reduces mammary carcinoma multiplicity by 50% and acts in a mammary cell-autonomous manner. We developed a megadeletion mouse model, which lacks 535 Kb of sequence containing the Mcs1a ortholog. Global gene expression analysis by RNA-seq revealed that in the mouse mammary gland, the orphan nuclear receptor gene Nr2f1/Coup-tf1 is regulated by Mcs1a. In resistant Mcs1a congenic rats, as compared with susceptible congenic control rats, we found Nr2f1 transcript levels to be elevated in mammary gland, epithelial cells, and carcinoma samples. Chromatin looping over ∼820 Kb of sequence from the Nr2f1 promoter to a strongly conserved element within the Mcs1a critical interval was identified. This element contains a 14 bp indel polymorphism that affects a human-rat-mouse conserved COUP-TF binding motif and is a functional Mcs1a candidate. In both the rat and mouse models, higher Nr2f1 transcript levels are associated with higher abundance of luminal mammary epithelial cells. In both the mouse mammary gland and a human breast cancer global gene expression data set, we found Nr2f1 transcript levels to be strongly anti-correlated to a gene cluster enriched in cell cycle-related genes. We queried 12 large publicly available human breast cancer gene expression studies and found that the median NR2F1 transcript level is consistently lower in 'triple-negative' (ER-PR-HER2-) breast cancers as compared with 'receptor-positive' breast cancers. Our data suggest that the non-protein coding locus Mcs1a regulates Nr2f1, which is a candidate modifier of differentiation, proliferation, and mammary cancer risk.

Project description:APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

Dataset Information

Mcs5c: a mammary carcinoma susceptibility locus located in a gene desert that associates with tenascin C expression.

Publications

Mcs5c: a mammary carcinoma susceptibility locus located in a gene desert that associates with tenascin C expression.

Similar Datasets

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