The 5p12 breast cancer susceptibility locus affects MRPS30 expression in estrogen-receptor positive tumors

• Published in: Molecular oncology Vol. 8; no. 2; pp. 273 - 284
• Main Authors: Quigley, David A., Fiorito, Elisa, Nord, Silje, Van Loo, Peter, Alnæs, Grethe Grenaker, Fleischer, Thomas, Tost, Jorg, Moen Vollan, Hans Kristian, Tramm, Trine, Overgaard, Jens, Bukholm, Ida R., Hurtado, Antoni, Balmain, Allan, Børresen-Dale, Anne-Lise, Kristensen, Vessela
• Format: Journal Article
• Language: English
• Published: United States Elsevier B.V 01-03-2014; John Wiley & Sons, Inc; FEBS Press; John Wiley and Sons Inc
• Subjects: Alleles; Apoptosis; Biochemistry, Molecular Biology; Breast cancer; Cancer; Cell Line, Tumor; chromatin; Chromatin remodeling; Datasets; DNA methylation; Estrogen; Estrogen receptors; Etiology; Expression Quantitative Trait Locus; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Genetics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genotype & phenotype; Genotypes; Grants; Humans; Life Sciences; Menopause; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Polymorphism; Quantitative Trait Loci; Receptors, Estrogen - biosynthesis; Receptors, Estrogen - genetics; Statistical analysis; Susceptibility; Tumor cells; Tumors; GWAS; SNP; Estrogen; FAIRE; Genetics; Breast cancer; eQTL; ChIP-PCR; chromatin; Expression Quantitative Trait Locus; ER; ATP
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1016/j.molonc.2013.11.008

Genome-wide association studies have identified numerous loci linked to breast cancer susceptibility, but the mechanism by which variations at these loci influence susceptibility is usually unknown. Some variants are only associated with particular clinical subtypes of breast cancer. Understanding how and why these variants influence subtype-specific cancer risk contributes to our understanding of cancer etiology. We conducted a genome-wide expression Quantitative Trait Locus (eQTL) study in a discovery set of 287 breast tumors and 97 normal mammary tissue samples and a replication set of 235 breast tumors. We found that the risk-associated allele of rs7716600 in the 5p12 estrogen receptor-positive (ER-positive) susceptibility locus was associated with elevated expression of the nearby gene MRPS30 exclusively in ER-positive tumors. We replicated this finding in 235 independent tumors. Further, we showed the rs7716600 risk genotype was associated with decreased MRPS30 promoter methylation exclusively in ER-positive breast tumors. In vitro studies in MCF-7 cells carrying the protective genotype showed that estrogen stimulation decreased MRPS30 promoter chromatin availability and mRNA levels. In contrast, in 600MPE cells carrying the risk genotype, estrogen increased MRPS30 expression and did not affect promoter availability. Our data suggest the 5p12 risk allele affects MRPS30 expression in estrogen-responsive tumor cells after tumor initiation by a mechanism affecting chromatin availability. These studies emphasize that the genetic architecture of breast cancer is context-specific, and integrated analysis of gene expression and chromatin remodeling in normal and tumor tissues will be required to explain the mechanisms of risk alleles.
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•We conducted an eQTL study in 287 breast tumors and 97 normal mammary tissue samples.•Risk SNP rs7716600 (5p12) is associated with MRPS30 expression in ER-positive tumors.•We validated this finding in an independent cohort of 235 tumors.•rs7716600 is also associated with MRPS30 promoter methylation in ER-positive tumors.•In vitro experiments suggest the variant affects promoter availability, ER binding.