Dataset Information

Racial disparity in breast cancer and functional germ line mutation in galectin-3 (rs4644): a pilot study.

ABSTRACT: For reasons largely unknown, Caucasian women are at a significantly higher risk of developing breast cancer than Asian women. Over a decade ago, mutations in BRCA1/2 were identified as genetic risk factors; however, the discovery of additional breast cancer genes and genes contributing to racial disparities are lacking. We report a functional germline mutation (polymorphism) in the galectin-3 gene at position 191 (rs4644) substituting proline with histidine (P64H), which results in susceptibility to matrix metalloproteinase cleavage and acquisition of resistance to drug-induced apoptosis. This substitution correlates with incidence of breast cancer and racial disparity. Genotype analysis of 338 Caucasian (194 disease free and 144 breast cancer patients) and 140 Asian (79 disease free and 61 breast cancer patients) women showed that the allele homozygous for H64 exists in disease free Caucasian and Asian women at a frequency of 12% and 5%, respectively, versus 37% and 82% in breast cancer patients. The data indicate that H/H allele is associated with increased breast cancer risk in both races. The data implicate galectin-3 H(64) in breast cancer and explain, in part, the noted racial disparity, thus providing a novel target for diagnosis and treatment.

SUBMITTER: Balan V

PROVIDER: S-EPMC2882172 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Racial disparity in breast cancer and functional germ line mutation in galectin-3 (rs4644): a pilot study.

Balan Vitaly V Nangia-Makker Pratima P Schwartz Ann G AG Jung Young Suk YS Tait Larry L Hogan Victor V Raz Tirza T Wang Yi Y Yang Zeng Quan ZQ Wu Gen Sheng GS Guo Yongjun Y Li Huixiang H Abrams Judith J Couch Fergus J FJ Lingle Wilma L WL Lloyd Ricardo V RV Ethier Stephen P SP Tainsky Michael A MA Raz Avraham A

Cancer research 20081201 24

For reasons largely unknown, Caucasian women are at a significantly higher risk of developing breast cancer than Asian women. Over a decade ago, mutations in BRCA1/2 were identified as genetic risk factors; however, the discovery of additional breast cancer genes and genes contributing to racial disparities are lacking. We report a functional germline mutation (polymorphism) in the galectin-3 gene at position 191 (rs4644) substituting proline with histidine (P64H), which results in susceptibilit ...[more]

PMID: 19074869

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Project description:UNLABELLED:Multiple lines of evidence suggest regulatory variation to play an important role in phenotypic evolution and disease development, but few regulatory polymorphisms have been characterized genetically and molecularly. Recent technological advances have made it possible to identify bona fide regulatory sequences experimentally on a genome-wide scale and opened the window for the biological interrogation of germ-line polymorphisms within these sequences. In this study, through a forward genetic analysis of bona fide p53 binding sites identified by a genome-wide chromatin immunoprecipitation and sequence analysis, we discovered a SNP (rs1860746) within the motif sequence of a p53 binding site where p53 can function as a regulator of transcription. We found that the minor allele (T) binds p53 poorly and has low transcriptional regulation activity as compared to the major allele (G). Significantly, the homozygosity of the minor allele was found to be associated with an increased risk of ER negative breast cancer (OR = 1.47, P = 0.038) from the analysis of five independent breast cancer samples of European origin consisting of 6,127 breast cancer patients and 5,197 controls. rs1860746 resides in the third intron of the PRKAG2 gene that encodes the ? subunit of the AMPK protein, a major sensor of metabolic stress and a modulator of p53 action. However, this gene does not appear to be regulated by p53 in lymphoblastoid cell lines nor in a cancer cell line. These results suggest that either the rs1860746 locus regulates another gene through distant interactions, or that this locus is in linkage disequilibrium with a second causal mutation. This study shows the feasibility of using genomic scale molecular data to uncover disease associated SNPs, but underscores the complexity of determining the function of regulatory variants in human populations. ELECTRONIC SUPPLEMENTARY MATERIAL:The online version of this article (doi:10.1007/s11568-010-9138-x) contains supplementary material, which is available to authorized users.

Dataset Information

Racial disparity in breast cancer and functional germ line mutation in galectin-3 (rs4644): a pilot study.

Publications

Racial disparity in breast cancer and functional germ line mutation in galectin-3 (rs4644): a pilot study.

Similar Datasets

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