Polymorphic variants in TSC1 and TSC2 and their association with breast cancer phenotypes

Mehta, M. S., Vazquez, A., Kulkarni, D. A., Kerrigan, J. E., Atwal, G. S., Metsugi, S., Toppmeyer, D. L., Levine, A. J., Hirshfield, K. M. (February 2011) Polymorphic variants in TSC1 and TSC2 and their association with breast cancer phenotypes. Breast Cancer Research and Treatment, 125 (3). pp. 861-868.

URL: http://www.ncbi.nlm.nih.gov/pubmed/20658316
DOI: 10.1007/s10549-010-1062-1

Abstract

TSC1 acts coordinately with TSC2 in a complex to inhibit mTOR, an emerging therapeutic target and known promoter of cell growth and cell cycle progression. Perturbation of the mTOR pathway, through abnormal expression or function of pathway genes, could lead to tumorigenesis. TSC1 and TSC2 expression is reduced in invasive breast cancer as compared with normal mammary epithelium. Because single nucleotide polymorphisms (SNPs) in regulatory genes have been implicated in risk and age at diagnosis of breast cancers, systematic SNP association studies were performed on TSC1 and TSC2 SNPs for their associations with clinical features of breast cancer. TSC1 and TSC2 haplotypes were constructed from genotyping of multiple loci in both genes in healthy volunteers. SNPs were selected for further study using a bioinformatics approach based on SNP associations with drug response in NCI-60 cell lines and evidence of selection bias based on haplotype frequencies. Genotyping for five TSC1 and one TSC2 loci were performed on genomic DNA from 1,137 women with breast cancer. This study found that for TSC1 rs7874234, TT variant carriers had a 9-year later age at diagnosis of estrogen receptor positive (ER+), but not ER-, ductal carcinomas (P = 0.0049). No other SNP locus showed an association with age at diagnosis, nor any other breast cancer phenotype. TSC1 rs7874234 is hypothesized to be functional in ER+ breast cancer because the T allele, but not the C allele, may create an estrogen receptor element (ERE) site, resulting in increased TSC1 transcription and subsequent inhibition of mTOR. © 2010 Springer Science+Business Media, LLC.

Item Type: Paper
Uncontrolled Keywords: Breast cancer risk Case study SNP TSC1/TSC2
Subjects: bioinformatics
diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > cancer > cancer types > breast cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > single nucleotide polymorphism
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL labs > Atwal lab
CSHL Cancer Center Program > Cancer Genetics
Depositing User: Matt Covey
Date: February 2011
Date Deposited: 07 Feb 2013 16:40
Last Modified: 14 Oct 2015 19:45
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27114

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