Germ-line variation at a functional p53 binding site increases susceptibility to breast cancer development
Tóm tắt
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 γ 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.
Tài liệu tham khảo
Ahmed S, Thomas G et al (2009) Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 41(5):585–590
Bond GL, Hu W et al (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119(5):591–602
Bourque G, Leong B et al (2008) Evolution of the mammalian transcription factor binding repertoire via transposable elements. Genome Res 11:1752–1762
Cawley S, Bekiranov S et al (2004) Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell 116(4):499–509
Dunning AM, Healey CS et al (2009) Association of ESR1 gene tagging SNPs with breast cancer risk. Hum Mol Genet 18(6):1131–1139
Easton DF, Pooley KA et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447(7148):1087–1093
Fullwood MJ, Liu MH et al (2009). An oestrogen-receptor-α-bound human chromatin interactome. Nature (in press)
Hu Z, Jin G et al (2007) MDM2 promoter polymorphism SNP309 contributes to tumor susceptibility: evidence from 21 case-control studies. Cancer Epidemiol Biomarkers Prev 16(12):2717–2723
Inoki K, Zhu T et al (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577–590
Jones RG, Plas DR et al (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18(3):283–293
King MC, Wilson AC (1975) Evolution at two levels in humans and chimpanzees. Science 188(4184):107–116
Knight JC (2005) Regulatory polymorphisms underlying complex disease traits. J Mol Med 83(2):97–109
Laderoute KR, Amin K et al (2006) 5′-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Mol Cell Biol 26(14):5336–5347
Menendez D, Inga A et al (2007) A single-nucleotide polymorphism in a half-binding site creates p53 and estrogen receptor control of vascular endothelial growth factor receptor 1. Mol Cell Biol 27(7):2590–2600
Miller LD, Smeds J et al (2005) An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci USA 102(38):13550–13555
Olivier M, Goldgar DE et al (2003) Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 63(20):6643–6650
Pastinen T, Hudson TJ (2004) Cis-acting regulatory variation in the human genome. Science 306(5696):647–650
Pietsch EC, Humbey O et al (2006) Polymorphisms in the p53 pathway. Oncogene 25(11):1602–1611
Shaw RJ (2006) Glucose metabolism and cancer. Curr Opin Cell Biol 18(6):598–608
Shaw RJ, Kosmatka M et al (2004) The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA 101(10):3329–3335
Sladek R, Hudson TJ (2006) Elucidating cis- and trans-regulatory variation using genetical genomics. Trends Genet 22(5):245–250
Tan J, Zhuang L et al (2005) Pharmacologic modulation of glycogen synthase kinase-3beta promotes p53-dependent apoptosis through a direct Bax-mediated mitochondrial pathway in colorectal cancer cells. Cancer Res 65(19):9012–9020
Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2(8):594–604
Wei CL, Wu Q et al (2006) A global map of p53 transcription-factor binding sites in the human genome. Cell 124(1):207–219
Weinmann AS, Farnham PJ (2002) Identification of unknown target genes of human transcription factors using chromatin immunoprecipitation. Methods 26(1):37–47
Wells J, Farnham PJ (2002) Characterizing transcription factor binding sites using formaldehyde crosslinking and immunoprecipitation. Methods 26(1):48–56
Wray GA (2007) The evolutionary significance of cis-regulatory mutations. Nat Rev Genet 8(3):206–216