The risk allele of SNP rs3803662 and the mRNA level of its closest genes TOX3 and LOC643714 predict adverse outcome for breast cancer patients

BMC Cancer

Eydis Th Gudmundsdottir¹  Rosa B Barkardottir²  Adalgeir Arason²  Haukur Gunnarsson⁴  Laufey Th Amundadottir³  Bjarni A Agnarsson²  Oskar Th Johannsson⁵  Inga Reynisdottir¹ 

[1] Department of Pathology, Landspitali-University Hospital, Hringbraut, 101, Reykjavik, Iceland

[2] BMC, Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101, Reykjavik, Iceland

[3] Department of Health and Human Services, Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

[4] Present address: Actavis, Hafnarfjordur, Iceland

[5] Department of Oncology, 20A, Landspitali-University Hospital, Hringbraut, 101, Reykjavik, Iceland

关键词: Oestrogen receptor;    Survival;    Pathological;    Clinical;    Breast cancer;    Risk allele;    rs380662;    LOC643714;    TOX3;   

Others  :  1079996
DOI  :  10.1186/1471-2407-12-621

 received in 2012-10-15, accepted in 2012-12-21,  发布年份 2012

【 摘 要 】

Background

The minor allele of SNP rs3803662 has been shown to correlate with increased breast cancer risk and with lower expression of TOX3. The SNP is closely located to TOX3 residing within an uncharacterised gene LOC643714. The aim of the study was to examine the association of the risk allele with expression of TOX3 and LOC643714, and of mRNA levels and genotype with clinical and pathological characteristics.

Methods

The SNP was genotyped in DNA isolated from blood and normal tissue from 160 breast cancer patients and mRNA levels were measured by microarrays and quantitative real-time (qRT)-PCR in breast tumours. Association with clinical and pathological characteristics was analysed by parametric tests.

Results

An association of the risk allele of rs3803662 with lower TOX3 expression was confirmed in oestrogen receptor (ER) positive tumours. It was more often observed in lobular tumours (p = 0.04), and carriers of the risk allele who had been diagnosed with luminal A tumours had shorter overall survival (OS) than carriers of the non-risk allele (p = 0.01). Positive correlation between the mRNA levels of TOX3 and LOC643714 was observed (r = 0.44 and p < 0.001). Association analysis with tumour pathology showed that low TOX3 and LOC643714 expression correlated with high Ki67 levels (p = 0.026 and p = 0.002) and the basal subtype (p < 0.001 and p < 0.001), whereas high expression correlated with ER (p = 0.004 and p < 0.001) and progesterone receptor (PgR) (p = 0.005 and p < 0.001) expression. Furthermore, high TOX3 and LOC643714 correlated with positive lymph nodes (p < 0.001 and p = 0.01). Patients with ER positive tumours and high levels of TOX3 mRNA had shorter overall- and distant metastasis free-survival (p = 0.017 and p = 0.021), an effect mostly attributable to patients with luminal B tumours.

Conclusions

The results suggest that the effect of the risk allele of rs3803662 is strongest in luminal A tumours and that the expression levels of TOX3 and/or LOC643714 affect the progression of breast cancer. The effect may vary depending on the subtype and developmental stage of the tumour.

【 授权许可】

   
2012 Gudmundsdottir et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010, 127(12):2893-2917.
• [2]Stratton MR, Rahman N: The emerging landscape of breast cancer susceptibility. Nat Genet 2008, 40(1):17-22.
• [3]Turnbull C, Rahman N: Genetic predisposition to breast cancer: past, present, and future. Annu Rev Genomics Hum Genet 2008, 9:321-345.
• [4]Mavaddat N, Antoniou AC, Easton DF, Garcia-Closas M: Genetic susceptibility to breast cancer. Mol Oncol 2010, 4(3):174-191.
• [5]Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R, et al.: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 2007, 447(7148):1087-1093.
• [6]Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, Gudjonsson SA, Masson G, Jakobsdottir M, Thorlacius S, Helgason A, et al.: Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 2007, 39(7):865-869.
• [7]Chen MB, Wu XY, Shen W, Wei MX, Li C, Cai B, Tao GQ, Lu PH: Association between polymorphisms of trinucleotide repeat containing 9 gene and breast cancer risk: evidence from 62,005 subjects. Breast Cancer Res Treat 2011, 126(1):177-183.
• [8]Hemminki K, Muller-Myhsok B, Lichtner P, Engel C, Chen B, Burwinkel B, Forsti A, Sutter C, Wappenschmidt B, Hellebrand H, et al.: Low-risk variants FGFR2, TNRC9 and LSP1 in German familial breast cancer patients. Int J Cancer 2010, 126(12):2858-2862.
• [9]Huijts PE, Vreeswijk MP, Kroeze-Jansema KH, Jacobi CE, Seynaeve C, Krol-Warmerdam EM, Wijers-Koster PM, Blom JC, Pooley KA, Klijn JG, et al.: Clinical correlates of low-risk variants in FGFR2, TNRC9, MAP3K1, LSP1 and 8q24 in a Dutch cohort of incident breast cancer cases. Breast Cancer Res 2007, 9(6):R78. BioMed Central Full Text
• [10]McInerney N, Colleran G, Rowan A, Walther A, Barclay E, Spain S, Jones AM, Tuohy S, Curran C, Miller N, et al.: Low penetrance breast cancer predisposition SNPs are site specific. Breast Cancer Res Treat 2009, 117(1):151-159.
• [11]Reeves GK, Travis RC, Green J, Bull D, Tipper S, Baker K, Beral V, Peto R, Bell J, Zelenika D, et al.: Incidence of breast cancer and its subtypes in relation to individual and multiple low-penetrance genetic susceptibility loci. JAMA 2010, 304(4):426-434.
• [12]Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A, Maranian M, Seal S, Ghoussaini M, Hines S, Healey CS, et al.: Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 2010, 42(6):504-507.
• [13]Udler MS, Ahmed S, Healey CS, Meyer K, Struewing J, Maranian M, Kwon EM, Zhang J, Tyrer J, Karlins E, et al.: Fine scale mapping of the breast cancer 16q12 locus. Hum Mol Genet 2010, 19(12):2507-2515.
• [14]Han W, Woo JH, Yu JH, Lee MJ, Moon HG, Kang D, Noh DY: Common genetic variants associated with breast cancer in Korean women and differential susceptibility according to intrinsic subtype. Cancer Epidemiol Biomarkers Prev 2011, 20(5):793-798.
• [15]Long J, Shu XO, Cai Q, Gao YT, Zheng Y, Li G, Li C, Gu K, Wen W, Xiang YB, et al.: Evaluation of breast cancer susceptibility loci in Chinese women. Cancer Epidemiol Biomarkers Prev 2010, 19(9):2357-2365.
• [16]Sueta A, Ito H, Kawase T, Hirose K, Hosono S, Yatabe Y, Tajima K, Tanaka H, Iwata H, Iwase H, et al.: A genetic risk predictor for breast cancer using a combination of low-penetrance polymorphisms in a Japanese population. Breast Cancer Res Treat 2011, 132(2):711-721.
• [17]Hutter CM, Young AM, Ochs-Balcom HM, Carty CL, Wang T, Chen CT, Rohan TE, Kooperberg C, Peters U: Replication of breast cancer GWAS susceptibility loci in the Women's Health Initiative African American SHARe Study. Cancer Epidemiol Biomarkers Prev 2011, 20(9):1950-1959.
• [18]Ruiz-Narvaez EA, Rosenberg L, Cozier YC, Cupples LA, Adams-Campbell LL, Palmer JR: Polymorphisms in the TOX3/LOC643714 locus and risk of breast cancer in African-American women. Cancer Epidemiol Biomarkers Prev 2010, 19(5):1320-1327.
• [19]Zheng W, Cai Q, Signorello LB, Long J, Hargreaves MK, Deming SL, Li G, Li C, Cui Y, Blot WJ: Evaluation of 11 breast cancer susceptibility loci in African-American women. Cancer Epidemiol Biomarkers Prev 2009, 18(10):2761-2764.
• [20]Liang J, Chen P, Hu Z, Shen H, Wang F, Chen L, Li M, Tang J, Wang H, Shen H: Genetic variants in trinucleotide repeat-containing 9 (TNRC9) are associated with risk of estrogen receptor positive breast cancer in a Chinese population. Breast Cancer Res Treat 2010, 124(1):237-241.
• [21]Broeks A, Schmidt MK, Sherman ME, Couch FJ, Hopper JL, Dite GS, Apicella C, Smith LD, Hammet F, Southey MC, et al.: Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium. Hum Mol Genet 2011, 20(16):3289-3303.
• [22]Garcia-Closas M, Hall P, Nevanlinna H, Pooley K, Morrison J, Richesson DA, Bojesen SE, Nordestgaard BG, Axelsson CK, Arias JI, et al.: Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet 2008, 4(4):e1000054.
• [23]Antoniou AC, Beesley J, McGuffog L, Sinilnikova OM, Healey S, Neuhausen SL, Ding YC, Rebbeck TR, Weitzel JN, Lynch HT, et al.: Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res 2010, 70(23):9742-9754.
• [24]Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA, Schmutzler RK, Versmold B, Engel C, Meindl A, Arnold N, et al.: Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet 2008, 82(4):937-948.
• [25]Orr N, Cooke R, Jones M, Fletcher O, Dudbridge F, Chilcott-Burns S, Tomczyk K, Broderick P, Houlston R, Ashworth A, et al.: Genetic variants at chromosomes 2q35, 5p12, 6q25.1, 10q26.13, and 16q12.1 influence the risk of breast cancer in men. PLoS Genet 2011, 7(9):e1002290.
• [26]National center for biotechnology information. http://www.ncbi.nlm.nih.gov/gene/643714 webcite
• [27]Margolis RL, Abraham MR, Gatchell SB, Li SH, Kidwai AS, Breschel TS, Stine OC, Callahan C, McInnis MG, Ross CA: cDNAs with long CAG trinucleotide repeats from human brain. Hum Genet 1997, 100(1):114-122.
• [28]O'Flaherty E, Kaye J: TOX defines a conserved subfamily of HMG-box proteins. BMC Genomics 2003, 4(1):13. BioMed Central Full Text
• [29]Yuan SH, Qiu Z, Ghosh A: TOX3 regulates calcium-dependent transcription in neurons. Proc Natl Acad Sci USA 2009, 106(8):2909-2914.
• [30]Dittmer S, Kovacs Z, Yuan SH, Siszler G, Kogl M, Summer H, Geerts A, Golz S, Shioda T, Methner A: TOX3 is a neuronal survival factor that induces transcription depending on the presence of CITED1 or phosphorylated CREB in the transcriptionally active complex. J Cell Sci 2010, 124(Pt 2):252-260.
• [31]Yahata T, Shao W, Endoh H, Hur J, Coser KR, Sun H, Ueda Y, Kato S, Isselbacher KJ, Brown M, et al.: Selective coactivation of estrogen-dependent transcription by CITED1 CBP/p300-binding protein. Genes Dev 2001, 15(19):2598-2612.
• [32]Shioda T, Lechleider RJ, Dunwoodie SL, Li H, Yahata T, de Caestecker MP, Fenner MH, Roberts AB, Isselbacher KJ: Transcriptional activating activity of Smad4: roles of SMAD hetero-oligomerization and enhancement by an associating transactivator. Proc Natl Acad Sci USA 1998, 95(17):9785-9790.
• [33]Riaz M, Berns EM, Sieuwerts AM, Ruigrok-Ritstier K, de Weerd V, Groenewoud A, Uitterlinden AG, Look MP, Klijn JG, Sleijfer S, et al.: Correlation of breast cancer susceptibility loci with patient characteristics, metastasis-free survival, and mRNA expression of the nearest genes. Breast Cancer Res Treat 2012, 133(3):843-851.
• [34]Smid M, Wang Y, Klijn JG, Sieuwerts AM, Zhang Y, Atkins D, Martens JW, Foekens JA: Genes associated with breast cancer metastatic to bone. J Clin Oncol 2006, 24(15):2261-2267.
• [35]Miller SA, Dykes DD, Polesky HF: A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988, 16(3):1215.
• [36]Jonsson G, Staaf J, Vallon-Christersson J, Ringner M, Holm K, Hegardt C, Gunnarsson H, Fagerholm R, Strand C, Agnarsson BA, et al.: Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics. Breast Cancer Res 2010, 12(3):R42. BioMed Central Full Text
• [37]GSE22133. http://www.ncbi.nlm.nih.gov/gds?term=GSE22133 webcite
• [38]Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, et al.: American society of clinical oncology/college of American pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med 2007, 131(1):18-43.
• [39]The R project for statistical computing. http://www.r-project.org webcite
• [40]Fasching PA, Pharoah PD, Cox A, Nevanlinna H, Bojesen SE, Karn T, Broeks A, van Leeuwen FE, Van't Veer LJ, Udo R, et al.: The role of genetic breast cancer susceptibility variants as prognostic factors. Hum Mol Genet 2012, 21(17):3926-3939.
• [41]Nordgard SH, Johansen FE, Alnaes GI, Naume B, Borresen-Dale AL, Kristensen VN: Genes harbouring susceptibility SNPs are differentially expressed in the breast cancer subtypes. Breast Cancer Res 2007, 9(6):113. BioMed Central Full Text
• [42]Mayol X, Grana X, Baldi A, Sang N, Hu Q, Giordano A: Cloning of a new member of the retinoblastoma gene family (pRb2) which binds to the E1A transforming domain. Oncogene 1993, 8(9):2561-2566.
• [43]Naylor TL, Greshock J, Wang Y, Colligon T, Yu QC, Clemmer V, Zaks TZ, Weber BL: High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization. Breast Cancer Res 2005, 7(6):R1186-1198. BioMed Central Full Text
• [44]Cowper-Sal Lari R, Zhang X, Wright JB, Bailey SD, Cole MD, Eeckhoute J, Moore JH, Lupien M: Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression. Nat Genet 2012, 44(11):1191-1198.
• [45]Badve S, Turbin D, Thorat MA, Morimiya A, Nielsen TO, Perou CM, Dunn S, Huntsman DG, Nakshatri H: FOXA1 expression in breast cancer–correlation with luminal subtype A and survival. Clin Cancer Res 2007, 13(15 Pt 1):4415-4421.