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Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.

ABSTRACT: A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.

SUBMITTER: Garcia-Closas M

PROVIDER: S-EPMC2291027 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.

Garcia-Closas Montserrat M Hall Per P Nevanlinna Heli H Pooley Karen K Morrison Jonathan J Richesson Douglas A DA Bojesen Stig E SE Nordestgaard Børge G BG Axelsson Christen K CK Arias Jose I JI Milne Roger L RL Ribas Gloria G González-Neira Anna A Benítez Javier J Zamora Pilar P Brauch Hiltrud H Justenhoven Christina C Hamann Ute U Ko Yon-Dschun YD Bruening Thomas T Haas Susanne S Dörk Thilo T Schürmann Peter P Hillemanns Peter P Bogdanova Natalia N Bremer Michael M Karstens Johann Hinrich JH Fagerholm Rainer R Aaltonen Kirsimari K Aittomäki Kristiina K von Smitten Karl K Blomqvist Carl C Mannermaa Arto A Uusitupa Matti M Eskelinen Matti M Tengström Maria M Kosma Veli-Matti VM Kataja Vesa V Chenevix-Trench Georgia G Spurdle Amanda B AB Beesley Jonathan J Chen Xiaoqing X Devilee Peter P van Asperen Christi J CJ Jacobi Catharina E CE Tollenaar Rob A E M RA Huijts Petra E A PE Klijn Jan G M JG Chang-Claude Jenny J Kropp Silke S Slanger Tracy T Flesch-Janys Dieter D Mutschelknauss Elke E Salazar Ramona R Wang-Gohrke Shan S Couch Fergus F Goode Ellen L EL Olson Janet E JE Vachon Celine C Fredericksen Zachary S ZS Giles Graham G GG Baglietto Laura L Severi Gianluca G Hopper John L JL English Dallas R DR Southey Melissa C MC Haiman Christopher A CA Henderson Brian E BE Kolonel Laurence N LN Le Marchand Loic L Stram Daniel O DO Hunter David J DJ Hankinson Susan E SE Cox David G DG Tamimi Rulla R Kraft Peter P Sherman Mark E ME Chanock Stephen J SJ Lissowska Jolanta J Brinton Louise A LA Peplonska Beata B Klijn Jan G M JG Hooning Maartje J MJ Meijers-Heijboer Han H Collee J Margriet JM van den Ouweland Ans A Uitterlinden Andre G AG Liu Jianjun J Lin Low Yen LY Yuqing Li L Humphreys Keith K Czene Kamila K Cox Angela A Balasubramanian Sabapathy P SP Cross Simon S SS Reed Malcolm W R MW Blows Fiona F Driver Kristy K Dunning Alison A Tyrer Jonathan J Ponder Bruce A J BA Sangrajrang Suleeporn S Brennan Paul P McKay James J Odefrey Fabrice F Gabrieau Valerie V Sigurdson Alice A Doody Michele M Struewing Jeffrey P JP Alexander Bruce B Easton Douglas F DF Pharoah Paul D PD

PLoS genetics 20080425 4

A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast ca ...[more]

PMID: 18437204

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Project description:Claudin-low breast cancer is a molecular type of breast cancer originally identified by gene expression profiling and reportedly associated with poor survival. Claudin-low tumors have been recognised to preferentially display a triple-negative phenotype, however only a minority of triple-negative breast cancers are claudin-low. We sought to identify an immunohistochemical profile for claudin-low tumors that could facilitate their identification in formalin fixed paraffin embedded tumor material. First, an in silico collection of ~1600 human breast cancer expression profiles was assembled and all claudin-low tumors identified. Second, genes differentially expressed between claudin-low tumors and all other molecular subtypes of breast cancer were identified. Third, a number of these top differentially expressed genes were tested using immunohistochemistry for expression in a diverse panel of breast cancer cell lines to determine their specificity for claudin-low tumors. Finally, the immunohistochemical panel found to be most characteristic of claudin-low tumors was examined in a cohort of 942 formalin fixed paraffin embedded human breast cancers with >10 years clinical follow-up to evaluate the clinico-pathologic and survival characteristics of this tumor subtype. Using this approach we determined that claudin-low breast cancer is typically negative for ER, PR, HER2, claudin 3, claudin 4, claudin 7 and E-cadherin. Claudin-low tumors identified with this immunohistochemical panel, were associated with young age of onset, higher tumor grade, larger tumor size, extensive lymphocytic infiltrate and a circumscribed tumor margin. Patients with claudin-low tumors had a worse overall survival when compared to patients with luminal A type breast cancer. Interestingly, claudin-low tumors were associated with a low local recurrence rate following breast conserving therapy. In conclusion, a limited panel of antibodies can facilitate the identification of claudin-low tumors. Furthermore, claudin-low tumors identified in this manner display similar clinical, pathologic and survival characteristics to claudin-low tumors identified from fresh frozen tumor material using gene expression profiling.

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Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.

Publications

Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.

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