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The role of genetic breast cancer susceptibility variants as prognostic factors.

ABSTRACT: Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.

SUBMITTER: Fasching PA

PROVIDER: S-EPMC3412377 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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The role of genetic breast cancer susceptibility variants as prognostic factors.

Fasching Peter A PA Pharoah Paul D P PD Cox Angela A Nevanlinna Heli H Bojesen Stig E SE Karn Thomas T Broeks Annegien A van Leeuwen Flora E FE van't Veer Laura J LJ Udo Renate R Dunning Alison M AM Greco Dario D Aittomäki Kristiina K Blomqvist Carl C Shah Mitul M Nordestgaard Børge G BG Flyger Henrik H Hopper John L JL Southey Melissa C MC Apicella Carmel C Garcia-Closas Montserrat M Sherman Mark M Lissowska Jolanta J Seynaeve Caroline C Huijts Petra E A PE Tollenaar Rob A E M RA Ziogas Argyrios A Ekici Arif B AB Rauh Claudia C Mannermaa Arto A Kataja Vesa V Kosma Veli-Matti VM Hartikainen Jaana M JM Andrulis Irene L IL Ozcelik Hilmi H Mulligan Anna-Marie AM Glendon Gord G Hall Per P Czene Kamila K Liu Jianjun J Chang-Claude Jenny J Wang-Gohrke Shan S Eilber Ursula U Nickels Stefan S Dörk Thilo T Schiekel Maria M Bremer Michael M Park-Simon Tjoung-Won TW Giles Graham G GG Severi Gianluca G Baglietto Laura L Hooning Maartje J MJ Martens John W M JW Jager Agnes A Kriege Mieke M Lindblom Annika A Margolin Sara S Couch Fergus J FJ Stevens Kristen N KN Olson Janet E JE Kosel Matthew M Cross Simon S SS Balasubramanian Sabapathy P SP Reed Malcolm W R MW Miron Alexander A John Esther M EM Winqvist Robert R Pylkäs Katri K Jukkola-Vuorinen Arja A Kauppila Saila S Burwinkel Barbara B Marme Frederik F Schneeweiss Andreas A Sohn Christof C Chenevix-Trench Georgia G Lambrechts Diether D Dieudonne Anne-Sophie AS Hatse Sigrid S van Limbergen Erik E Benitez Javier J Milne Roger L RL Zamora M Pilar MP Pérez José Ignacio Arias JI Bonanni Bernardo B Peissel Bernard B Loris Bernard B Peterlongo Paolo P Rajaraman Preetha P Schonfeld Sara J SJ Anton-Culver Hoda H Devilee Peter P Beckmann Matthias W MW Slamon Dennis J DJ Phillips Kelly-Anne KA Figueroa Jonine D JD Humphreys Manjeet K MK Easton Douglas F DF Schmidt Marjanka K MK

Human molecular genetics 20120424 17

Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available foll ...[more]

PMID: 22532573

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Project description:BACKGROUND:Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer. METHODS:To assess interactions between single-nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11?892 control subjects nested within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7-rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 × 10(-4)) was done. Case-case comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided. RESULTS:We confirmed the association of 14 SNPs with breast cancer risk (P(trend) = 2.57 × 10(-3) -3.96 × 10(-19)). Three SNPs (LSP1-rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor-positive than estrogen receptor-negative breast cancer (P(heterogeneity) = .0016 for FGFR2-rs2981582 and P(heterogeneity) = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor-positive than progesterone receptor-negative breast cancer (P(heterogeneity) = .0028). CONCLUSION:This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer.

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The role of genetic breast cancer susceptibility variants as prognostic factors.

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The role of genetic breast cancer susceptibility variants as prognostic factors.

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