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FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

ABSTRACT: BACKGROUND:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS:Data were combined from 49 studies, including 53?835 cases and 50?156 controls, of which 89?050 (46?450 cases and 42?600 controls) were of European ancestry, 12?893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.

SUBMITTER: Agarwal D

PROVIDER: S-EPMC3929867 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

Agarwal D D Pineda S S Michailidou K K Herranz J J Pita G G Moreno L T LT Alonso M R MR Dennis J J Wang Q Q Bolla M K MK Meyer K B KB Menéndez-Rodríguez P P Hardisson D D Mendiola M M González-Neira A A Lindblom A A Margolin S S Swerdlow A A Ashworth A A Orr N N Jones M M Matsuo K K Ito H H Iwata H H Kondo N N Hartman M M Hui M M Lim W Y WY Iau P T -C PT Sawyer E E Tomlinson I I Kerin M M Miller N N Kang D D Choi J -Y J- Park S K SK Noh D -Y D- Hopper J L JL Schmidt D F DF Makalic E E Southey M C MC Teo S H SH Yip C H CH Sivanandan K K Tay W -T W- Brauch H H Brüning T T Hamann U U Dunning A M AM Shah M M Andrulis I L IL Knight J A JA Glendon G G Tchatchou S S Schmidt M K MK Broeks A A Rosenberg E H EH van't Veer L J LJ Fasching P A PA Renner S P SP Ekici A B AB Beckmann M W MW Shen C -Y C- Hsiung C -N C- Yu J -C J- Hou M -F M- Blot W W Cai Q Q Wu A H AH Tseng C -C C- Van Den Berg D D Stram D O DO Cox A A Brock I W IW Reed M W R MW Muir K K Lophatananon A A Stewart-Brown S S Siriwanarangsan P P Zheng W W Deming-Halverson S S Shrubsole M J MJ Long J J Shu X -O X- Lu W W Gao Y -T Y- Zhang B B Radice P P Peterlongo P P Manoukian S S Mariette F F Sangrajrang S S McKay J J Couch F J FJ Toland A E AE Yannoukakos D D Fletcher O O Johnson N N dos Santos Silva I I Peto J J Marme F F Burwinkel B B Guénel P P Truong T T Sanchez M M Mulot C C Bojesen S E SE Nordestgaard B G BG Flyer H H Brenner H H Dieffenbach A K AK Arndt V V Stegmaier C C Mannermaa A A Kataja V V Kosma V -M V- Hartikainen J M JM Lambrechts D D Yesilyurt B T BT Floris G G Leunen K K Chang-Claude J J Rudolph A A Seibold P P Flesch-Janys D D Wang X X Olson J E JE Vachon C C Purrington K K Giles G G GG Severi G G Baglietto L L Haiman C A CA Henderson B E BE Schumacher F F Marchand L Le LL Simard J J Dumont M M Goldberg M S MS Labréche F F Winqvist R R Pylkäs K K Jukkola-Vuorinen A A Grip M M Devilee P P Tollenaar R A E M RA Seynaeve C C García-Closas M M Chanock S J SJ Lissowska J J Figueroa J D JD Czene K K Eriksson M M Humphreys K K Darabi H H Hooning M J MJ Kriege M M Collée J M JM Tilanus-Linthorst M M Li J J Jakubowska A A Lubinski J J Jaworska-Bieniek K K Durda K K Nevanlinna H H Muranen T A TA Aittomäki K K Blomqvist C C Bogdanova N N Dörk T T Hall P P Chenevix-Trench G G Easton D F DF Pharroah P D P PD Arias-Perez J I JI Zamora P P Benítez J J Milne R L RL

British journal of cancer 20140201 4

<h4>Background</h4>Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.<h4>Methods</h4>Data were combined from 49 studies, ...[more]

PMID: 24548884

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Project description:Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.

Dataset Information

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

Publications

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

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