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Title: The role of genetic breast cancer susceptibility variants as prognostic factors.
Authors: Fasching PA,  Pharoah PD,  Cox A,  Nevanlinna H,  Bojesen SE,  Karn T,  Broeks A,  van Leeuwen FE,  van't Veer LJ,  Udo R,  Dunning AM,  Greco D,  Aittomäki K,  Blomqvist C,  Shah M,  Nordestgaard BG,  Flyger H,  Hopper JL,  Southey MC,  Apicella C,  Garcia-Closas M,  Sherman M,  Lissowska J,  Seynaeve C,  Huijts PE,  Tollenaar RA,  Ziogas A,  Ekici AB,  Rauh C,  Mannermaa A,  Kataja V,  Kosma VM,  Hartikainen JM,  Andrulis IL,  Ozcelik H,  Mulligan AM,  Glendon G,  Hall P,  Czene K,  Liu J,  Chang-Claude J,  Wang-Gohrke S,  Eilber U,  Nickels S,  Dörk T,  Schiekel M,  Bremer M,  Park-Simon TW,  Giles GG,  Severi G,  Baglietto L,  Hooning MJ,  Martens JW,  Jager A,  Kriege M,  Lindblom A,  Margolin S,  Couch FJ,  Stevens KN,  Olson JE,  Kosel M,  Cross SS,  Balasubramanian SP,  Reed MW,  Miron A,  John EM,  Winqvist R,  Pylkäs K,  Jukkola-Vuorinen A,  Kauppila S,  Burwinkel B,  Marme F,  Schneeweiss A,  Sohn C,  Chenevix-Trench G,  kConFab Investigators,  Lambrechts D,  Dieudonne AS,  Hatse S,  van Limbergen E,  Benitez J,  Milne RL,  Zamora MP,  Pérez JI,  Bonanni B,  Peissel B,  Loris B,  Peterlongo P,  Rajaraman P,  Schonfeld SJ,  Anton-Culver H,  Devilee P,  Beckmann MW,  Slamon DJ,  Phillips KA,  Figueroa JD,  Humphreys MK,  Easton DF,  Schmidt MK
Journal: Hum Mol Genet
Date: 2012 Sep 1
Branches: HREB
PubMed ID: 22532573
PMC ID: PMC3412377
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.