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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]

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