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Title: Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.
Authors: Kabisch M,  Lorenzo Bermejo J,  Dünnebier T,  Ying S,  Michailidou K,  Bolla MK,  Wang Q,  Dennis J,  Shah M,  Perkins BJ,  Czene K,  Darabi H,  Eriksson M,  Bojesen SE,  Nordestgaard BG,  Nielsen SF,  Flyger H,  Lambrechts D,  Neven P,  Peeters S,  Weltens C,  Couch FJ,  Olson JE,  Wang X,  Purrington K,  Chang-Claude J,  Rudolph A,  Seibold P,  Flesch-Janys D,  Peto J,  Dos-Santos-Silva I,  Johnson N,  Fletcher O,  Nevanlinna H,  Muranen TA,  Aittomäki K,  Blomqvist C,  Schmidt MK,  Broeks A,  Cornelissen S,  Hogervorst FB,  Li J,  Brand JS,  Humphreys K,  Guénel P,  Truong T,  Menegaux F,  Sanchez M,  Burwinkel B,  Marmé F,  Yang R,  Bugert P,  González-Neira A,  Benitez J,  Pilar Zamora M,  Arias Perez JI,  Cox A,  Cross SS,  Reed MW,  Andrulis IL,  Knight JA,  Glendon G,  Tchatchou S,  Sawyer EJ,  Tomlinson I,  Kerin MJ,  Miller N,  kConFab Investigators,  Australian Ovarian Cancer Study Group,  Haiman CA,  Schumacher F,  Henderson BE,  Le Marchand L,  Lindblom A,  Margolin S,  Hooning MJ,  Hollestelle A,  Kriege M,  Koppert LB,  Hopper JL,  Southey MC,  Tsimiklis H,  Apicella C,  Slettedahl S,  Toland AE,  Vachon C,  Yannoukakos D,  Giles GG,  Milne RL,  McLean C,  Fasching PA,  Ruebner M,  Ekici AB,  Beckmann MW,  Brenner H,  Dieffenbach AK,  Arndt V,  Stegmaier C,  Ashworth A,  Orr N,  Schoemaker MJ,  Swerdlow A,  García-Closas M,  Figueroa J,  Chanock SJ,  Lissowska J,  Goldberg MS,  Labrčche F,  Dumont M,  Winqvist R,  Pylkäs K,  Jukkola-Vuorinen A,  Grip M,  Brauch H,  Brüning T,  Ko YD,  GENICA Network,  Radice P,  Peterlongo P,  Scuvera G,  Fortuzzi S,  Bogdanova N,  Dörk T,  Mannermaa A,  Kataja V,  Kosma VM,  Hartikainen JM,  Devilee P,  Tollenaar RA,  Seynaeve C,  Van Asperen CJ,  Jakubowska A,  Lubinski J,  Jaworska-Bieniek K,  Durda K,  Zheng W,  Shrubsole MJ,  Cai Q,  Torres D,  Anton-Culver H,  Kristensen V,  Bacot F,  Tessier DC,  Vincent D,  Luccarini C,  Baynes C,  Ahmed S,  Maranian M,  Simard J,  Chenevix-Trench G,  Hall P,  Pharoah PD,  Dunning AM,  Easton DF,  Hamann U
Journal: Carcinogenesis
Date: 2015 Feb
Branches: HREB, LTG, OD, OEEB
PubMed ID: 25586992
PMC ID: PMC4335262
Abstract: The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3' untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated.