Dataset Information

Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.

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.

SUBMITTER: Kabisch M

PROVIDER: S-EPMC4335262 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.

Kabisch Maria M Lorenzo Bermejo Justo J Dünnebier Thomas T Ying Shibo S Michailidou Kyriaki K Bolla Manjeet K MK Wang Qin Q Dennis Joe J Shah Mitul M Perkins Barbara J BJ Czene Kamila K Darabi Hatef H Eriksson Mikael M Bojesen Stig E SE Nordestgaard Børge G BG Nielsen Sune F SF Flyger Henrik H Lambrechts Diether D Neven Patrick P Peeters Stephanie S Weltens Caroline C Couch Fergus J FJ Olson Janet E JE Wang Xianshu X Purrington Kristen K Chang-Claude Jenny J Rudolph Anja A Seibold Petra P Flesch-Janys Dieter D Peto Julian J dos-Santos-Silva Isabel I Johnson Nichola N Fletcher Olivia O Nevanlinna Heli H Muranen Taru A TA Aittomäki Kristiina K Blomqvist Carl C Schmidt Marjanka K MK Broeks Annegien A Cornelissen Sten S Hogervorst Frans B L FB Li Jingmei J Brand Judith S JS Humphreys Keith K Guénel Pascal P Truong Thérèse T Menegaux Florence F Sanchez Marie M Burwinkel Barbara B Marmé Frederik F Yang Rongxi R Bugert Peter P González-Neira Anna A Benitez Javier J Pilar Zamora M M Arias Perez Jose I JI Cox Angela A Cross Simon S SS Reed Malcolm W R MW Andrulis Irene L IL Knight Julia A JA Glendon Gord G Tchatchou Sandrine S Sawyer Elinor J EJ Tomlinson Ian I Kerin Michael J MJ Miller Nicola N Haiman Christopher A CA Schumacher Fredrick F Henderson Brian E BE Le Marchand Loic L Lindblom Annika A Margolin Sara S Hooning Maartje J MJ Hollestelle Antoinette A Kriege Mieke M Koppert Linetta B LB Hopper John L JL Southey Melissa C MC Tsimiklis Helen H Apicella Carmel C Slettedahl Seth S Toland Amanda E AE Vachon Celine C Yannoukakos Drakoulis D Giles Graham G GG Milne Roger L RL McLean Catriona C Fasching Peter A PA Ruebner Matthias M Ekici Arif B AB Beckmann Matthias W MW Brenner Hermann H Dieffenbach Aida K AK Arndt Volker V Stegmaier Christa C Ashworth Alan A Orr Nicholas N Schoemaker Minouk J MJ Swerdlow Anthony A García-Closas Montserrat M Figueroa Jonine J Chanock Stephen J SJ Lissowska Jolanta J Goldberg Mark S MS Labrèche France F Dumont Martine M Winqvist Robert R Pylkäs Katri K Jukkola-Vuorinen Arja A Grip Mervi M Brauch Hiltrud H Brüning Thomas T Ko Yon-Dschun YD Radice Paolo P Peterlongo Paolo P Scuvera Giulietta G Fortuzzi Stefano S Bogdanova Natalia N Dörk Thilo T Mannermaa Arto A Kataja Vesa V Kosma Veli-Matti VM Hartikainen Jaana M JM Devilee Peter P Tollenaar Robert A E M RA Seynaeve Caroline C Van Asperen Christi J CJ Jakubowska Anna A Lubinski Jan J Jaworska-Bieniek Katarzyna K Durda Katarzyna K Zheng Wei W Shrubsole Martha J MJ Cai Qiuyin Q Torres Diana D Anton-Culver Hoda H Kristensen Vessela V Bacot François F Tessier Daniel C DC Vincent Daniel D Luccarini Craig C Baynes Caroline C Ahmed Shahana S Maranian Mel M Simard Jacques J Chenevix-Trench Georgia G Hall Per P Pharoah Paul D P PD Dunning Alison M AM Easton Douglas F DF Hamann Ute U

Carcinogenesis 20150113 2

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 Ass ...[more]

PMID: 25586992

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Project description:A single inner centromere protein (INCENP) found throughout eukaryotes modulates Aurora B kinase activity and chromosomal passenger complex (CPC) localization, which is essential for timely mitotic progression. It has been proposed that INCENP might act as a rheostat to regulate Aurora B activity through mitosis, with successively higher activity threshold levels for chromosome alignment, the spindle checkpoint, anaphase spindle transfer and finally spindle elongation and cytokinesis. It remains mechanistically unclear how this would be achieved. Here, we reveal that the urochordate, Oikopleura dioica, possesses two INCENP paralogs, which display distinct localizations and subfunctionalization in order to complete M-phase. INCENPa was localized on chromosome arms and centromeres by prometaphase, and modulated Aurora B activity to mediate H3S10/S28 phosphorylation, chromosome condensation, spindle assembly and transfer of the CPC to the central spindle. Polo-like kinase (Plk1) recruitment to CDK1 phosphorylated INCENPa was crucial for INCENPa-Aurora B enrichment on centromeres. The second paralog, INCENPb was enriched on centromeres from prometaphase, and relocated to the central spindle at anaphase onset. In the absence of INCENPa, meiotic spindles failed to form, and homologous chromosomes did not segregate. INCENPb was not required for early to mid M-phase events but became essential for the activity and localization of Aurora B on the central spindle and midbody during cytokinesis in order to allow abscission to occur. Together, our results demonstrate that INCENP paralog switching on centromeres modulates Aurora B kinase localization, thus chronologically regulating CPC functions during fast embryonic divisions in the urochordate O. dioica. Abbreviations: CCAN: constitutive centromere-associated network; CENPs: centromere proteins; cmRNA: capped messenger RNA; CPC: chromosomal passenger complex; INCENP: inner centromere protein; Plk1: polo-like kinase 1; PP1: protein phosphatase 1; PP2A: protein phosphatase 2A; SAC: spindle assembly checkpoint; SAH: single ?-helix domain.

Dataset Information

Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.

Publications

Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.

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