PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1.
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ABSTRACT:
SUBMITTER: Jiao X
PROVIDER: S-EPMC5732689 | biostudies-literature | 2017 Nov
REPOSITORIES: biostudies-literature
Publications
<i>PHIP</i> - a novel candidate breast cancer susceptibility locus on 6q14.1.
Jiao Xiang X Aravidis Christos C Marikkannu Rajeshwari R Rantala Johanna J Picelli Simone S Adamovic Tatjana T Liu Tao T Maguire Paula P Kremeyer Barbara B Luo Liping L von Holst Susanna S Kontham Vinaykumar V Thutkawkorapin Jessada J Margolin Sara S Du Quan Q Lundin Johanna J Michailidou Kyriaki K Bolla Manjeet K MK Wang Qin Q Dennis Joe J Lush Michael M Ambrosone Christine B CB Andrulis Irene L IL Anton-Culver Hoda H Antonenkova Natalia N NN Arndt Volker V Beckmann Matthias W MW Blomqvist Carl C Blot William W Boeckx Bram B Bojesen Stig E SE Bonanni Bernardo B Brand Judith S JS Brauch Hiltrud H Brenner Hermann H Broeks Annegien A Brüning Thomas T Burwinkel Barbara B Cai Qiuyin Q Chang-Claude Jenny J Couch Fergus J FJ Cox Angela A Cross Simon S SS Deming-Halverson Sandra L SL Devilee Peter P Dos-Santos-Silva Isabel I Dörk Thilo T Eriksson Mikael M Fasching Peter A PA Figueroa Jonine J Flesch-Janys Dieter D Flyger Henrik H Gabrielson Marike M García-Closas Montserrat M Giles Graham G GG González-Neira Anna A Guénel Pascal P Guo Qi Q Gündert Melanie M Haiman Christopher A CA Hallberg Emily E Hamann Ute U Harrington Patricia P Hooning Maartje J MJ Hopper John L JL Huang Guanmengqian G Jakubowska Anna A Jones Michael E ME Kerin Michael J MJ Kosma Veli-Matti VM Kristensen Vessela N VN Lambrechts Diether D Le Marchand Loic L Lubinski Jan J Mannermaa Arto A Martens John W M JWM Meindl Alfons A Milne Roger L RL Mulligan Anna Marie AM Neuhausen Susan L SL Nevanlinna Heli H Peto Julian J Pylkäs Katri K Radice Paolo P Rhenius Valerie V Sawyer Elinor J EJ Schmidt Marjanka K MK Schmutzler Rita K RK Seynaeve Caroline C Shah Mitul M Simard Jacques J Southey Melissa C MC Swerdlow Anthony J AJ Truong Thérèse T Wendt Camilla C Winqvist Robert R Zheng Wei W Benitez Javier J Dunning Alison M AM Pharoah Paul D P PDP Easton Douglas F DF Czene Kamila K Hall Per P Lindblom Annika A
Oncotarget 20171012 61
Most non-<i>BRCA1/2</i> breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to br ...[more]
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Project description:BackgroundThe arcOGEN genome-wide association study reported the rs9350591 C/T single nucleotide polymorphism (SNP) as marking a region on chromosome 6q14.1 that is associated with hip osteoarthritis (OA) in Europeans, with an odds ratio (OR) of 1.18 and a p-value of 2.42 × 10(-9). rs9350591 is an intergenic SNP surrounded by seven genes within 1 Mb. Six of the genes are expressed in cartilage. We sought to characterise this signal to assess whether the association of rs9350591 with OA is mediated by modulating gene expression.MethodsTotal RNA was extracted from hip or knee cartilage of 161 OA patients and from hip cartilage of 29 non-OA patients who had undergone hip replacements as a result of neck-of-femur (NOF) fractures. We used quantitative PCR (qPCR) to measure overall gene expression, and pyrosequencing to assess allelic expression of the genes. A mesenchymal stem cell (MSC) differentiation model was used to assess gene expression during chondrogenesis.ResultsWe identified a significant decrease in the expression of SENP6 (p = 0.005) and MYO6 (p = 0.026) in OA hip cartilage relative to the non-OA hip control cartilage. However, we found no evidence for a correlation between gene expression and rs9350591 genotype for any of the six genes. In addition, we identified expression quantitative trait loci (eQTLs) operating on COL12A1, TMEM30A, SENP6 and MYO6, although these were not relevant to the OA associated signal. Finally, all genes were dynamically expressed during chondrogenesis.ConclusionsThe regulation of gene expression at this locus is complex, highlighted by the down-regulation of SENP6 and MYO6 in OA hip cartilage and by eQTLs operating on four of the genes at the locus. However, modulation of gene expression in the end-stage OA cartilage that we have investigated is not the mechanism by which this association signal is operating. As implied by the dynamic patterns of gene expression throughout chondrogenesis, the association signal marked by rs9350591 could instead be exerting its effects during joint development.
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