Dataset Information

Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.

ABSTRACT: There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.

SUBMITTER: Hamdi Y

PROVIDER: S-EPMC5340257 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.

Hamdi Yosr Y Soucy Penny P Adoue Véronique V Michailidou Kyriaki K Canisius Sander S Lemaçon Audrey A Droit Arnaud A Andrulis Irene L IL Anton-Culver Hoda H Arndt Volker V Baynes Caroline C Blomqvist Carl C Bogdanova Natalia V NV Bojesen Stig E SE Bolla Manjeet K MK Bonanni Bernardo B Borresen-Dale Anne-Lise AL Brand Judith S JS Brauch Hiltrud H Brenner Hermann H Broeks Annegien A Burwinkel Barbara B Chang-Claude Jenny J Couch Fergus J FJ Cox Angela A Cross Simon S SS Czene Kamila K Darabi Hatef H Dennis Joe J Devilee Peter P Dörk Thilo T Dos-Santos-Silva Isabel I Eriksson Mikael M Fasching Peter A PA Figueroa Jonine J Flyger Henrik H García-Closas Montserrat M Giles Graham G GG Goldberg Mark S MS González-Neira Anna A Grenaker-Alnæs Grethe G Guénel Pascal P Haeberle Lothar L Haiman Christopher A CA Hamann Ute U Hallberg Emily E Hooning Maartje J MJ Hopper John L JL Jakubowska Anna A Jones Michael M Kabisch Maria M Kataja Vesa V Lambrechts Diether D Le Marchand Loic L Lindblom Annika A Lubinski Jan J Mannermaa Arto A Maranian Mel M Margolin Sara S Marme Frederik F Milne Roger L RL Neuhausen Susan L SL Nevanlinna Heli H Neven Patrick P Olswold Curtis C Peto Julian J Plaseska-Karanfilska Dijana D Pylkäs Katri K Radice Paolo P Rudolph Anja A Sawyer Elinor J EJ Schmidt Marjanka K MK Shu Xiao-Ou XO Southey Melissa C MC Swerdlow Anthony A Tollenaar Rob A E M RA Tomlinson Ian I Torres Diana D Truong Thérèse T Vachon Celine C Van Den Ouweland Ans M W AM Wang Qin Q Winqvist Robert R Zheng Wei W Benitez Javier J Chenevix-Trench Georgia G Dunning Alison M AM Pharoah Paul D P PD Kristensen Vessela V Hall Per P Easton Douglas F DF Pastinen Tomi T Nord Silje S Simard Jacques J

Oncotarget 20161201 49

There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a li ...[more]

PMID: 27792995

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Project description:Breast cancer is a heterogeneous disease with various histological features and molecular markers. These are utilized for the prediction of clinical outcome and therapeutic decision making. In addition to well established markers such as HER2 overexpression and estrogen and progesterone receptor (ER and PR) status, chromosomal instability is evolving as an important hallmark of cancers. The HER2/TOP2A locus is of great importance in breast cancer. The copy number variability at this locus has been proposed to be a marker for the degree of chromosomal instability. We therefore developed a Single Nucleotide Polymorphism (SNP) assay to evaluate allelic imbalance at the HER2/TOP2A locus in three different entities of primary breast tumors.Eleven SNPs were carefully selected and detected by real time PCR using DNA extracted from paired (histologically normal and tumor) paraffin-embedded tissues. Primary breast tumors of 44 patients were included, 15 tumors with HER2 overexpression, 16 triple negative tumors, defined by the absence of HER2 overexpression and a negative ER and PR status and 13 ER and PR positive tumors without HER2 overexpression. As controls, histologically normal breast tissues from 10 patients with no breast tumor were included.Allelic imbalance was observed in 13/15 (87 %) HER2 positive tumors, the remaining 2 being inconclusive. Of the 16 triple negative tumors, 12 (75 %) displayed instability, 3 (19 %) displayed no instability, and 1 was inconclusive. Of the 13 hormone receptor positive tumors, 5 (38 %) displayed allelic imbalance, while 8 did not.We conclude that the SNP assay is suitable for rapid testing of allelic (im)balance at the HER2/TOP2A locus using paraffin-embedded tissues. Based on allelic imbalance at this locus, both triple negative and ER and PR positive breast tumors can be subcategorized. The clinical relevance of the allelic (im)balance status at the HER2/TOP2A locus in breast cancer is subject of future study.The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2086062232155220.

Project description:BackgroundBreast cancer is a partially heritable trait and genome-wide association studies (GWAS) have identified over 180 common genetic variants associated with breast cancer. We have previously performed breast cancer GWAS in Latinas and identified a strongly protective single nucleotide polymorphism (SNP) at 6q25, with the protective minor allele originating from indigenous American ancestry. Here we report on fine mapping of the 6q25 locus in an expanded sample of Latinas.MethodsWe performed GWAS in 2385 cases and 6416 controls who were either US Latinas or Mexican women. We replicated the top SNPs in 2412 cases and 1620 controls of US Latina, Mexican, and Colombian women. In addition, we validated the top novel variants in studies of African, Asian and European ancestry. In each dataset we used logistic regression models to test the association between SNPs and breast cancer risk and corrected for genetic ancestry using either principal components or genetic ancestry inferred from ancestry informative markers using a model-based approach.ResultsWe identified a novel set of SNPs at the 6q25 locus associated with genome-wide levels of significance (p = 3.3 × 10- 8 - 6.0 × 10- 9) not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD (r2 > 0.9) with each other, with the top SNP, rs3778609, associated with breast cancer with an odds ratio (OR) and 95% confidence interval (95% CI) of 0.76 (0.70-0.84). In a replication in women of Latin American origin, we also observed a consistent effect (OR 0.88; 95% CI 0.78-0.99; p = 0.037). We also performed a meta-analysis of these SNPs in East Asians, African ancestry and European ancestry populations and also observed a consistent effect (rs3778609, OR 0.95; 95% CI 0.91-0.97; p = 0.0017).ConclusionOur study adds to evidence about the importance of the 6q25 locus for breast cancer susceptibility. Our finding also highlights the utility of performing additional searches for genetic variants for breast cancer in non-European populations.

Dataset Information

Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.

Publications

Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.

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