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

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

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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 in expression of these genes in breast carcinomas.

Original languageEnglish
Pages (from-to)80140-80163
Number of pages24
JournalOncotarget
Volume7
Issue number49
DOIs
Publication statusPublished - 6 Dec 2016
Externally publishedYes

Keywords

  • Association studies
  • Breast cancer
  • Cis-regulatory variants
  • Differential allelic expression
  • Genetic susceptibility

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