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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ICR Authors

Jones, Michael
 Swerdlow, Anthony

Authors

Hamdi, Y
Soucy, P
Adoue, V
Michailidou, K
Canisius, S
Lemaçon, A
Droit, A
Andrulis, IL
Anton-Culver, H
Arndt, V
Baynes, C
Blomqvist, C
Bogdanova, NV
Bojesen, SE
Bolla, MK
Bonanni, B
Borresen-Dale, A-L
Brand, JS
Brauch, H
Brenner, H
Broeks, A
Burwinkel, B
Chang-Claude, J
NBCS Collaborators,
Couch, FJ
Cox, A
Cross, SS
Czene, K
Darabi, H
Dennis, J
Devilee, P
Dörk, T
Dos-Santos-Silva, I
Eriksson, M
Fasching, PA
Figueroa, J
Flyger, H
García-Closas, M
Giles, GG
Goldberg, MS
González-Neira, A
Grenaker-Alnæs, G
Guénel, P
Haeberle, L
Haiman, CA
Hamann, U
Hallberg, E
Hooning, MJ
Hopper, JL
Jakubowska, A
Jones, M
Kabisch, M
Kataja, V
Lambrechts, D
Le Marchand, L
Lindblom, A
Lubinski, J
Mannermaa, A
Maranian, M
Margolin, S
Marme, F
Milne, RL
Neuhausen, SL
Nevanlinna, H
Neven, P
Olswold, C
Peto, J
Plaseska-Karanfilska, D
Pylkäs, K
Radice, P
Rudolph, A
Sawyer, EJ
Schmidt, MK
Shu, X-O
Southey, MC
Swerdlow, A
Tollenaar, RAEM
Tomlinson, I
Torres, D
Truong, T
Vachon, C
Van Den Ouweland, AMW
Wang, Q
Winqvist, R
kConFab/AOCS Investigators,
Zheng, W
Benitez, J
Chenevix-Trench, G
Dunning, AM
Pharoah, PDP
Kristensen, V
Hall, P
Easton, DF
Pastinen, T
Nord, S
Simard, J

Document Type

Journal Article

Date

2016-12-06

Date Accepted

2016-10-13

Date Available

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.

Citation

Oncotarget, 2016, 7 (49), pp. 80140 - 80163

DOI

10.18632/oncotarget.12818

URI

https://repository.icr.ac.uk/handle/internal/204

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

IMPACT JOURNALS LLC

ISSN

1949-2553

eISSN

1949-2553

Collections

Breast Cancer Research
Genetics and Epidemiology

Research Team

Aetiological Epidemiology

Notes