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 Brenner; Annegien 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 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; NBCS Collaborators

doi:10.18632/oncotarget.12818

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 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, NBCS Collaborators

Department of Clinical Medicine

19 Citations (Scopus)

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.

Original language	English
Journal	OncoTarget
Volume	7
Issue number	49
Pages (from-to)	80140-80163
Number of pages	24
ISSN	1949-2553
DOIs	https://doi.org/10.18632/oncotarget.12818
Publication status	Published - 6 Dec 2016

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Hamdi, Y., Soucy, P., Adoue, V., Michailidou, K., Canisius, S., Lemaçon, A., Droit, A., Andrulis, I. L., Anton-Culver, H., Arndt, V., Baynes, C., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Bonanni, B., Borresen-Dale, A.-L., Brand, J. S., Brauch, H., ... NBCS Collaborators (2016). Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21. OncoTarget, 7(49), 80140-80163. https://doi.org/10.18632/oncotarget.12818

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, 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 & NBCS Collaborators 2016, 'Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21', OncoTarget, vol. 7, no. 49, pp. 80140-80163. https://doi.org/10.18632/oncotarget.12818

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title = "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.",

author = "Yosr Hamdi and Penny Soucy and V{\'e}ronique Adoue and Kyriaki Michailidou and Sander Canisius and Audrey Lema{\c c}on and Arnaud Droit and Andrulis, {Irene L} and Hoda Anton-Culver and Volker Arndt and Caroline Baynes and Carl Blomqvist and Bogdanova, {Natalia V} and Bojesen, {Stig E} and Bolla, {Manjeet K} and Bernardo Bonanni and Anne-Lise Borresen-Dale and Brand, {Judith S} and Hiltrud Brauch and Hermann Brenner and Annegien Broeks and Barbara Burwinkel and Jenny Chang-Claude and Couch, {Fergus J} and Angela Cox and Cross, {Simon S} and Kamila Czene and Hatef Darabi and Joe Dennis and Peter Devilee and Thilo D{\"o}rk and Isabel Dos-Santos-Silva and Mikael Eriksson and Fasching, {Peter A} and Jonine Figueroa and Henrik Flyger and Montserrat Garc{\'i}a-Closas and Giles, {Graham G} and Goldberg, {Mark S} and Anna Gonz{\'a}lez-Neira and Grethe Grenaker-Aln{\ae}s and Pascal Gu{\'e}nel and Lothar Haeberle and Haiman, {Christopher A} and Ute Hamann and Emily Hallberg and Hooning, {Maartje J} and Hopper, {John L} and Anna Jakubowska and Michael Jones and {NBCS Collaborators}",

year = "2016",

month = dec,

day = "6",

doi = "10.18632/oncotarget.12818",

language = "English",

volume = "7",

pages = "80140--80163",

journal = "OncoTarget",

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T1 - Association of breast cancer risk with genetic variants showing differential allelic expression

T2 - Identification of a novel breast cancer susceptibility locus at 4q21

AU - Hamdi, Yosr

AU - Soucy, Penny

AU - Adoue, Véronique

AU - Michailidou, Kyriaki

AU - Canisius, Sander

AU - Lemaçon, Audrey

AU - Droit, Arnaud

AU - Andrulis, Irene L

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Baynes, Caroline

AU - Blomqvist, Carl

AU - Bogdanova, Natalia V

AU - Bojesen, Stig E

AU - Bolla, Manjeet K

AU - Bonanni, Bernardo

AU - Borresen-Dale, Anne-Lise

AU - Brand, Judith S

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Broeks, Annegien

AU - Burwinkel, Barbara

AU - Chang-Claude, Jenny

AU - Couch, Fergus J

AU - Cox, Angela

AU - Cross, Simon S

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Dennis, Joe

AU - Devilee, Peter

AU - Dörk, Thilo

AU - Dos-Santos-Silva, Isabel

AU - Eriksson, Mikael

AU - Fasching, Peter A

AU - Figueroa, Jonine

AU - Flyger, Henrik

AU - García-Closas, Montserrat

AU - Giles, Graham G

AU - Goldberg, Mark S

AU - González-Neira, Anna

AU - Grenaker-Alnæs, Grethe

AU - Guénel, Pascal

AU - Haeberle, Lothar

AU - Haiman, Christopher A

AU - Hamann, Ute

AU - Hallberg, Emily

AU - Hooning, Maartje J

AU - Hopper, John L

AU - Jakubowska, Anna

AU - Jones, Michael

AU - NBCS Collaborators

PY - 2016/12/6

Y1 - 2016/12/6

N2 - 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.

AB - 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.

U2 - 10.18632/oncotarget.12818

DO - 10.18632/oncotarget.12818

M3 - Journal article

C2 - 27792995

SN - 1949-2553

VL - 7

SP - 80140

EP - 80163

JO - OncoTarget

JF - OncoTarget

IS - 49

ER -

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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