Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

Y. Hamdi, P. Soucy, K.B. Kuchenbaeker, T. Pastinen, A. Droit, A. Lemaçon, J. Adlard, K. Aittomäki, I.L. Andrulis, A. Arason, N. Arnold, B.K. Arun, J. Azzollini, A. Bane, L. Barjhoux, D. Barrowdale, J. Benitez, P. Berthet, M.J. Blok, K. Bobolis & 152 others V. Bonadona, B. Bonanni, A.R. Bradbury, C. Brewer, B. Buecher, S.S. Buys, M.A. Caligo, J. Chiquette, W.K. Chung, K.B.M. Claes, M.B. Daly, F. Damiola, R. Davidson, M. De la Hoya, K. De Leeneer, O. Diez, Y.C. Ding, R. Dolcetti, S.M. Domchek, C.M. Dorfling, D. Eccles, R. Eeles, Z. Einbeigi, B. Ejlertsen, EMBRACE [Unknown], C. Engel, D. Gareth Evans, L. Feliubadalo, L. Foretova, F. Fostira, W.D. Foulkes, G. Fountzilas, E. Friedman, D. Frost, P. Ganschow, P.A. Ganz, J. Garber, S.A. Gayther, GEMO Study Collaborators, A.-M. Gerdes, G. Glendon, A.K. Godwin, D.E. Goldgar, M.H. Greene, J. Gronwald, E. Hahnen, U. Hamann, T.V.O. Hansen, S. Hart, J.L. Hays, HEBON [Unknown], F.B.L. Hogervorst, P.J. Hulick, E.N. Imyanitov, C. Isaacs, L. Izatt, A. Jakubowska, P. James, R. Janavicius, U.B. Jensen, E.M. John, V. Joseph, W. Just, K. Kaczmarek, B.Y. Karlan, KConFab Investigators, C.M. Kets, J. Kirk, M. Kriege, Y. Laitman, M. Laurent, C. Lazaro, G. Leslie, J. Lester, F. Lesueur, A. Liljegren, N. Loman, J.T. Loud, S. Manoukian, M. Mariani, S. Mazoyer, L. McGuffog, H.E.J. Meijers-Heijboer, A. Meindl, A. Miller, M. Montagna, A.M. Mulligan, K.L. Nathanson, S.L. Neuhausen, H. Nevanlinna, R.L. Nussbaum, E. Olah, O.I. Olopade, K.-R. Ong, J.C. Oosterwijk, A. Osorio, L. Papi, S.K. Park, I.S. Pedersen, B. Peissel, P.P. Segura, P. Peterlongo, C.M. Phelan, P. Radice, J. Rantala, C. Rappaport-Fuerhauser, G. Rennert, A. Richardson, M. Robson, G.C. Rodriguez, M.A. Rookus, R.K. Schmutzler, N. Sevenet, P.D. Shah, C.F. Singer, T.P. Slavin, K. Snape, J. Sokolowska, I.M.H. Sønderstrup, M. Southey, A.B. Spurdle, Z. Stadler, D. Stoppa-Lyonnet, G. Sukiennicki, C. Sutter, Y. Tan, M.-K. Tea, M.R. Teixeira, A. Teulé, S.-H. Teo, M.B. Terry, M. Thomassen, L. Tihomirova, M. Tischkowitz, S. Tognazzo, A.E. Toland, N. Tung, A.M.W. van den Ouweland, R.B. van der Luijt, K. van Engelen, E.J. van Rensburg, R. Varon-Mateeva, B. Wappenschmidt, J.T. Wijnen, T. Rebbeck, G. Chenevix-Trench, K. Offit, F.J. Couch, S. Nord, D.F. Easton, A.C. Antoniou, J. Simard

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk. © 2016, The Author(s).
Original languageEnglish
Pages (from-to)117-134
Number of pages18
JournalBreast Cancer Research and Treatment
Volume161
Issue number1
DOIs
Publication statusPublished - 2017

Fingerprint

Heterozygote
Single Nucleotide Polymorphism
Breast Neoplasms
Mutation
Estrogen Receptors
Genes
Quantitative Trait Loci
Progesterone Receptors
Computer Simulation
Ovarian Neoplasms
Breast
Research Personnel
Genome
Neoplasms

Keywords

  • BRCA1 and BRCA2 mutation carriers
  • Breast cancer
  • Cis-regulatory variants
  • Differential allelic expression
  • Genetic modifiers
  • Genetic susceptibility
  • ACAT1 gene
  • adult
  • Article
  • ATM gene
  • breast cancer
  • cancer risk
  • cancer susceptibility
  • chromosome 11q
  • computer model
  • controlled study
  • female
  • gene
  • gene expression
  • gene locus
  • gene mutation
  • genetic association
  • genetic variability
  • heterozygote
  • human
  • major clinical study
  • NPAT gene
  • oncogene
  • priority journal
  • quantitative trait locus
  • single nucleotide polymorphism
  • tumor suppressor gene
  • allele
  • breast tumor
  • chromosome 11
  • genetic predisposition
  • genetic variation
  • mutation
  • risk
  • tumor marker
  • Alleles
  • Biomarkers, Tumor
  • Breast Neoplasms
  • Chromosomes, Human, Pair 11
  • Female
  • Gene Expression
  • Genes, BRCA1
  • Genes, BRCA2
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Heterozygote
  • Humans
  • Mutation
  • Quantitative Trait Loci
  • Risk

Cite this

Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3. / Hamdi, Y.; Soucy, P.; Kuchenbaeker, K.B.; Pastinen, T.; Droit, A.; Lemaçon, A.; Adlard, J.; Aittomäki, K.; Andrulis, I.L.; Arason, A.; Arnold, N.; Arun, B.K.; Azzollini, J.; Bane, A.; Barjhoux, L.; Barrowdale, D.; Benitez, J.; Berthet, P.; Blok, M.J.; Bobolis, K.; Bonadona, V.; Bonanni, B.; Bradbury, A.R.; Brewer, C.; Buecher, B.; Buys, S.S.; Caligo, M.A.; Chiquette, J.; Chung, W.K.; Claes, K.B.M.; Daly, M.B.; Damiola, F.; Davidson, R.; De la Hoya, M.; De Leeneer, K.; Diez, O.; Ding, Y.C.; Dolcetti, R.; Domchek, S.M.; Dorfling, C.M.; Eccles, D.; Eeles, R.; Einbeigi, Z.; Ejlertsen, B.; [Unknown], EMBRACE; Engel, C.; Gareth Evans, D.; Feliubadalo, L.; Foretova, L.; Fostira, F.; Foulkes, W.D.; Fountzilas, G.; Friedman, E.; Frost, D.; Ganschow, P.; Ganz, P.A.; Garber, J.; Gayther, S.A.; Collaborators, GEMO Study; Gerdes, A.-M.; Glendon, G.; Godwin, A.K.; Goldgar, D.E.; Greene, M.H.; Gronwald, J.; Hahnen, E.; Hamann, U.; Hansen, T.V.O.; Hart, S.; Hays, J.L.; [Unknown], HEBON; Hogervorst, F.B.L.; Hulick, P.J.; Imyanitov, E.N.; Isaacs, C.; Izatt, L.; Jakubowska, A.; James, P.; Janavicius, R.; Jensen, U.B.; John, E.M.; Joseph, V.; Just, W.; Kaczmarek, K.; Karlan, B.Y.; Investigators, KConFab; Kets, C.M.; Kirk, J.; Kriege, M.; Laitman, Y.; Laurent, M.; Lazaro, C.; Leslie, G.; Lester, J.; Lesueur, F.; Liljegren, A.; Loman, N.; Loud, J.T.; Manoukian, S.; Mariani, M.; Mazoyer, S.; McGuffog, L.; Meijers-Heijboer, H.E.J.; Meindl, A.; Miller, A.; Montagna, M.; Mulligan, A.M.; Nathanson, K.L.; Neuhausen, S.L.; Nevanlinna, H.; Nussbaum, R.L.; Olah, E.; Olopade, O.I.; Ong, K.-R.; Oosterwijk, J.C.; Osorio, A.; Papi, L.; Park, S.K.; Pedersen, I.S.; Peissel, B.; Segura, P.P.; Peterlongo, P.; Phelan, C.M.; Radice, P.; Rantala, J.; Rappaport-Fuerhauser, C.; Rennert, G.; Richardson, A.; Robson, M.; Rodriguez, G.C.; Rookus, M.A.; Schmutzler, R.K.; Sevenet, N.; Shah, P.D.; Singer, C.F.; Slavin, T.P.; Snape, K.; Sokolowska, J.; Sønderstrup, I.M.H.; Southey, M.; Spurdle, A.B.; Stadler, Z.; Stoppa-Lyonnet, D.; Sukiennicki, G.; Sutter, C.; Tan, Y.; Tea, M.-K.; Teixeira, M.R.; Teulé, A.; Teo, S.-H.; Terry, M.B.; Thomassen, M.; Tihomirova, L.; Tischkowitz, M.; Tognazzo, S.; Toland, A.E.; Tung, N.; van den Ouweland, A.M.W.; van der Luijt, R.B.; van Engelen, K.; van Rensburg, E.J.; Varon-Mateeva, R.; Wappenschmidt, B.; Wijnen, J.T.; Rebbeck, T.; Chenevix-Trench, G.; Offit, K.; Couch, F.J.; Nord, S.; Easton, D.F.; Antoniou, A.C.; Simard, J.

In: Breast Cancer Research and Treatment, Vol. 161, No. 1, 2017, p. 117-134.

Research output: Contribution to journalArticle

Hamdi, Y, Soucy, P, Kuchenbaeker, KB, Pastinen, T, Droit, A, Lemaçon, A, Adlard, J, Aittomäki, K, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Azzollini, J, Bane, A, Barjhoux, L, Barrowdale, D, Benitez, J, Berthet, P, Blok, MJ, Bobolis, K, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caligo, MA, Chiquette, J, Chung, WK, Claes, KBM, Daly, MB, Damiola, F, Davidson, R, De la Hoya, M, De Leeneer, K, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, Eccles, D, Eeles, R, Einbeigi, Z, Ejlertsen, B, [Unknown], EMBRACE, Engel, C, Gareth Evans, D, Feliubadalo, L, Foretova, L, Fostira, F, Foulkes, WD, Fountzilas, G, Friedman, E, Frost, D, Ganschow, P, Ganz, PA, Garber, J, Gayther, SA, Collaborators, GEMOS, Gerdes, A-M, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gronwald, J, Hahnen, E, Hamann, U, Hansen, TVO, Hart, S, Hays, JL, [Unknown], HEBON, Hogervorst, FBL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Joseph, V, Just, W, Kaczmarek, K, Karlan, BY, Investigators, KC, Kets, CM, Kirk, J, Kriege, M, Laitman, Y, Laurent, M, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Liljegren, A, Loman, N, Loud, JT, Manoukian, S, Mariani, M, Mazoyer, S, McGuffog, L, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nussbaum, RL, Olah, E, Olopade, OI, Ong, K-R, Oosterwijk, JC, Osorio, A, Papi, L, Park, SK, Pedersen, IS, Peissel, B, Segura, PP, Peterlongo, P, Phelan, CM, Radice, P, Rantala, J, Rappaport-Fuerhauser, C, Rennert, G, Richardson, A, Robson, M, Rodriguez, GC, Rookus, MA, Schmutzler, RK, Sevenet, N, Shah, PD, Singer, CF, Slavin, TP, Snape, K, Sokolowska, J, Sønderstrup, IMH, Southey, M, Spurdle, AB, Stadler, Z, Stoppa-Lyonnet, D, Sukiennicki, G, Sutter, C, Tan, Y, Tea, M-K, Teixeira, MR, Teulé, A, Teo, S-H, Terry, MB, Thomassen, M, Tihomirova, L, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van den Ouweland, AMW, van der Luijt, RB, van Engelen, K, van Rensburg, EJ, Varon-Mateeva, R, Wappenschmidt, B, Wijnen, JT, Rebbeck, T, Chenevix-Trench, G, Offit, K, Couch, FJ, Nord, S, Easton, DF, Antoniou, AC & Simard, J 2017, 'Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3', Breast Cancer Research and Treatment, vol. 161, no. 1, pp. 117-134. https://doi.org/10.1007/s10549-016-4018-2
Hamdi, Y. ; Soucy, P. ; Kuchenbaeker, K.B. ; Pastinen, T. ; Droit, A. ; Lemaçon, A. ; Adlard, J. ; Aittomäki, K. ; Andrulis, I.L. ; Arason, A. ; Arnold, N. ; Arun, B.K. ; Azzollini, J. ; Bane, A. ; Barjhoux, L. ; Barrowdale, D. ; Benitez, J. ; Berthet, P. ; Blok, M.J. ; Bobolis, K. ; Bonadona, V. ; Bonanni, B. ; Bradbury, A.R. ; Brewer, C. ; Buecher, B. ; Buys, S.S. ; Caligo, M.A. ; Chiquette, J. ; Chung, W.K. ; Claes, K.B.M. ; Daly, M.B. ; Damiola, F. ; Davidson, R. ; De la Hoya, M. ; De Leeneer, K. ; Diez, O. ; Ding, Y.C. ; Dolcetti, R. ; Domchek, S.M. ; Dorfling, C.M. ; Eccles, D. ; Eeles, R. ; Einbeigi, Z. ; Ejlertsen, B. ; [Unknown], EMBRACE ; Engel, C. ; Gareth Evans, D. ; Feliubadalo, L. ; Foretova, L. ; Fostira, F. ; Foulkes, W.D. ; Fountzilas, G. ; Friedman, E. ; Frost, D. ; Ganschow, P. ; Ganz, P.A. ; Garber, J. ; Gayther, S.A. ; Collaborators, GEMO Study ; Gerdes, A.-M. ; Glendon, G. ; Godwin, A.K. ; Goldgar, D.E. ; Greene, M.H. ; Gronwald, J. ; Hahnen, E. ; Hamann, U. ; Hansen, T.V.O. ; Hart, S. ; Hays, J.L. ; [Unknown], HEBON ; Hogervorst, F.B.L. ; Hulick, P.J. ; Imyanitov, E.N. ; Isaacs, C. ; Izatt, L. ; Jakubowska, A. ; James, P. ; Janavicius, R. ; Jensen, U.B. ; John, E.M. ; Joseph, V. ; Just, W. ; Kaczmarek, K. ; Karlan, B.Y. ; Investigators, KConFab ; Kets, C.M. ; Kirk, J. ; Kriege, M. ; Laitman, Y. ; Laurent, M. ; Lazaro, C. ; Leslie, G. ; Lester, J. ; Lesueur, F. ; Liljegren, A. ; Loman, N. ; Loud, J.T. ; Manoukian, S. ; Mariani, M. ; Mazoyer, S. ; McGuffog, L. ; Meijers-Heijboer, H.E.J. ; Meindl, A. ; Miller, A. ; Montagna, M. ; Mulligan, A.M. ; Nathanson, K.L. ; Neuhausen, S.L. ; Nevanlinna, H. ; Nussbaum, R.L. ; Olah, E. ; Olopade, O.I. ; Ong, K.-R. ; Oosterwijk, J.C. ; Osorio, A. ; Papi, L. ; Park, S.K. ; Pedersen, I.S. ; Peissel, B. ; Segura, P.P. ; Peterlongo, P. ; Phelan, C.M. ; Radice, P. ; Rantala, J. ; Rappaport-Fuerhauser, C. ; Rennert, G. ; Richardson, A. ; Robson, M. ; Rodriguez, G.C. ; Rookus, M.A. ; Schmutzler, R.K. ; Sevenet, N. ; Shah, P.D. ; Singer, C.F. ; Slavin, T.P. ; Snape, K. ; Sokolowska, J. ; Sønderstrup, I.M.H. ; Southey, M. ; Spurdle, A.B. ; Stadler, Z. ; Stoppa-Lyonnet, D. ; Sukiennicki, G. ; Sutter, C. ; Tan, Y. ; Tea, M.-K. ; Teixeira, M.R. ; Teulé, A. ; Teo, S.-H. ; Terry, M.B. ; Thomassen, M. ; Tihomirova, L. ; Tischkowitz, M. ; Tognazzo, S. ; Toland, A.E. ; Tung, N. ; van den Ouweland, A.M.W. ; van der Luijt, R.B. ; van Engelen, K. ; van Rensburg, E.J. ; Varon-Mateeva, R. ; Wappenschmidt, B. ; Wijnen, J.T. ; Rebbeck, T. ; Chenevix-Trench, G. ; Offit, K. ; Couch, F.J. ; Nord, S. ; Easton, D.F. ; Antoniou, A.C. ; Simard, J. / Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3. In: Breast Cancer Research and Treatment. 2017 ; Vol. 161, No. 1. pp. 117-134.
@article{cc43a9151d624de59ad543f18007b5f2,
title = "Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3",
abstract = "Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk. {\circledC} 2016, The Author(s).",
keywords = "BRCA1 and BRCA2 mutation carriers, Breast cancer, Cis-regulatory variants, Differential allelic expression, Genetic modifiers, Genetic susceptibility, ACAT1 gene, adult, Article, ATM gene, breast cancer, cancer risk, cancer susceptibility, chromosome 11q, computer model, controlled study, female, gene, gene expression, gene locus, gene mutation, genetic association, genetic variability, heterozygote, human, major clinical study, NPAT gene, oncogene, priority journal, quantitative trait locus, single nucleotide polymorphism, tumor suppressor gene, allele, breast tumor, chromosome 11, genetic predisposition, genetic variation, mutation, risk, tumor marker, Alleles, Biomarkers, Tumor, Breast Neoplasms, Chromosomes, Human, Pair 11, Female, Gene Expression, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Genetic Variation, Heterozygote, Humans, Mutation, Quantitative Trait Loci, Risk",
author = "Y. Hamdi and P. Soucy and K.B. Kuchenbaeker and T. Pastinen and A. Droit and A. Lema{\cc}on and J. Adlard and K. Aittom{\"a}ki and I.L. Andrulis and A. Arason and N. Arnold and B.K. Arun and J. Azzollini and A. Bane and L. Barjhoux and D. Barrowdale and J. Benitez and P. Berthet and M.J. Blok and K. Bobolis and V. Bonadona and B. Bonanni and A.R. Bradbury and C. Brewer and B. Buecher and S.S. Buys and M.A. Caligo and J. Chiquette and W.K. Chung and K.B.M. Claes and M.B. Daly and F. Damiola and R. Davidson and {De la Hoya}, M. and {De Leeneer}, K. and O. Diez and Y.C. Ding and R. Dolcetti and S.M. Domchek and C.M. Dorfling and D. Eccles and R. Eeles and Z. Einbeigi and B. Ejlertsen and EMBRACE [Unknown] and C. Engel and {Gareth Evans}, D. and L. Feliubadalo and L. Foretova and F. Fostira and W.D. Foulkes and G. Fountzilas and E. Friedman and D. Frost and P. Ganschow and P.A. Ganz and J. Garber and S.A. Gayther and Collaborators, {GEMO Study} and A.-M. Gerdes and G. Glendon and A.K. Godwin and D.E. Goldgar and M.H. Greene and J. Gronwald and E. Hahnen and U. Hamann and T.V.O. Hansen and S. Hart and J.L. Hays and HEBON [Unknown] and F.B.L. Hogervorst and P.J. Hulick and E.N. Imyanitov and C. Isaacs and L. Izatt and A. Jakubowska and P. James and R. Janavicius and U.B. Jensen and E.M. John and V. Joseph and W. Just and K. Kaczmarek and B.Y. Karlan and KConFab Investigators and C.M. Kets and J. Kirk and M. Kriege and Y. Laitman and M. Laurent and C. Lazaro and G. Leslie and J. Lester and F. Lesueur and A. Liljegren and N. Loman and J.T. Loud and S. Manoukian and M. Mariani and S. Mazoyer and L. McGuffog and H.E.J. Meijers-Heijboer and A. Meindl and A. Miller and M. Montagna and A.M. Mulligan and K.L. Nathanson and S.L. Neuhausen and H. Nevanlinna and R.L. Nussbaum and E. Olah and O.I. Olopade and K.-R. Ong and J.C. Oosterwijk and A. Osorio and L. Papi and S.K. Park and I.S. Pedersen and B. Peissel and P.P. Segura and P. Peterlongo and C.M. Phelan and P. Radice and J. Rantala and C. Rappaport-Fuerhauser and G. Rennert and A. Richardson and M. Robson and G.C. Rodriguez and M.A. Rookus and R.K. Schmutzler and N. Sevenet and P.D. Shah and C.F. Singer and T.P. Slavin and K. Snape and J. Sokolowska and I.M.H. S{\o}nderstrup and M. Southey and A.B. Spurdle and Z. Stadler and D. Stoppa-Lyonnet and G. Sukiennicki and C. Sutter and Y. Tan and M.-K. Tea and M.R. Teixeira and A. Teul{\'e} and S.-H. Teo and M.B. Terry and M. Thomassen and L. Tihomirova and M. Tischkowitz and S. Tognazzo and A.E. Toland and N. Tung and {van den Ouweland}, A.M.W. and {van der Luijt}, R.B. and {van Engelen}, K. and {van Rensburg}, E.J. and R. Varon-Mateeva and B. Wappenschmidt and J.T. Wijnen and T. Rebbeck and G. Chenevix-Trench and K. Offit and F.J. Couch and S. Nord and D.F. Easton and A.C. Antoniou and J. Simard",
note = "Cited By :1 Export Date: 14 February 2018 CODEN: BCTRD Correspondence Address: Simard, J.; Genomics Center, Centre Hospitalier Universitaire de Qu{\'e}bec Research Center and Laval University, 2705 Laurier Boulevard, Canada; email: Jacques.Simard@crchudequebec.ulaval.ca",
year = "2017",
doi = "10.1007/s10549-016-4018-2",
language = "English",
volume = "161",
pages = "117--134",
journal = "Breast Cancer Research and Treatment",
issn = "0167-6806",
publisher = "Springer New York LLC",
number = "1",

}

TY - JOUR

T1 - Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

AU - Hamdi, Y.

AU - Soucy, P.

AU - Kuchenbaeker, K.B.

AU - Pastinen, T.

AU - Droit, A.

AU - Lemaçon, A.

AU - Adlard, J.

AU - Aittomäki, K.

AU - Andrulis, I.L.

AU - Arason, A.

AU - Arnold, N.

AU - Arun, B.K.

AU - Azzollini, J.

AU - Bane, A.

AU - Barjhoux, L.

AU - Barrowdale, D.

AU - Benitez, J.

AU - Berthet, P.

AU - Blok, M.J.

AU - Bobolis, K.

AU - Bonadona, V.

AU - Bonanni, B.

AU - Bradbury, A.R.

AU - Brewer, C.

AU - Buecher, B.

AU - Buys, S.S.

AU - Caligo, M.A.

AU - Chiquette, J.

AU - Chung, W.K.

AU - Claes, K.B.M.

AU - Daly, M.B.

AU - Damiola, F.

AU - Davidson, R.

AU - De la Hoya, M.

AU - De Leeneer, K.

AU - Diez, O.

AU - Ding, Y.C.

AU - Dolcetti, R.

AU - Domchek, S.M.

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AU - Collaborators, GEMO Study

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N1 - Cited By :1 Export Date: 14 February 2018 CODEN: BCTRD Correspondence Address: Simard, J.; Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Canada; email: Jacques.Simard@crchudequebec.ulaval.ca

PY - 2017

Y1 - 2017

N2 - Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk. © 2016, The Author(s).

AB - Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk. © 2016, The Author(s).

KW - BRCA1 and BRCA2 mutation carriers

KW - Breast cancer

KW - Cis-regulatory variants

KW - Differential allelic expression

KW - Genetic modifiers

KW - Genetic susceptibility

KW - ACAT1 gene

KW - adult

KW - Article

KW - ATM gene

KW - breast cancer

KW - cancer risk

KW - cancer susceptibility

KW - chromosome 11q

KW - computer model

KW - controlled study

KW - female

KW - gene

KW - gene expression

KW - gene locus

KW - gene mutation

KW - genetic association

KW - genetic variability

KW - heterozygote

KW - human

KW - major clinical study

KW - NPAT gene

KW - oncogene

KW - priority journal

KW - quantitative trait locus

KW - single nucleotide polymorphism

KW - tumor suppressor gene

KW - allele

KW - breast tumor

KW - chromosome 11

KW - genetic predisposition

KW - genetic variation

KW - mutation

KW - risk

KW - tumor marker

KW - Alleles

KW - Biomarkers, Tumor

KW - Breast Neoplasms

KW - Chromosomes, Human, Pair 11

KW - Female

KW - Gene Expression

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Heterozygote

KW - Humans

KW - Mutation

KW - Quantitative Trait Loci

KW - Risk

U2 - 10.1007/s10549-016-4018-2

DO - 10.1007/s10549-016-4018-2

M3 - Article

VL - 161

SP - 117

EP - 134

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 1

ER -