RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.

Antonis C Antoniou; Olga M Sinilnikova; Jacques Simard; Mélanie Léoné; Martine Dumont; Susan L Neuhausen; Jeffery P Struewing; Dominique Stoppa-Lyonnet; Laure Barjhoux; David J Hughes; Isabelle Coupier; Muriel Belotti; Christine Lasset; Valérie Bonadona; Yves-Jean Bignon; Timothy R Rebbeck; Theresa Wagner; Henry T Lynch; Susan M Domchek; Katherine L Nathanson; Judy E Garber; Jeffrey Weitzel; Steven A Narod; Gail Tomlinson; Olufunmilayo I Olopade; Andrew Godwin; Claudine Isaacs; Anna Jakubowska; Jan Lubinski; Jacek Gronwald; Bohdan Górski; Tomasz Byrski; Tomasz Huzarski; Susan Peock; Margaret Cook; Caroline Baynes; Alexandra Murray; Mark Rogers; Peter A Daly; Huw Dorkins; Rita K Schmutzler; Beatrix Versmold; Christoph Engel; Alfons Meindl; Norbert Arnold; Dieter Niederacher; Helmut Deissler; Amanda B Spurdle; Xiaoqing Chen; Nicola Waddell; Nicole Cloonan; Tomas Kirchhoff; Kenneth Offit; Eitan Friedman; Bella Kaufmann; Yael Laitman; Gilli Galore; Gad Rennert; Flavio Lejbkowicz; Leon Raskin; Irene L Andrulis; Eduard Ilyushik; Hilmi Ozcelik; Peter Devilee; Maaike P G Vreeswijk; Mark H Greene; Sheila A Prindiville; Ana Osorio; Javier Benitez; Michal Zikan; Csilla I Szabo; Outi Kilpivaara; Heli Nevanlinna; Ute Hamann; Francine Durocher; Adalgeir Arason; Fergus J Couch; Douglas F Easton; Georgia Chenevix-Trench

doi:10.1086/522611

RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.

Antonis C Antoniou, Olga M Sinilnikova, Jacques Simard, Mélanie Léoné, Martine Dumont, Susan L Neuhausen, Jeffery P Struewing, Dominique Stoppa-Lyonnet, Laure Barjhoux, David J Hughes, Isabelle Coupier, Muriel Belotti, Christine Lasset, Valérie Bonadona, Yves-Jean Bignon, Timothy R Rebbeck, Theresa Wagner, Henry T Lynch, Susan M Domchek, Katherine L NathansonJudy E Garber, Jeffrey Weitzel, Steven A Narod, Gail Tomlinson, Olufunmilayo I Olopade, Andrew Godwin, Claudine Isaacs, Anna Jakubowska, Jan Lubinski, Jacek Gronwald, Bohdan Górski, Tomasz Byrski, Tomasz Huzarski, Susan Peock, Margaret Cook, Caroline Baynes, Alexandra Murray, Mark Rogers, Peter A Daly, Huw Dorkins, Rita K Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Norbert Arnold, Dieter Niederacher, Helmut Deissler, Amanda B Spurdle, Xiaoqing Chen, Nicola Waddell, Nicole Cloonan, Tomas Kirchhoff, Kenneth Offit, Eitan Friedman, Bella Kaufmann, Yael Laitman, Gilli Galore, Gad Rennert, Flavio Lejbkowicz, Leon Raskin, Irene L Andrulis, Eduard Ilyushik, Hilmi Ozcelik, Peter Devilee, Maaike P G Vreeswijk, Mark H Greene, Sheila A Prindiville, Ana Osorio, Javier Benitez, Michal Zikan, Csilla I Szabo, Outi Kilpivaara, Heli Nevanlinna, Ute Hamann, Francine Durocher, Adalgeir Arason, Fergus J Couch, Douglas F Easton, Georgia Chenevix-Trench

Landspitali - The National University Hospital of Iceland

Research output: Contribution to journal › Article › peer-review

Abstract

RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of RAD51, 135G-->C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.

Original language	English
Journal	American Journal of Human Genetics
DOIs	https://doi.org/10.1086/522611
Publication status	Published - 1 Dec 2007

Other keywords

Adolescent
Adult
Alternative Splicing
BRCA1 Protein
BRCA2 Protein
Breast Neoplasms
DNA Primers
DNA Repair
Family
Female
Genetic Variation
Heterozygote
Homozygote
Humans
Middle Aged
Mutation
Polymorphism, Single Nucleotide
Rad51 Recombinase
Reverse Transcriptase Polymerase Chain Reaction

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10.1086/522611

http://dx.doi.org/10.1086/522611

Cite this

Antoniou, A. C., Sinilnikova, O. M., Simard, J., Léoné, M., Dumont, M., Neuhausen, S. L., Struewing, J. P., Stoppa-Lyonnet, D., Barjhoux, L., Hughes, D. J., Coupier, I., Belotti, M., Lasset, C., Bonadona, V., Bignon, Y.-J., Rebbeck, T. R., Wagner, T., Lynch, H. T., Domchek, S. M., ... Chenevix-Trench, G. (2007). RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. American Journal of Human Genetics. https://doi.org/10.1086/522611

@article{10673b4296ac478091916338a344c453,

title = "RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.",

abstract = "RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of RAD51, 135G-->C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.",

keywords = "Adolescent, Adult, Alternative Splicing, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, DNA Primers, DNA Repair, Family, Female, Genetic Variation, Heterozygote, Homozygote, Humans, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Rad51 Recombinase, Reverse Transcriptase Polymerase Chain Reaction, Adolescent, Adult, Alternative Splicing, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, DNA Primers, DNA Repair, Family, Female, Genetic Variation, Heterozygote, Homozygote, Humans, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Rad51 Recombinase, Reverse Transcriptase Polymerase Chain Reaction",

author = "Antoniou, {Antonis C} and Sinilnikova, {Olga M} and Jacques Simard and M{\'e}lanie L{\'e}on{\'e} and Martine Dumont and Neuhausen, {Susan L} and Struewing, {Jeffery P} and Dominique Stoppa-Lyonnet and Laure Barjhoux and Hughes, {David J} and Isabelle Coupier and Muriel Belotti and Christine Lasset and Val{\'e}rie Bonadona and Yves-Jean Bignon and Rebbeck, {Timothy R} and Theresa Wagner and Lynch, {Henry T} and Domchek, {Susan M} and Nathanson, {Katherine L} and Garber, {Judy E} and Jeffrey Weitzel and Narod, {Steven A} and Gail Tomlinson and Olopade, {Olufunmilayo I} and Andrew Godwin and Claudine Isaacs and Anna Jakubowska and Jan Lubinski and Jacek Gronwald and Bohdan G{\'o}rski and Tomasz Byrski and Tomasz Huzarski and Susan Peock and Margaret Cook and Caroline Baynes and Alexandra Murray and Mark Rogers and Daly, {Peter A} and Huw Dorkins and Schmutzler, {Rita K} and Beatrix Versmold and Christoph Engel and Alfons Meindl and Norbert Arnold and Dieter Niederacher and Helmut Deissler and Spurdle, {Amanda B} and Xiaoqing Chen and Nicola Waddell and Nicole Cloonan and Tomas Kirchhoff and Kenneth Offit and Eitan Friedman and Bella Kaufmann and Yael Laitman and Gilli Galore and Gad Rennert and Flavio Lejbkowicz and Leon Raskin and Andrulis, {Irene L} and Eduard Ilyushik and Hilmi Ozcelik and Peter Devilee and Vreeswijk, {Maaike P G} and Greene, {Mark H} and Prindiville, {Sheila A} and Ana Osorio and Javier Benitez and Michal Zikan and Szabo, {Csilla I} and Outi Kilpivaara and Heli Nevanlinna and Ute Hamann and Francine Durocher and Adalgeir Arason and Couch, {Fergus J} and Easton, {Douglas F} and Georgia Chenevix-Trench",

year = "2007",

month = dec,

day = "1",

doi = "10.1086/522611",

language = "English",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

}

Antoniou, AC, Sinilnikova, OM, Simard, J, Léoné, M, Dumont, M, Neuhausen, SL, Struewing, JP, Stoppa-Lyonnet, D, Barjhoux, L, Hughes, DJ, Coupier, I, Belotti, M, Lasset, C, Bonadona, V, Bignon, Y-J, Rebbeck, TR, Wagner, T, Lynch, HT, Domchek, SM, Nathanson, KL, Garber, JE, Weitzel, J, Narod, SA, Tomlinson, G, Olopade, OI, Godwin, A, Isaacs, C, Jakubowska, A, Lubinski, J, Gronwald, J, Górski, B, Byrski, T, Huzarski, T, Peock, S, Cook, M, Baynes, C, Murray, A, Rogers, M, Daly, PA, Dorkins, H, Schmutzler, RK, Versmold, B, Engel, C, Meindl, A, Arnold, N, Niederacher, D, Deissler, H, Spurdle, AB, Chen, X, Waddell, N, Cloonan, N, Kirchhoff, T, Offit, K, Friedman, E, Kaufmann, B, Laitman, Y, Galore, G, Rennert, G, Lejbkowicz, F, Raskin, L, Andrulis, IL, Ilyushik, E, Ozcelik, H, Devilee, P, Vreeswijk, MPG, Greene, MH, Prindiville, SA, Osorio, A, Benitez, J, Zikan, M, Szabo, CI, Kilpivaara, O, Nevanlinna, H, Hamann, U, Durocher, F, Arason, A, Couch, FJ, Easton, DF & Chenevix-Trench, G 2007, 'RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.', American Journal of Human Genetics. https://doi.org/10.1086/522611

TY - JOUR

T1 - RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.

AU - Antoniou, Antonis C

AU - Sinilnikova, Olga M

AU - Simard, Jacques

AU - Léoné, Mélanie

AU - Dumont, Martine

AU - Neuhausen, Susan L

AU - Struewing, Jeffery P

AU - Stoppa-Lyonnet, Dominique

AU - Barjhoux, Laure

AU - Hughes, David J

AU - Coupier, Isabelle

AU - Belotti, Muriel

AU - Lasset, Christine

AU - Bonadona, Valérie

AU - Bignon, Yves-Jean

AU - Rebbeck, Timothy R

AU - Wagner, Theresa

AU - Lynch, Henry T

AU - Domchek, Susan M

AU - Nathanson, Katherine L

AU - Garber, Judy E

AU - Weitzel, Jeffrey

AU - Narod, Steven A

AU - Tomlinson, Gail

AU - Olopade, Olufunmilayo I

AU - Godwin, Andrew

AU - Isaacs, Claudine

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Gronwald, Jacek

AU - Górski, Bohdan

AU - Byrski, Tomasz

AU - Huzarski, Tomasz

AU - Peock, Susan

AU - Cook, Margaret

AU - Baynes, Caroline

AU - Murray, Alexandra

AU - Rogers, Mark

AU - Daly, Peter A

AU - Dorkins, Huw

AU - Schmutzler, Rita K

AU - Versmold, Beatrix

AU - Engel, Christoph

AU - Meindl, Alfons

AU - Arnold, Norbert

AU - Niederacher, Dieter

AU - Deissler, Helmut

AU - Spurdle, Amanda B

AU - Chen, Xiaoqing

AU - Waddell, Nicola

AU - Cloonan, Nicole

AU - Kirchhoff, Tomas

AU - Offit, Kenneth

AU - Friedman, Eitan

AU - Kaufmann, Bella

AU - Laitman, Yael

AU - Galore, Gilli

AU - Rennert, Gad

AU - Lejbkowicz, Flavio

AU - Raskin, Leon

AU - Andrulis, Irene L

AU - Ilyushik, Eduard

AU - Ozcelik, Hilmi

AU - Devilee, Peter

AU - Vreeswijk, Maaike P G

AU - Greene, Mark H

AU - Prindiville, Sheila A

AU - Osorio, Ana

AU - Benitez, Javier

AU - Zikan, Michal

AU - Szabo, Csilla I

AU - Kilpivaara, Outi

AU - Nevanlinna, Heli

AU - Hamann, Ute

AU - Durocher, Francine

AU - Arason, Adalgeir

AU - Couch, Fergus J

AU - Easton, Douglas F

AU - Chenevix-Trench, Georgia

PY - 2007/12/1

Y1 - 2007/12/1

N2 - RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of RAD51, 135G-->C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.

AB - RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of RAD51, 135G-->C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.

KW - Adolescent

KW - Adult

KW - Alternative Splicing

KW - BRCA1 Protein

KW - BRCA2 Protein

KW - Breast Neoplasms

KW - DNA Primers

KW - DNA Repair

KW - Family

KW - Female

KW - Genetic Variation

KW - Heterozygote

KW - Homozygote

KW - Humans

KW - Middle Aged

KW - Mutation

KW - Polymorphism, Single Nucleotide

KW - Rad51 Recombinase

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Adolescent

KW - Adult

KW - Alternative Splicing

KW - BRCA1 Protein

KW - BRCA2 Protein

KW - Breast Neoplasms

KW - DNA Primers

KW - DNA Repair

KW - Family

KW - Female

KW - Genetic Variation

KW - Heterozygote

KW - Homozygote

KW - Humans

KW - Middle Aged

KW - Mutation

KW - Polymorphism, Single Nucleotide

KW - Rad51 Recombinase

KW - Reverse Transcriptase Polymerase Chain Reaction

U2 - 10.1086/522611

DO - 10.1086/522611

M3 - Article

C2 - 17999359

SN - 0002-9297

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

ER -

RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.

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