BRCA2 hypomorphic missense variants confer moderate risks of breast cancer

Hermela Shimelis, Romy L.S. Mesman, Catharina Von Nicolai, Asa Ehlen, Lucia Guidugli, Charlotte Martin, Fabienne M.G.R. Calléja, Huong Meeks, Emily Hallberg, Jamie Hinton, Jenna Lilyquist, Chunling Hu, Cora M. Aalfs, Kristiina Aittomäki, Irene Andrulis, Hoda Anton-Culver, Volker Arndt, Matthias W. Beckmann, Javier Benitez, Natalia V. Bogdanova & 32 others Stig E. Bojesen, Manjeet K. Bolla, Anne Lise Borresen-Dale, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Annegien Broeks, Barbara Brouwers, Thomas Brüning, Barbara Burwinkel, Jenny Chang-Claude, Georgia Chenevix-Trench, Ching Yu Cheng, Ji Yeob Choi, J. Margriet Collée, Angela Cox, Simon S. Cross, Kamila Czene, Hatef Darabi, Joe Dennis, Thilo Dörk, Isabel Dos-Santos-Silva, Alison M. Dunning, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, Montserrat García-Closas, Graham G. Giles, Gord Glendon, Pascal Guénel, kConFab/AOCS Investigators, NBCS Collaborators

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants.

Original languageEnglish
Pages (from-to)2789-2799
Number of pages11
JournalCancer Research
Volume77
Issue number11
DOIs
Publication statusPublished - 1 Jun 2017

Cite this

Shimelis, H., Mesman, R. L. S., Von Nicolai, C., Ehlen, A., Guidugli, L., Martin, C., ... NBCS Collaborators (2017). BRCA2 hypomorphic missense variants confer moderate risks of breast cancer. Cancer Research, 77(11), 2789-2799. https://doi.org/10.1158/0008-5472.CAN-16-2568
Shimelis, Hermela ; Mesman, Romy L.S. ; Von Nicolai, Catharina ; Ehlen, Asa ; Guidugli, Lucia ; Martin, Charlotte ; Calléja, Fabienne M.G.R. ; Meeks, Huong ; Hallberg, Emily ; Hinton, Jamie ; Lilyquist, Jenna ; Hu, Chunling ; Aalfs, Cora M. ; Aittomäki, Kristiina ; Andrulis, Irene ; Anton-Culver, Hoda ; Arndt, Volker ; Beckmann, Matthias W. ; Benitez, Javier ; Bogdanova, Natalia V. ; Bojesen, Stig E. ; Bolla, Manjeet K. ; Borresen-Dale, Anne Lise ; Brauch, Hiltrud ; Brennan, Paul ; Brenner, Hermann ; Broeks, Annegien ; Brouwers, Barbara ; Brüning, Thomas ; Burwinkel, Barbara ; Chang-Claude, Jenny ; Chenevix-Trench, Georgia ; Cheng, Ching Yu ; Choi, Ji Yeob ; Collée, J. Margriet ; Cox, Angela ; Cross, Simon S. ; Czene, Kamila ; Darabi, Hatef ; Dennis, Joe ; Dörk, Thilo ; Dos-Santos-Silva, Isabel ; Dunning, Alison M. ; Fasching, Peter A. ; Figueroa, Jonine ; Flyger, Henrik ; García-Closas, Montserrat ; Giles, Graham G. ; Glendon, Gord ; Guénel, Pascal ; kConFab/AOCS Investigators ; NBCS Collaborators. / BRCA2 hypomorphic missense variants confer moderate risks of breast cancer. In: Cancer Research. 2017 ; Vol. 77, No. 11. pp. 2789-2799.
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abstract = "Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants.",
author = "Hermela Shimelis and Mesman, {Romy L.S.} and {Von Nicolai}, Catharina and Asa Ehlen and Lucia Guidugli and Charlotte Martin and Call{\'e}ja, {Fabienne M.G.R.} and Huong Meeks and Emily Hallberg and Jamie Hinton and Jenna Lilyquist and Chunling Hu and Aalfs, {Cora M.} and Kristiina Aittom{\"a}ki and Irene Andrulis and Hoda Anton-Culver and Volker Arndt and Beckmann, {Matthias W.} and Javier Benitez and Bogdanova, {Natalia V.} and Bojesen, {Stig E.} and Bolla, {Manjeet K.} and Borresen-Dale, {Anne Lise} and Hiltrud Brauch and Paul Brennan and Hermann Brenner and Annegien Broeks and Barbara Brouwers and Thomas Br{\"u}ning and Barbara Burwinkel and Jenny Chang-Claude and Georgia Chenevix-Trench and Cheng, {Ching Yu} and Choi, {Ji Yeob} and Coll{\'e}e, {J. Margriet} and Angela Cox and Cross, {Simon S.} and Kamila Czene and Hatef Darabi and Joe Dennis and Thilo D{\"o}rk and Isabel Dos-Santos-Silva and Dunning, {Alison M.} and Fasching, {Peter A.} and Jonine Figueroa and Henrik Flyger and Montserrat Garc{\'i}a-Closas and Giles, {Graham G.} and Gord Glendon and Pascal Gu{\'e}nel and {kConFab/AOCS Investigators} and {NBCS Collaborators}",
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Shimelis, H, Mesman, RLS, Von Nicolai, C, Ehlen, A, Guidugli, L, Martin, C, Calléja, FMGR, Meeks, H, Hallberg, E, Hinton, J, Lilyquist, J, Hu, C, Aalfs, CM, Aittomäki, K, Andrulis, I, Anton-Culver, H, Arndt, V, Beckmann, MW, Benitez, J, Bogdanova, NV, Bojesen, SE, Bolla, MK, Borresen-Dale, AL, Brauch, H, Brennan, P, Brenner, H, Broeks, A, Brouwers, B, Brüning, T, Burwinkel, B, Chang-Claude, J, Chenevix-Trench, G, Cheng, CY, Choi, JY, Collée, JM, Cox, A, Cross, SS, Czene, K, Darabi, H, Dennis, J, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Fasching, PA, Figueroa, J, Flyger, H, García-Closas, M, Giles, GG, Glendon, G, Guénel, P, kConFab/AOCS Investigators & NBCS Collaborators 2017, 'BRCA2 hypomorphic missense variants confer moderate risks of breast cancer' Cancer Research, vol. 77, no. 11, pp. 2789-2799. https://doi.org/10.1158/0008-5472.CAN-16-2568

BRCA2 hypomorphic missense variants confer moderate risks of breast cancer. / Shimelis, Hermela; Mesman, Romy L.S.; Von Nicolai, Catharina; Ehlen, Asa; Guidugli, Lucia; Martin, Charlotte; Calléja, Fabienne M.G.R.; Meeks, Huong; Hallberg, Emily; Hinton, Jamie; Lilyquist, Jenna; Hu, Chunling; Aalfs, Cora M.; Aittomäki, Kristiina; Andrulis, Irene; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Benitez, Javier; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Borresen-Dale, Anne Lise; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Broeks, Annegien; Brouwers, Barbara; Brüning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Cheng, Ching Yu; Choi, Ji Yeob; Collée, J. Margriet; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dunning, Alison M.; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G.; Glendon, Gord; Guénel, Pascal; kConFab/AOCS Investigators; NBCS Collaborators.

In: Cancer Research, Vol. 77, No. 11, 01.06.2017, p. 2789-2799.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - BRCA2 hypomorphic missense variants confer moderate risks of breast cancer

AU - Shimelis, Hermela

AU - Mesman, Romy L.S.

AU - Von Nicolai, Catharina

AU - Ehlen, Asa

AU - Guidugli, Lucia

AU - Martin, Charlotte

AU - Calléja, Fabienne M.G.R.

AU - Meeks, Huong

AU - Hallberg, Emily

AU - Hinton, Jamie

AU - Lilyquist, Jenna

AU - Hu, Chunling

AU - Aalfs, Cora M.

AU - Aittomäki, Kristiina

AU - Andrulis, Irene

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Beckmann, Matthias W.

AU - Benitez, Javier

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Borresen-Dale, Anne Lise

AU - Brauch, Hiltrud

AU - Brennan, Paul

AU - Brenner, Hermann

AU - Broeks, Annegien

AU - Brouwers, Barbara

AU - Brüning, Thomas

AU - Burwinkel, Barbara

AU - Chang-Claude, Jenny

AU - Chenevix-Trench, Georgia

AU - Cheng, Ching Yu

AU - Choi, Ji Yeob

AU - Collée, J. Margriet

AU - Cox, Angela

AU - Cross, Simon S.

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Dennis, Joe

AU - Dörk, Thilo

AU - Dos-Santos-Silva, Isabel

AU - Dunning, Alison M.

AU - Fasching, Peter A.

AU - Figueroa, Jonine

AU - Flyger, Henrik

AU - García-Closas, Montserrat

AU - Giles, Graham G.

AU - Glendon, Gord

AU - Guénel, Pascal

AU - kConFab/AOCS Investigators

AU - NBCS Collaborators

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants.

AB - Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants.

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DO - 10.1158/0008-5472.CAN-16-2568

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JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

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Shimelis H, Mesman RLS, Von Nicolai C, Ehlen A, Guidugli L, Martin C et al. BRCA2 hypomorphic missense variants confer moderate risks of breast cancer. Cancer Research. 2017 Jun 1;77(11):2789-2799. https://doi.org/10.1158/0008-5472.CAN-16-2568