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 & 31 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, Paolo Radice, Liliana Varesco, for kConFab/AOCS Investigators

Research output: Contribution to journalArticle

16 Citations (Scopus)

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. Cancer Res; 77(11); 2789-99. ©2017 AACR.

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

Fingerprint

Breast Neoplasms
BRCA2 Gene
BRCA1 Gene
Risk Management
Case-Control Studies
Guidelines
Neoplasms
Proteins

Keywords

  • Aged
  • Amino Acid Substitution
  • Animals
  • BRCA2 Protein
  • Breast Neoplasms
  • Case-Control Studies
  • Female
  • Genotype
  • Germ-Line Mutation
  • Humans
  • Mice
  • Mutation, Missense
  • Risk
  • Journal Article

Cite this

Shimelis, H., Mesman, R. L. S., Von Nicolai, C., Ehlen, A., Guidugli, L., Martin, C., ... for kConFab/AOCS Investigators (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

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; Radice, Paolo; Varesco, Liliana; for kConFab/AOCS Investigators.

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

Research output: Contribution to journalArticle

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, A-L, Brauch, H, Brennan, P, Brenner, H, Broeks, A, Brouwers, B, Brüning, T, Burwinkel, B, Chang-Claude, J, Chenevix-Trench, G, Cheng, C-Y, Choi, J-Y, 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, Radice, P, Varesco, L & for kConFab/AOCS Investigators 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
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
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 ; Radice, Paolo ; Varesco, Liliana ; for kConFab/AOCS Investigators. / 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. Cancer Res; 77(11); 2789-99. {\circledC}2017 AACR.",
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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 - Radice, Paolo

AU - Varesco, Liliana

AU - for kConFab/AOCS Investigators

N1 - ©2017 American Association for Cancer Research.

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. Cancer Res; 77(11); 2789-99. ©2017 AACR.

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. Cancer Res; 77(11); 2789-99. ©2017 AACR.

KW - Aged

KW - Amino Acid Substitution

KW - Animals

KW - BRCA2 Protein

KW - Breast Neoplasms

KW - Case-Control Studies

KW - Female

KW - Genotype

KW - Germ-Line Mutation

KW - Humans

KW - Mice

KW - Mutation, Missense

KW - Risk

KW - Journal Article

U2 - 10.1158/0008-5472.CAN-16-2568

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

M3 - Article

VL - 77

SP - 2789

EP - 2799

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 11

ER -