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. Calleja; Huong Meeks; Emily Hallberg; Jamie Hinton; Jenna Lilyquist; Chunling Hu; Cora M. Aalfs; Kristiina Aittomaki; Irene Andrulis; Hoda Anton-Culver; Volker Arndt; Matthias W. Beckmann; Javier Benitez; Natalia V. Bogdanova; Stig E. Bojesen; Manjeet K. Bolla; Anne-Lise Borresen-Dale; Hiltrud Brauch; Paul Brennan; Hermann Brenner; Annegien Broeks; Barbara Brouwers; Thomas Bruning; Barbara Burwinkel; Jenny Chang-Claude; Georgia Chenevix-Trench; Ching-Yu Cheng; Ji-Yeob Choi; J. Margriet Collee; Angela Cox; Simon S. Cross; Kamila Czene; Hatef Darabi; Joe Dennis; Thilo Dork; Isabel dos-Santos-Silva; Alison M. Dunning; Peter A. Fasching; Jonine Figueroa; Henrik Flyger; Montserrat Garcia-Closas; Graham G. Giles; Gord Glendon; Jan J. C. Oosterwijk; KConFab AOCS Investigators; NBCS Collaborators

doi:10.1158/0008-5472.CAN-16-2568

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. Calleja, Huong Meeks, Emily Hallberg, Jamie Hinton, Jenna Lilyquist, Chunling Hu, Cora M. Aalfs, Kristiina Aittomaki, Irene Andrulis, Hoda Anton-Culver, Volker Arndt, Matthias W. Beckmann, Javier Benitez, Natalia V. BogdanovaStig E. Bojesen, Manjeet K. Bolla, Anne-Lise Borresen-Dale, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Annegien Broeks, Barbara Brouwers, Thomas Bruning, Barbara Burwinkel, Jenny Chang-Claude, Georgia Chenevix-Trench, Ching-Yu Cheng, Ji-Yeob Choi, J. Margriet Collee, Angela Cox, Simon S. Cross, Kamila Czene, Hatef Darabi, Joe Dennis, Thilo Dork, Isabel dos-Santos-Silva, Alison M. Dunning, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, Montserrat Garcia-Closas, Graham G. Giles, Gord Glendon, Jan J. C. Oosterwijk, KConFab AOCS Investigators, NBCS Collaborators

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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. (C) 2017 AACR.

Original language	English
Pages (from-to)	2789-2799
Number of pages	11
Journal	Cancer Research
Volume	77
Issue number	11
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-2568
Publication status	Published - 1-Jun-2017

Keywords

UNKNOWN CLINICAL-SIGNIFICANCE
CELL-BASED ASSAY
UNCERTAIN SIGNIFICANCE
OVARIAN-CANCER
UNCLASSIFIED VARIANTS
SEQUENCE VARIANTS
DNA-BINDING
FUNCTIONAL-EVALUATION
GENES
CLASSIFICATION

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Shimelis, H., Mesman, R. L. S., Von Nicolai, C., Ehlen, A., Guidugli, L., Martin, C., Calleja, F. M. G. R., Meeks, H., Hallberg, E., Hinton, J., Lilyquist, J., Hu, C., Aalfs, C. M., Aittomaki, K., Andrulis, I., Anton-Culver, H., Arndt, V., Beckmann, M. W., Benitez, J., ... 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

@article{3b4f6c01305b422b8237d68e891937f1,

title = "BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer",

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. (C) 2017 AACR.",

keywords = "UNKNOWN CLINICAL-SIGNIFICANCE, CELL-BASED ASSAY, UNCERTAIN SIGNIFICANCE, OVARIAN-CANCER, UNCLASSIFIED VARIANTS, SEQUENCE VARIANTS, DNA-BINDING, FUNCTIONAL-EVALUATION, GENES, CLASSIFICATION",

author = "Hermela Shimelis and Mesman, {Romy L. S.} and {Von Nicolai}, Catharina and Asa Ehlen and Lucia Guidugli and Charlotte Martin and Calleja, {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 Aittomaki 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 Anne-Lise Borresen-Dale and Hiltrud Brauch and Paul Brennan and Hermann Brenner and Annegien Broeks and Barbara Brouwers and Thomas Bruning and Barbara Burwinkel and Jenny Chang-Claude and Georgia Chenevix-Trench and Ching-Yu Cheng and Ji-Yeob Choi and Collee, {J. Margriet} and Angela Cox and Cross, {Simon S.} and Kamila Czene and Hatef Darabi and Joe Dennis and Thilo Dork and Isabel dos-Santos-Silva and Dunning, {Alison M.} and Fasching, {Peter A.} and Jonine Figueroa and Henrik Flyger and Montserrat Garcia-Closas and Giles, {Graham G.} and Gord Glendon and Oosterwijk, {Jan J. C.} and {KConFab AOCS Investigators} and {NBCS Collaborators}",

year = "2017",

month = jun,

day = "1",

doi = "10.1158/0008-5472.CAN-16-2568",

language = "English",

volume = "77",

pages = "2789--2799",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "AMER ASSOC CANCER RESEARCH",

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Shimelis, H, Mesman, RLS, Von Nicolai, C, Ehlen, A, Guidugli, L, Martin, C, Calleja, FMGR, Meeks, H, Hallberg, E, Hinton, J, Lilyquist, J, Hu, C, Aalfs, CM, Aittomaki, 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, Bruning, T, Burwinkel, B, Chang-Claude, J, Chenevix-Trench, G, Cheng, C-Y, Choi, J-Y, Collee, JM, Cox, A, Cross, SS, Czene, K, Darabi, H, Dennis, J, Dork, T, dos-Santos-Silva, I, Dunning, AM, Fasching, PA, Figueroa, J, Flyger, H, Garcia-Closas, M, Giles, GG, Glendon, G, Oosterwijk, JJC, 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

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 - Calleja, Fabienne M. G. R.

AU - Meeks, Huong

AU - Hallberg, Emily

AU - Hinton, Jamie

AU - Lilyquist, Jenna

AU - Hu, Chunling

AU - Aalfs, Cora M.

AU - Aittomaki, 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 - Bruning, Thomas

AU - Burwinkel, Barbara

AU - Chang-Claude, Jenny

AU - Chenevix-Trench, Georgia

AU - Cheng, Ching-Yu

AU - Choi, Ji-Yeob

AU - Collee, J. Margriet

AU - Cox, Angela

AU - Cross, Simon S.

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Dennis, Joe

AU - Dork, Thilo

AU - dos-Santos-Silva, Isabel

AU - Dunning, Alison M.

AU - Fasching, Peter A.

AU - Figueroa, Jonine

AU - Flyger, Henrik

AU - Garcia-Closas, Montserrat

AU - Giles, Graham G.

AU - Glendon, Gord

AU - Oosterwijk, Jan J. C.

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. (C) 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. (C) 2017 AACR.

KW - UNKNOWN CLINICAL-SIGNIFICANCE

KW - CELL-BASED ASSAY

KW - UNCERTAIN SIGNIFICANCE

KW - OVARIAN-CANCER

KW - UNCLASSIFIED VARIANTS

KW - SEQUENCE VARIANTS

KW - DNA-BINDING

KW - FUNCTIONAL-EVALUATION

KW - GENES

KW - CLASSIFICATION

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

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

M3 - Article

SN - 0008-5472

VL - 77

SP - 2789

EP - 2799

JO - Cancer Research

JF - Cancer Research

IS - 11

ER -

BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Abstract

Keywords

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