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 language | English |
|---|---|
| Pages (from-to) | 2789-2799 |
| Number of pages | 11 |
| Journal | Cancer Research |
| Volume | 77 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Jun 1 2017 |
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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
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 journal › Article
}
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 - 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 -