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.
Originalsprog | Engelsk |
---|---|
Tidsskrift | Cancer Research |
Vol/bind | 77 |
Udgave nummer | 11 |
Sider (fra-til) | 2789-2799 |
ISSN | 0008-5472 |
DOI | |
Status | Udgivet - 2017 |
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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; Haiman, Christopher A; Hall, Per; Hamann, Ute; Hartman, Mikael; Hogervorst, Frans B; Hollestelle, Antoinette; Hopper, John L; Ito, Hidemi; Jakubowska, Anna; Kang, Daehee; Kosma, Veli-Matti; Kristensen, Vessela; Lai, Kah-Nyin; Lambrechts, Diether; Marchand, Loic Le; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Machackova, Eva; Mannermaa, Arto; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; Miao, Hui; Michailidou, Kyriaki; Milne, Roger L; Muir, Kenneth; Neuhausen, Susan L; Nevanlinna, Heli; Olson, Janet E; Olswold, Curtis; Oosterwijk, Jan J C; Osorio, Ana; Peterlongo, Paolo; Peto, Julian; Pharoah, Paul D P; Pylkäs, Katri; Radice, Paolo; Rashid, Muhammad Usman; Rhenius, Valerie; Rudolph, Anja; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Marjanka K; Schoemaker, Minouk J; Seynaeve, Caroline; Shah, Mitul; Shen, Chen-Yang; Shrubsole, Martha; Shu, Xiao-Ou; Slager, Susan; Southey, Melissa C; Stram, Daniel O; Swerdlow, Anthony; Teo, Soo H; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; van Asperen, Christi J; van der Kolk, Lizet E; Wang, Qin; Winqvist, Robert; Wu, Anna H; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Leary, Jennifer; Walker, Logan; Foretova, Lenka; Fostira, Florentia; Claes, Kathleen B M; Varesco, Liliana; Moghadasi, Setareh; Easton, Douglas F; Spurdle, Amanda; Devilee, Peter; Vrieling, Harry; Monteiro, Alvaro N A; Goldgar, David E; Carreira, Aura; Vreeswijk, Maaike P G; Couch, Fergus J.
I: Cancer Research, Bind 77, Nr. 11, 2017, s. 2789-2799.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer 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 - Haiman, Christopher A
AU - Hall, Per
AU - Hamann, Ute
AU - Hartman, Mikael
AU - Hogervorst, Frans B
AU - Hollestelle, Antoinette
AU - Hopper, John L
AU - Ito, Hidemi
AU - Jakubowska, Anna
AU - Kang, Daehee
AU - Kosma, Veli-Matti
AU - Kristensen, Vessela
AU - Lai, Kah-Nyin
AU - Lambrechts, Diether
AU - Marchand, Loic Le
AU - Li, Jingmei
AU - Lindblom, Annika
AU - Lophatananon, Artitaya
AU - Lubinski, Jan
AU - Machackova, Eva
AU - Mannermaa, Arto
AU - Margolin, Sara
AU - Marme, Frederik
AU - Matsuo, Keitaro
AU - Miao, Hui
AU - Michailidou, Kyriaki
AU - Milne, Roger L
AU - Muir, Kenneth
AU - Neuhausen, Susan L
AU - Nevanlinna, Heli
AU - Olson, Janet E
AU - Olswold, Curtis
AU - Oosterwijk, Jan J C
AU - Osorio, Ana
AU - Peterlongo, Paolo
AU - Peto, Julian
AU - Pharoah, Paul D P
AU - Pylkäs, Katri
AU - Radice, Paolo
AU - Rashid, Muhammad Usman
AU - Rhenius, Valerie
AU - Rudolph, Anja
AU - Sangrajrang, Suleeporn
AU - Sawyer, Elinor J
AU - Schmidt, Marjanka K
AU - Schoemaker, Minouk J
AU - Seynaeve, Caroline
AU - Shah, Mitul
AU - Shen, Chen-Yang
AU - Shrubsole, Martha
AU - Shu, Xiao-Ou
AU - Slager, Susan
AU - Southey, Melissa C
AU - Stram, Daniel O
AU - Swerdlow, Anthony
AU - Teo, Soo H
AU - Tomlinson, Ian
AU - Torres, Diana
AU - Truong, Thérèse
AU - van Asperen, Christi J
AU - van der Kolk, Lizet E
AU - Wang, Qin
AU - Winqvist, Robert
AU - Wu, Anna H
AU - Yu, Jyh-Cherng
AU - Zheng, Wei
AU - Zheng, Ying
AU - Leary, Jennifer
AU - Walker, Logan
AU - Foretova, Lenka
AU - Fostira, Florentia
AU - Claes, Kathleen B M
AU - Varesco, Liliana
AU - Moghadasi, Setareh
AU - Easton, Douglas F
AU - Spurdle, Amanda
AU - Devilee, Peter
AU - Vrieling, Harry
AU - Monteiro, Alvaro N A
AU - Goldgar, David E
AU - Carreira, Aura
AU - Vreeswijk, Maaike P G
AU - Couch, Fergus J
N1 - ©2017 American Association for Cancer Research.
PY - 2017
Y1 - 2017
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 - Journal article
C2 - 28283652
VL - 77
SP - 2789
EP - 2799
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 11
ER -