TY - JOUR
T1 - Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade
AU - The GENICA Network
AU - The GENICA Network
AU - The GENICA Network
AU - The GENICA Network
AU - ABCTB Investigators
AU - kConFab Investigators
AU - The GENICA Network
AU - The GENICA Network
AU - The GENICA Network
AU - Purrington, Kristen S.
AU - Slettedahl, Seth
AU - Bolla, Manjeet K.
AU - Michailidou, Kyriaki
AU - Czene, Kamila
AU - Nevanlinna, Heli
AU - Bojesen, Stig E.
AU - Andrulis, Irene L.
AU - Cox, Angela
AU - Hall, Per
AU - Carpenter, Jane
AU - Yannoukakos, Drakoulis
AU - A. Haiman, Christopher
AU - Fasching, Peter A.
AU - Mannermaa, Arto
AU - Winqvist, Robert
AU - Brenner, Hermann
AU - Lindblom, Annika
AU - Chenevix-Trench, Georgia
AU - Benitez, Javier
AU - Swerdlow, Anthony
AU - Kristensen, Vessela
AU - Guénel, Pascal
AU - Meindl, Alfons
AU - Darabi, Hatef
AU - Eriksson, Mikael
AU - Fagerholm, Rainer
AU - Aittomaki, Kristiina
AU - Blomqvist, Carl
AU - Nordestgaard, Børge G.
AU - Nielsen, Sune F.
AU - Flyger, Henrik
AU - Wang, Xianshu
AU - Olswold, Curtis
AU - Olson, Janet E.
AU - Mulligan, Anna Marie
AU - Knight, Julia A.
AU - Tchatchou, Sandrine
AU - Reed, Malcolm W.R.
AU - Cross, Simon S.
AU - Liu, Jianjun
AU - Li, Jingmei
AU - Humphreys, Keith
AU - Clarke, Christine
AU - Scott, Rodney
AU - Balleine, Rosemary
AU - Baxter, Robert
AU - Braye, Stephen
AU - Dahlstrom, Jane
AU - Torres, Diana
N1 - Publisher Copyright:
© Published by Oxford University Press 2014.
PY - 2014/11/15
Y1 - 2014/11/15
N2 - Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10-10)and EIF3H(rs799890: OR = 1.07, 95% C11.041.11, P = 8.7 × 10-6) were significantly associated with risk of low-grade breast cancer. The TACC2signal was retained (rs17550038: OR = 1.15, 95% C11.07-1.23, P = 7.9 × 10-5) after adjustment for breast cancer risk SNPs in the nearby FGFR2gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk(P = 2.1 × 10-3). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.
AB - Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10-10)and EIF3H(rs799890: OR = 1.07, 95% C11.041.11, P = 8.7 × 10-6) were significantly associated with risk of low-grade breast cancer. The TACC2signal was retained (rs17550038: OR = 1.15, 95% C11.07-1.23, P = 7.9 × 10-5) after adjustment for breast cancer risk SNPs in the nearby FGFR2gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk(P = 2.1 × 10-3). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.
UR - http://www.scopus.com/inward/record.url?scp=84911431178&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddu300
DO - 10.1093/hmg/ddu300
M3 - Article
C2 - 24927736
AN - SCOPUS:84911431178
SN - 0964-6906
VL - 23
SP - 6034
EP - 6046
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 22
ER -
