Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

Kristen S Purrington; Seth Slettedahl; Manjeet K Bolla; Kyriaki Michailidou; Kamila Czene; Heli Nevanlinna; Stig E Bojesen; Irene L Andrulis; Angela Cox; Per Hall; Jane Carpenter; Drakoulis Yannoukakos; Christopher A Haiman; Peter A Fasching; Arto Mannermaa; Robert Winqvist; Hermann Brenner; Annika Lindblom; Georgia Chenevix-Trench; Javier Benitez; Anthony Swerdlow; Vessela Kristensen; Pascal Guénel; Alfons Meindl; Hatef Darabi; Mikael Eriksson; Rainer Fagerholm; Kristiina Aittomäki; Carl Blomqvist; Børge G Nordestgaard; Sune F Nielsen; Henrik Flyger; Xianshu Wang; Curtis Olswold; Janet E Olson; Anna Marie Mulligan; Julia A Knight; Sandrine Tchatchou; Malcolm W R Reed; Simon S Cross; Jianjun Liu; Jingmei Li; Keith Humphreys; Christine Clarke; Rodney Scott; Florentia Fostira; George Fountzilas; Irene Konstantopoulou; Brian E Henderson; Fredrick Schumacher; ABCTB Investigators

doi:10.1093/hmg/ddu300

Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

Kristen S Purrington, Seth Slettedahl, Manjeet K Bolla, Kyriaki Michailidou, Kamila Czene, Heli Nevanlinna, Stig E Bojesen, Irene L Andrulis, Angela Cox, Per Hall, Jane Carpenter, Drakoulis Yannoukakos, Christopher A Haiman, Peter A Fasching, Arto Mannermaa, Robert Winqvist, Hermann Brenner, Annika Lindblom, Georgia Chenevix-Trench, Javier BenitezAnthony Swerdlow, Vessela Kristensen, Pascal Guénel, Alfons Meindl, Hatef Darabi, Mikael Eriksson, Rainer Fagerholm, Kristiina Aittomäki, Carl Blomqvist, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Xianshu Wang, Curtis Olswold, Janet E Olson, Anna Marie Mulligan, Julia A Knight, Sandrine Tchatchou, Malcolm W R Reed, Simon S Cross, Jianjun Liu, Jingmei Li, Keith Humphreys, Christine Clarke, Rodney Scott, Florentia Fostira, George Fountzilas, Irene Konstantopoulou, Brian E Henderson, Fredrick Schumacher, ABCTB Investigators

Department of Clinical Medicine

11 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Human Molecular Genetics
Volume	23
Issue number	22
Pages (from-to)	6034-6046
Number of pages	13
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddu300
Publication status	Published - 15 Nov 2014

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Purrington, K. S., Slettedahl, S., Bolla, M. K., Michailidou, K., Czene, K., Nevanlinna, H., Bojesen, S. E., Andrulis, I. L., Cox, A., Hall, P., Carpenter, J., Yannoukakos, D., Haiman, C. A., Fasching, P. A., Mannermaa, A., Winqvist, R., Brenner, H., Lindblom, A., Chenevix-Trench, G., ... ABCTB Investigators (2014). Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade. Human Molecular Genetics, 23(22), 6034-6046. https://doi.org/10.1093/hmg/ddu300

Purrington, KS, Slettedahl, S, Bolla, MK, Michailidou, K, Czene, K, Nevanlinna, H, Bojesen, SE, Andrulis, IL, Cox, A, Hall, P, Carpenter, J, Yannoukakos, D, Haiman, CA, Fasching, PA, Mannermaa, A, Winqvist, R, Brenner, H, Lindblom, A, Chenevix-Trench, G, Benitez, J, Swerdlow, A, Kristensen, V, Guénel, P, Meindl, A, Darabi, H, Eriksson, M, Fagerholm, R, Aittomäki, K, Blomqvist, C, Nordestgaard, BG, Nielsen, SF, Flyger, H, Wang, X, Olswold, C, Olson, JE, Mulligan, AM, Knight, JA, Tchatchou, S, Reed, MWR, Cross, SS, Liu, J, Li, J, Humphreys, K, Clarke, C, Scott, R, Fostira, F, Fountzilas, G, Konstantopoulou, I, Henderson, BE, Schumacher, F & ABCTB Investigators 2014, 'Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade', Human Molecular Genetics, vol. 23, no. 22, pp. 6034-6046. https://doi.org/10.1093/hmg/ddu300

@article{68765682c2d24a45a433a2691a2ea2bf,

title = "Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade",

abstract = "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.",

author = "Purrington, {Kristen S} and Seth Slettedahl and Bolla, {Manjeet K} and Kyriaki Michailidou and Kamila Czene and Heli Nevanlinna and Bojesen, {Stig E} and Andrulis, {Irene L} and Angela Cox and Per Hall and Jane Carpenter and Drakoulis Yannoukakos and Haiman, {Christopher A} and Fasching, {Peter A} and Arto Mannermaa and Robert Winqvist and Hermann Brenner and Annika Lindblom and Georgia Chenevix-Trench and Javier Benitez and Anthony Swerdlow and Vessela Kristensen and Pascal Gu{\'e}nel and Alfons Meindl and Hatef Darabi and Mikael Eriksson and Rainer Fagerholm and Kristiina Aittom{\"a}ki and Carl Blomqvist and Nordestgaard, {B{\o}rge G} and Nielsen, {Sune F} and Henrik Flyger and Xianshu Wang and Curtis Olswold and Olson, {Janet E} and Mulligan, {Anna Marie} and Knight, {Julia A} and Sandrine Tchatchou and Reed, {Malcolm W R} and Cross, {Simon S} and Jianjun Liu and Jingmei Li and Keith Humphreys and Christine Clarke and Rodney Scott and Florentia Fostira and George Fountzilas and Irene Konstantopoulou and Henderson, {Brian E} and Fredrick Schumacher and {ABCTB Investigators}",

note = "Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.",

year = "2014",

month = nov,

day = "15",

doi = "10.1093/hmg/ddu300",

language = "English",

volume = "23",

pages = "6034--6046",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

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TY - JOUR

T1 - Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

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 - Haiman, Christopher A

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 - Aittomäki, 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 - Fostira, Florentia

AU - Fountzilas, George

AU - Konstantopoulou, Irene

AU - Henderson, Brian E

AU - Schumacher, Fredrick

AU - ABCTB Investigators

N1 - Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

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.

U2 - 10.1093/hmg/ddu300

DO - 10.1093/hmg/ddu300

M3 - Journal article

C2 - 24927736

SN - 0964-6906

VL - 23

SP - 6034

EP - 6046

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 22

ER -

Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

Abstract

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