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 & 39 others Anthony Swerdlow, Vessela Kristensen, Pascal Guénel, Alfons Meindl, Hatef Darabi, Mikael Eriksson, Rainer Fagerholm, Kristiina Aittomaki, 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, Christine Clarke, Rosemary Balleine, Robert Baxter, Stephen Braye, Stephen Chanock, ABCTB Investigators, KConFab Investigators, The Genica Network, The Genica Network, The Genica Network, The Genica Network, The Genica Network, The Genica Network, The Genica Network

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)6034-6046
Number of pages13
JournalHuman Molecular Genetics
Volume23
Issue number22
DOIs
StatePublished - Nov 15 2014
Externally publishedYes

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Regulator Genes
Breast Neoplasms
Single Nucleotide Polymorphism
Genes
Odds Ratio
Mitotic Index
Genetic Loci
Carcinogenesis
Breast
Genome
Confidence Intervals

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Purrington, K. S., Slettedahl, S., Bolla, M. K., Michailidou, K., Czene, K., Nevanlinna, H., ... The Genica Network (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

Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade. / Purrington, Kristen S.; Slettedahl, Seth; Bolla, Manjeet K.; Michailidou, Kyriaki; Czene, Kamila; Nevanlinna, Heli; Bojesen, Stig E.; Andrulis, Irene L.; Cox, Angela; Hall, Per; Carpenter, Jane; Yannoukakos, Drakoulis; A. Haiman, Christopher; Fasching, Peter A.; Mannermaa, Arto; Winqvist, Robert; Brenner, Hermann; Lindblom, Annika; Chenevix-Trench, Georgia; Benitez, Javier; Swerdlow, Anthony; Kristensen, Vessela; Guénel, Pascal; Meindl, Alfons; Darabi, Hatef; Eriksson, Mikael; Fagerholm, Rainer; Aittomaki, Kristiina; Blomqvist, Carl; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Wang, Xianshu; Olswold, Curtis; Olson, Janet E.; Mulligan, Anna Marie; Knight, Julia A.; Tchatchou, Sandrine; Reed, Malcolm W R; Cross, Simon S.; Liu, Jianjun; Li, Jingmei; Humphreys, Keith; Clarke, Christine; Scott, Rodney; Clarke, Christine; Balleine, Rosemary; Baxter, Robert; Braye, Stephen; Chanock, Stephen; ABCTB Investigators; KConFab Investigators; The Genica Network; The Genica Network; The Genica Network; The Genica Network; The Genica Network; The Genica Network; The Genica Network.

In: Human Molecular Genetics, Vol. 23, No. 22, 15.11.2014, p. 6034-6046.

Research output: Contribution to journalArticle

Purrington, KS, Slettedahl, S, Bolla, MK, Michailidou, K, Czene, K, Nevanlinna, H, Bojesen, SE, Andrulis, IL, Cox, A, Hall, P, Carpenter, J, Yannoukakos, D, A. Haiman, C, 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, Aittomaki, 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, Clarke, C, Balleine, R, Baxter, R, Braye, S, Chanock, S, ABCTB Investigators, KConFab Investigators, The Genica Network, The Genica Network, The Genica Network, The Genica Network, The Genica Network, The Genica Network & The Genica Network 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
Purrington KS, Slettedahl S, Bolla MK, Michailidou K, Czene K, Nevanlinna H et al. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade. Human Molecular Genetics. 2014 Nov 15;23(22):6034-6046. https://doi.org/10.1093/hmg/ddu300
Purrington, Kristen S. ; Slettedahl, Seth ; Bolla, Manjeet K. ; Michailidou, Kyriaki ; Czene, Kamila ; Nevanlinna, Heli ; Bojesen, Stig E. ; Andrulis, Irene L. ; Cox, Angela ; Hall, Per ; Carpenter, Jane ; Yannoukakos, Drakoulis ; A. Haiman, Christopher ; Fasching, Peter A. ; Mannermaa, Arto ; Winqvist, Robert ; Brenner, Hermann ; Lindblom, Annika ; Chenevix-Trench, Georgia ; Benitez, Javier ; Swerdlow, Anthony ; Kristensen, Vessela ; Guénel, Pascal ; Meindl, Alfons ; Darabi, Hatef ; Eriksson, Mikael ; Fagerholm, Rainer ; Aittomaki, Kristiina ; Blomqvist, Carl ; Nordestgaard, Børge G. ; Nielsen, Sune F. ; Flyger, Henrik ; Wang, Xianshu ; Olswold, Curtis ; Olson, Janet E. ; Mulligan, Anna Marie ; Knight, Julia A. ; Tchatchou, Sandrine ; Reed, Malcolm W R ; Cross, Simon S. ; Liu, Jianjun ; Li, Jingmei ; Humphreys, Keith ; Clarke, Christine ; Scott, Rodney ; Clarke, Christine ; Balleine, Rosemary ; Baxter, Robert ; Braye, Stephen ; Chanock, Stephen ; ABCTB Investigators ; KConFab Investigators ; The Genica Network ; The Genica Network ; The Genica Network ; The Genica Network ; The Genica Network ; The Genica Network ; The Genica Network. / Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 22. pp. 6034-6046.
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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.",
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AU - Czene, Kamila

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AU - Bojesen, Stig E.

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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.

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