Evaluation of associations between common variation in mitotic regulatory pathways and risk of overall and high grade breast cancer

  • Kristen N. Stevens
  • Xianshu Wang
  • Zachary Fredericksen
  • V. Shane Pankratz
  • James Cerhan
  • Celine M. Vachon
  • Janet E. Olson
  • Fergus J. Couch
Brief Report

Abstract

Mitotic regulatory pathways insure proper timing of mitotic entry, sister chromatid cohesion and separation, and cytokinesis. Disruption of this process results in inappropriate chromosome segregation and aneuploidy, and appears to contribute to cancer. Specifically, disregulation and somatic mutation of mitotic regulators has been observed in human cancers, and overexpression of mitotic regulators is common in aggressive and late stage tumors. However, the role of germline variation in mitotic pathways and risk of cancer is not well understood. We tested 1,084 haplotype-tagging and functional variants from 164 genes in mitotic regulatory pathways in 791 Caucasian women with breast cancer and 843 healthy controls for association with risk of overall and high grade breast cancer. Sixty-one single nucleotide polymorphisms (SNPs) from 40 genes were associated (P < 0.05) with risk of breast cancer in a log-additive model. In addition, 60 SNPs were associated (P < 0.05) with risk of high grade breast cancer. However, none of these associations were significant after Bonferroni correction for multiple testing. In gene-level analyses, CDC25C, SCC1/RAD21, TLK2, and SMC6L1 were associated (P < 0.05) with overall breast cancer risk, CDC6, CDC27, SUMO3, RASSF1, KIF2, and CDC14A were associated with high grade breast cancer risk, and EIF3S10 and CDC25A were associated with both. Further investigation in breast and other cancers are needed to understand the influence of inherited variation in mitotic genes on tumor grade and cancer risk.

Keywords

Breast cancer Genetics Mitotic Grade 

Supplementary material

10549_2011_1587_MOESM1_ESM.doc (574 kb)
Supplementary material 1 (DOC 574 kb)

References

  1. 1.
    Tirkkonen M, Tanner M, Karhu R, Kallioniemi A, Isola J, Kallioniemi OP (1998) Molecular cytogenetics of primary breast cancer by CGH. Genes Chromosom Cancer 21(3):177–184PubMedCrossRefGoogle Scholar
  2. 2.
    Mendelin J, Grayson M, Wallis T, Visscher DW (1999) Analysis of chromosome aneuploidy in breast carcinoma progression by using fluorescence in situ hybridization. Lab Invest 79(4):387–393PubMedGoogle Scholar
  3. 3.
    Thompson SL, Bakhoum SF, Compton DA (2010) Mechanisms of chromosomal instability. Curr Biol 20(6):R285–R295PubMedCrossRefGoogle Scholar
  4. 4.
    Molinari M (2000) Cell cycle checkpoints and their inactivation in human cancer. Cell Prolif 33(5):261–274PubMedCrossRefGoogle Scholar
  5. 5.
    Baker DJ, Jin F, Jeganathan KB, van Deursen JM (2009) Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity. Cancer Cell 16(6):475–486PubMedCrossRefGoogle Scholar
  6. 6.
    Sotillo R, Hernando E, Diaz-Rodriguez E, Teruya-Feldstein J, Cordon-Cardo C, Lowe SW, Benezra R (2007) Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11(1):9–23PubMedCrossRefGoogle Scholar
  7. 7.
    Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D (2005) Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437(7061):1043–1047PubMedCrossRefGoogle Scholar
  8. 8.
    Hawkins GA, Mychaleckyj JC, Zheng SL, Faith DA, Kelly B, Isaacs SD, Wiley KE, Chang BL, Ewing CM, Bujnovszky P, Bleecker ER, Walsh PC, Meyers DA, Isaacs WB, Xu J (2002) Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk. Cancer Genet Cytogenet 137(1):1–7PubMedCrossRefGoogle Scholar
  9. 9.
    Guo Y, Zhang X, Yang M, Miao X, Shi Y, Yao J, Tan W, Sun T, Zhao D, Yu D, Liu J, Lin D (2010) Functional evaluation of missense variations in the human MAD1L1 and MAD2L1 genes and their impact on susceptibility to lung cancer. J Med Genet 47(9):616–622PubMedCrossRefGoogle Scholar
  10. 10.
    Milam MR, Gu J, Yang H, Celestino J, Wu W, Horwitz IB, Lacour RA, Westin SN, Gershenson DM, Wu X, Lu KH (2007) STK15 F31I polymorphism is associated with increased uterine cancer risk: a pilot study. Gynecol Oncol 107(1):71–74PubMedCrossRefGoogle Scholar
  11. 11.
    Ahmed S, Thomas G, Ghoussaini M, Healey CS, Humphreys MK, Platte R, Morrison J, Maranian M, Pooley KA, Luben R, Eccles D, Evans DG, Fletcher O, Johnson N, dos Santos Silva I, Peto J, Stratton MR, Rahman N, Jacobs K, Prentice R, Anderson GL, Rajkovic A, Curb JD, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Diver WR, Bojesen S, Nordestgaard BG, Flyger H, Dork T, Schurmann P, Hillemanns P, Karstens JH, Bogdanova NV, Antonenkova NN, Zalutsky IV, Bermisheva M, Fedorova S, Khusnutdinova E, Kang D, Yoo KY, Noh DY, Ahn SH, Devilee P, van Asperen CJ, Tollenaar RA, Seynaeve C, Garcia-Closas M, Lissowska J, Brinton L, Peplonska B, Nevanlinna H, Heikkinen T, Aittomaki K, Blomqvist C, Hopper JL, Southey MC, Smith L, Spurdle AB, Schmidt MK, Broeks A, van Hien RR, Cornelissen S, Milne RL, Ribas G, Gonzalez-Neira A, Benitez J, Schmutzler RK, Burwinkel B, Bartram CR, Meindl A, Brauch H, Justenhoven C, Hamann U, Chang-Claude J, Hein R, Wang-Gohrke S, Lindblom A, Margolin S, Mannermaa A, Kosma VM, Kataja V, Olson JE, Wang X, Fredericksen Z, Giles GG, Severi G, Baglietto L, English DR, Hankinson SE, Cox DG, Kraft P, Vatten LJ, Hveem K, Kumle M, Sigurdson A, Doody M, Bhatti P, Alexander BH, Hooning MJ, van den Ouweland AM, Oldenburg RA, Schutte M, Hall P, Czene K, Liu J, Li Y, Cox A, Elliott G, Brock I, Reed MW, Shen CY, Yu JC, Hsu GC, Chen ST, Anton-Culver H, Ziogas A, Andrulis IL, Knight JA, Beesley J, Goode EL, Couch F, Chenevix-Trench G, Hoover RN, Ponder BA, Hunter DJ, Pharoah PD, Dunning AM, Chanock SJ, Easton DF (2009) Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 41 (5):585–590Google Scholar
  12. 12.
    Ewart-Toland A, Dai Q, Gao YT, Nagase H, Dunlop MG, Farrington SM, Barnetson RA, Anton-Culver H, Peel D, Ziogas A, Lin D, Miao X, Sun T, Ostrander EA, Stanford JL, Langlois M, Chan JM, Yuan J, Harris CC, Bowman ED, Clayman GL, Lippman SM, Lee JJ, Zheng W, Balmain A (2005) Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types. Carcinogenesis 26(8):1368–1373PubMedCrossRefGoogle Scholar
  13. 13.
    Gazouli M, Tzanakis N, Rallis G, Theodoropoulos G, Papaconstantinou I, Kostakis A, Anagnou NP, Nikiteas N (2009) Survivin-31G/C promoter polymorphism and sporadic colorectal cancer. Int J Colorectal Dis 24(2):145–150PubMedCrossRefGoogle Scholar
  14. 14.
    Jang JS, Kim KM, Kang KH, Choi JE, Lee WK, Kim CH, Kang YM, Kam S, Kim IS, Jun JE, Jung TH, Park JY (2008) Polymorphisms in the survivin gene and the risk of lung cancer. Lung Cancer 60(1):31–39PubMedCrossRefGoogle Scholar
  15. 15.
    Kelemen LE, Wang X, Fredericksen ZS, Pankratz VS, Pharoah PD, Ahmed S, Dunning AM, Easton DF, Vierkant RA, Cerhan JR, Goode EL, Olson JE, Couch FJ (2009) Genetic variation in the chromosome 17q23 amplicon and breast cancer risk. Cancer Epidemiol Biomarkers Prev 18(6):1864–1868PubMedCrossRefGoogle Scholar
  16. 16.
    Ignatiadis M, Sotiriou C (2008) Understanding the molecular basis of histologic grade. Pathobiology 75(2):104–111PubMedCrossRefGoogle Scholar
  17. 17.
    Outwin EA, Irmisch A, Murray JM, O’Connell MJ (2009) Smc5-Smc6-dependent removal of cohesin from mitotic chromosomes. Mol Cell Biol 29(16):4363–4375PubMedCrossRefGoogle Scholar
  18. 18.
    Holt LJ, Krutchinsky AN, Morgan DO (2008) Positive feedback sharpens the anaphase switch. Nature 454(7202):353–357PubMedCrossRefGoogle Scholar
  19. 19.
    Park KH, Choi SE, Eom M, Kang Y (2005) Downregulation of the anaphase-promoting complex (APC)7 in invasive ductal carcinomas of the breast and its clinicopathologic relationships. Breast Cancer Res 7(2):R238–R247PubMedCrossRefGoogle Scholar
  20. 20.
    Olson JE, Wang X, Pankratz VS, Fredericksen ZS, Vachon CM, Vierkant RA, Cerhan JR, Couch FJ (2011) Centrosome-related genes, genetic variation, and risk of breast cancer. Breast Cancer Res Treat 125(1):221–228PubMedCrossRefGoogle Scholar
  21. 21.
    Olson JE, Wang X, Goode EL, Pankratz VS, Fredericksen ZS, Vierkant RA, Pharoah PD, Cerhan JR, Couch FJ (2010) Variation in genes required for normal mitosis and risk of breast cancer. Breast Cancer Res Treat 119(2):423–430PubMedCrossRefGoogle Scholar
  22. 22.
    Wang X, Fredericksen ZS, Vierkant RA, Kosel ML, Pankratz VS, Cerhan JR, Justenhoven C, Brauch H, Olson JE, Couch FJ (2010) Association of genetic variation in mitotic kinases with breast cancer risk. Breast Cancer Res Treat 119(2):453–462PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Kristen N. Stevens
    • 1
  • Xianshu Wang
    • 2
  • Zachary Fredericksen
    • 1
  • V. Shane Pankratz
    • 1
  • James Cerhan
    • 1
  • Celine M. Vachon
    • 1
  • Janet E. Olson
    • 1
  • Fergus J. Couch
    • 2
  1. 1.Department of Health Sciences ResearchMayo Clinic College of MedicineRochesterUSA
  2. 2.Department of Laboratory Medicine and PathologyMayo Clinic College of MedicineRochesterUSA

Personalised recommendations