Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Nov 15;23(22):6034-46.
doi: 10.1093/hmg/ddu300. Epub 2014 Jun 13.

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

Kristen S Purrington  1 , Seth Slettedahl  2 , Manjeet K Bolla  3 , Kyriaki Michailidou  3 , Kamila Czene  4 , Heli Nevanlinna  5 , Stig E Bojesen  6 , Irene L Andrulis  7 , Angela Cox  8 , Per Hall  4 , Jane Carpenter  9 , Drakoulis Yannoukakos  10 , Christopher A Haiman  11 , Peter A Fasching  12 , Arto Mannermaa  13 , Robert Winqvist  14 , Hermann Brenner  15 , Annika Lindblom  16 , Georgia Chenevix-Trench  17 , Javier Benitez  18 , Anthony Swerdlow  19 , Vessela Kristensen  20 , Pascal Guénel  21 , Alfons Meindl  22 , Hatef Darabi  4 , Mikael Eriksson  4 , Rainer Fagerholm  23 , Kristiina Aittomäki  24 , Carl Blomqvist  25 , Børge G Nordestgaard  26 , Sune F Nielsen  27 , Henrik Flyger  28 , Xianshu Wang  29 , Curtis Olswold  2 , Janet E Olson  2 , Anna Marie Mulligan  30 , Julia A Knight  31 , Sandrine Tchatchou  32 , Malcolm W R Reed  8 , Simon S Cross  33 , Jianjun Liu  34 , Jingmei Li  34 , Keith Humphreys  4 , Christine Clarke  35 , Rodney Scott  36 ; ABCTB Investigators; Florentia Fostira  10 , George Fountzilas  37 , Irene Konstantopoulou  10 , Brian E Henderson  11 , Fredrick Schumacher  11 , Loic Le Marchand  38 , Arif B Ekici  39 , Arndt Hartmann  40 , Matthias W Beckmann  41 , Jaana M Hartikainen  13 , Veli-Matti Kosma  13 , Vesa Kataja  42 , Arja Jukkola-Vuorinen  43 , Katri Pylkäs  14 , Saila Kauppila  44 , Aida Karina Dieffenbach  15 , Christa Stegmaier  45 , Volker Arndt  46 , Sara Margolin  47 ; Australian Ovarian Cancer Study Group; kConFab Investigators; Rosemary Balleine  48 , Jose Ignacio Arias Perez  49 , M Pilar Zamora  50 , Primitiva Menéndez  51 , Alan Ashworth  52 , Michael Jones  53 , Nick Orr  52 , Patrick Arveux  54 , Pierre Kerbrat  55 , Thérèse Truong  21 , Peter Bugert  56 , Amanda E Toland  57 , Christine B Ambrosone  58 , France Labrèche  59 , Mark S Goldberg  60 , Martine Dumont  61 , Argyrios Ziogas  62 , Eunjung Lee  11 , Gillian S Dite  63 , Carmel Apicella  63 , Melissa C Southey  64 , Jirong Long  65 , Martha Shrubsole  57 , Sandra Deming-Halverson  65 , Filomena Ficarazzi  66 , Monica Barile  67 , Paolo Peterlongo  68 , Katarzyna Durda  69 , Katarzyna Jaworska-Bieniek  69 , Robert A E M Tollenaar  70 , Caroline Seynaeve  71 ; GENICA Network; Thomas Brüning  72 , Yon-Dschun Ko  73 , Carolien H M Van Deurzen  74 , John W M Martens  75 , Mieke Kriege  75 , Jonine D Figueroa  76 , Stephen J Chanock  76 , Jolanta Lissowska  77 , Ian Tomlinson  78 , Michael J Kerin  79 , Nicola Miller  79 , Andreas Schneeweiss  80 , William J Tapper  81 , Susan M Gerty  81 , Lorraine Durcan  81 , Catriona Mclean  82 , Roger L Milne  83 , Laura Baglietto  83 , Isabel dos Santos Silva  84 , Olivia Fletcher  85 , Nichola Johnson  85 , Laura J Van'T Veer  86 , Sten Cornelissen  86 , Asta Försti  87 , Diana Torres  88 , Thomas Rüdiger  89 , Anja Rudolph  90 , Dieter Flesch-Janys  91 , Stefan Nickels  90 , Caroline Weltens  92 , Giuseppe Floris  92 , Matthieu Moisse  93 , Joe Dennis  3 , Qin Wang  3 , Alison M Dunning  94 , Mitul Shah  94 , Judith Brown  3 , Jacques Simard  61 , Hoda Anton-Culver  62 , Susan L Neuhausen  95 , John L Hopper  63 , Natalia Bogdanova  96 , Thilo Dörk  97 , Wei Zheng  65 , Paolo Radice  98 , Anna Jakubowska  69 , Jan Lubinski  69 , Peter Devillee  99 , Hiltrud Brauch  100 , Maartje Hooning  75 , Montserrat García-Closas  52 , Elinor Sawyer  101 , Barbara Burwinkel  102 , Frederick Marmee  80 , Diana M Eccles  81 , Graham G Giles  83 , Julian Peto  84 , Marjanka Schmidt  86 , Annegien Broeks  86 , Ute Hamann  103 , Jenny Chang-Claude  90 , Diether Lambrechts  93 , Paul D P Pharoah  104 , Douglas Easton  104 , V Shane Pankratz  2 , Susan Slager  2 , Celine M Vachon  2 , Fergus J Couch  105
Affiliations

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

Kristen S Purrington et al. Hum Mol Genet. .

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 = 39 067 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% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, 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.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Overlap between putative functional SNPs and ENCODE tracks in HMECs. Figures were generated in the UCSC Genome Browser (http://genome.ucsc.edu, last accessed on 19 June 2014) using ENCODE and custom tracks. ChromHMM, Hidden Markov Model predicted chromatin state segmentation; bright red, active promoter; light red, weak promoter; purple, inactive promoter; orange, strong enhancer; yellow, weak enhancer; blue, insulator; dark green, transcriptional elongation; light green, weakly transcribed; dark gray, polycomb-repressed; light gray, repetitive/copy number variation.
See this image and copyright information in PMC

References

    1. Hawkins G.A., Mychaleckyj J.C., Zheng S.L., Faith D.A., Kelly B., Isaacs S.D., Wiley K.E., Chang B.L., Ewing C.M., Bujnovszky P., et al. Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk. Cancer Genet. Cytogenet. 2002;137:1–7. - PubMed
    1. Guo Y., Zhang X., Yang M., Miao X., Shi Y., Yao J., Tan W., Sun T., Zhao D., Yu D., et al. Functional evaluation of missense variations in the human MAD1L1 and MAD2L1 genes and their impact on susceptibility to lung cancer. J. Med. Genet. 2010;47:616–622. - PubMed
    1. Milam M.R., Gu J., Yang H., Celestino J., Wu W., Horwitz I.B., Lacour R.A., Westin S.N., Gershenson D.M., Wu X., et al. STK15 F31I polymorphism is associated with increased uterine cancer risk: a pilot study. Gynecol. Oncol. 2007;107:71–74. - PubMed
    1. Ahmed S., Thomas G., Ghoussaini M., Healey C.S., Humphreys M.K., Platte R., Morrison J., Maranian M., Pooley K.A., Luben R., et al. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat. Genet. 2009;41:585–590. - PMC - PubMed
    1. Ewart-Toland A., Dai Q., Gao Y.T., Nagase H., Dunlop M.G., Farrington S.M., Barnetson R.A., Anton-Culver H., Peel D., Ziogas A., et al. Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types. Carcinogenesis. 2005;26:1368–1373. - PubMed

Publication types

Substances

Grants and funding