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1. WO2006121208 - POLYMORPHISMS OF THE E2F-1 BINDING ELEMENT AND METHODS OF DETERMINING CANCER SUSCEPTIBILITY

Publication Number WO/2006/121208
Publication Date 16.11.2006
International Application No. PCT/JP2006/309887
International Filing Date 11.05.2006
IPC
C12Q 1/68 2006.1
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12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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1Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
68involving nucleic acids
CPC
C12Q 1/6886
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1Measuring or testing processes involving enzymes, nucleic acids or microorganisms
68involving nucleic acids
6876Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
6883for diseases caused by alterations of genetic material
6886for cancer
C12Q 2600/156
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2600Oligonucleotides characterized by their use
156Polymorphic or mutational markers
C12Q 2600/16
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2600Oligonucleotides characterized by their use
16Primer sets for multiplex assays
C12Q 2600/178
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2600Oligonucleotides characterized by their use
178miRNA, siRNA or ncRNA
Applicants
  • ONCOTHERAPY SCIENCE, INC. [JP]/[JP] (AllExceptUS)
  • THE UNIVERSITY OF TOKYO [JP]/[JP] (AllExceptUS)
  • NAKAMURA, Yusuke [JP]/[JP] (UsOnly)
  • FURUKAWA, Yoichi [JP]/[JP] (UsOnly)
  • NAKATSURU, Shuichi [JP]/[JP] (UsOnly)
Inventors
  • NAKAMURA, Yusuke
  • FURUKAWA, Yoichi
  • NAKATSURU, Shuichi
Agents
  • SHIMIZU, Hatsushi
Priority Data
60/681,11112.05.2005US
Publication Language English (en)
Filing Language English (EN)
Designated States
Title
(EN) POLYMORPHISMS OF THE E2F-1 BINDING ELEMENT AND METHODS OF DETERMINING CANCER SUSCEPTIBILITY
(FR) POLYMORPHISMES DE L’ELEMENT DE LIAISON DE E2F-1 ET PROCEDES DE DETERMINATION DE LA SENSIBILITE AU CANCER
Abstract
(EN) Up-regulated ZNFN3A1, a histone methyltransferase, is a critical promoter of cell growth in a great majority of the human colorectal, liver, and breast cancers. Herein, transcriptional regulatory regions in the 5' flanking region of ZNFN3A1 that contains four E2F-1 binding motifs and one Nrf1 binding motif are identified. In particular, experimental data disclosed herein suggest that E2F-1 induces of ZNFN3A1 expression by transcriptional activation through a binding to the promoter region. In addition, a significant association between a variable number tandem repeat (VNTR) polymorphism of a CCGCC unit in the regulatory region of the ZNFN3A1 gene and an increased risk of colorectal cancer ( Chi-square=17.86, p=3.8 x 10^-5, odds ratio=2.20), hepatocellular carcinoma ( Chi-square=25.39, p=4.7 x 10^-7, odds ratio=2.74) and also breast cancer ( Chi-square=38.91, p=3.4 x 10^-9, odds ratio=3.79) was discovered. This tandem-repeated sequence was shown to be a binding-site for the transcriptional factor E2F-1 and the common VNTR polymorphism in ZNFN3A1 is shown herein to be a susceptibility factor for certain types of human cancer.
(FR) La ZNFN3A1 régulée à la hausse, une histone méthyltransférase, est un promoteur critique de la croissance cellulaire dans une grande majorité des cancers humains colorectaux, du foie, et du sein. Ici, les régions régulatrices transcriptionnelles dans la région flanquante 5’ de ZNFN3A1 qui contient quatre motifs de liaison E2F-1 et un motif de liaison Nrf1 sont identifiées. En particulier, les données expérimentales décrites ici suggèrent que E2F-1 induit l’expression de ZNFN3A1 au moyen de l’activation transcriptionnelle à travers une liaison à la région du promoteur. De plus, une association significative entre une séquence de polymorphisme répété en tandem d’un nombre variable (VNTR) d’une unité CCGCC dans la région régulatrice du gène ZNFN3A1 et un risque accru de cancer colorectal (khi-carré = 17,86, p=3,8 x 10^-5, risque relatif approché = 2,20), carcinome hépatocellulaire (khi-carré = 25,39, p=4,7 x 10^-7, risque relatif approché = 2,74) et aussi le cancer du sein ( khi-carré = 38,91, p=3,4 x 10^-9, risque relatif approché = 3,79) a été découverte. On a montré que cette séquence répétée en tandem est un site de liaison pour le facteur transcriptionnel E2F-1 et le polymorphisme VNTR commun dans ZNFN3A1 est montré ici comme étant un facteur de sensibilité pour certains types de cancers humains.
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