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2007 Fiscal Year Final Research Report Summary

Prognosis value of aberrant p16^<INK4a> gene methylation in colorectal cancer

Research Project

Project/Area Number 18591494
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionClinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital

Principal Investigator

KANAZAWA Hideki  Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital, National Hospital Organization Sagamihara Hospital, Department of Surgery and Clinical Research Laboratory(Pathology Division), Staff Physician (90265661)

Co-Investigator(Kenkyū-buntansha) MITOMI Hiroyuki  Clinical Research Center, National Hospital Organization Sagamihara Hospital, Department of Pathomechanisms, Chief Physician (90181940)
WATANABE Masahiko  Kitasato University, Department of ^5Surgery, School of Medicine, Professor (80146604)
Project Period (FY) 2006 – 2007
KeywordsColorectal cancer / Prognosis / p16INK4a / Promoter Methylation
Research Abstract

Materials and MethodsThe subjects of our study comprised a series of 151 patients(mean age, 65.8 years ; range, 39-86) diagnosed and undergoing surgery for colorectal carcinoma. The median duration of follow-up was 79 months(range, 60-123). Slides stained with hematoxylin and eosin were examined, and pT, pN and pathological staging was completed according to the UICC/TNM classification. In addition, fresh tumor tissues and matched normal mucosa away from the tumor were currently obtained from 25 patients. Genomic DNA was extracted from formalin-fixed paraffin-embedded sections of 151 tumor and 10 normal tissues, with additional extraction from the frozen sections of 25 tumor tissues. Total RNA was extracted from the frozen sections of 25 tumor tissues and 4 matched normal mucosas. Bisulfite-modified DNA was amplified using specifically designed primers for the methylated and unmethylated p16 sequence. The real-time quantitative methylation specific PCR was performed, and the methylatio … More n index was calculated according to the equation : (concentration of methylated p16 sequence/concentrations of methylated plus unmethylated p16 sequence) X 100. Total RNA was employed to synthesize cDNA which was then used for real-time quantitative PCR. The primer pairs located in exons lα and 2 with flanking intron 1 of the p16 gene. Immunostaining was performed with monoclonal anti-p16(E6H4, Dako). In addition, image analysis was performed on p16 immunostained slides from randomly selected cases.
Results Normal mucosa samples showed p16 methylation indices varying from 0 to 2%, and the indices of tumor samples represented 0 to 100%(median, 14.2% ; P=0.01) . Aberrant methylation of p16(methylation indices >2%) was detected in 100/151(66%) tumor samples. Loss of p16 expression(immunoreactivity <5%) was observed in 22/151(15%) cases. In image analyses, pl6-immunolabehng indices varied from 0 to 53% with no significant correlation to p16 methylation index. The expression level of p16 mRNA in normal tissues was consistently low whereas the value in tumor tissue was, in some cases, high level, which was statistically different(P=0.003). No significant correlation was observed between pl6 mRNA levels and methylation indiceswhereas p16 mRNA levels were positively correlated with p16-immunolabeling indices with statistically significant(P=0.043). Presence of p16 methylation was significantly associated with smaller tumor(P=0.048), but not with other clinicopathological features. In the Cox's regression model, present p16 methylation(P=0.007), high pT(P=0.007) and advanced tumor stage(P<0.001), proved to be independent predictors of short cancer-related survival. Cox's regression multivariate analysis also showed that p16 methylation(P<0.001), and advanced pN(P<0.001) and pT stages(P=0.014) predicted short recurrence-free survival. Less

  • Research Products

    (6 results)

All 2008 2007 Other

All Journal Article (4 results) (of which Peer Reviewed: 2 results) Presentation (2 results)

  • [Journal Article] Abnormal Expression of p16^<ink4a>,CyclinD1,Cyclin-Dependent Kinase 4 and Retinoblastoma Protein in Gastric Carcinomas2008

    • Author(s)
      Ichiro Kishimoto
    • Journal Title

      Jounal of Surgical Oncology

      Pages: 60-66

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Abnormal Expression of p16^<ink4a>, CyclinD1, Cyclin-Dependent Kinase 4 and Retinoblastoma Protein in Gastric Carcinomas2008

    • Author(s)
      Ichiro. Kishimoto
    • Journal Title

      Journal of Surgical Oncology

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Tumor budding at invasive margins and outcome in colorectal cancer2007

    • Author(s)
      H.Kanazawa
    • Journal Title

      Colorectal Disease

      Pages: 1463-1318

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Tumor budding at invasive margins and outcome in colorectal cancer2007

    • Author(s)
      H. Kanazawa
    • Journal Title

      Colorectal Disease.

      Pages: 1463-1318

    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Tumor budding at the invasive margin can predict prognosis in colorectal cancer2007

    • Author(s)
      H.Kanazawa
    • Organizer
      第66回日本癌学会
    • Place of Presentation
      横浜
    • Year and Date
      2007-10-03
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Tumor budding at the invasive margin can predict prognosis in colorectal cancer

    • Author(s)
      H. Kanazawa
    • Organizer
      The Japanese Cancer Association
    • Place of Presentation
      Yokohama
    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2010-02-04  

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