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Genetic and epigenetic alterations of Ras signalling pathway in colorectal neoplasia: analysis based on tumour

K Harada1, S Hiraoka, J Kato

  • 1Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

British Journal of Cancer
|October 10, 2007
PubMed

Insights

RAS pathway alterations in colorectal tumors are common. RASSF2 methylation frequently co-occurs with K-ras/BRAF mutations, particularly in serrated adenomas and proximal colon cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gastroenterology

Background:

  • RAS signaling activation via K-ras/BRAF mutations is a key feature of colorectal tumors.
  • Ras association domain family 1 (RASSF1) and Ras association domain family 2 (RASSF2) genes, negative regulators of K-ras, are often inactivated by promoter methylation in these tumors.
  • Limited data exists on how these molecular alterations correlate with specific tumor characteristics.

Purpose of the Study:

  • To investigate the association between K-ras/BRAF mutations, RASSF1/RASSF2 promoter methylation, and clinicopathological features in colorectal adenomas.
  • To compare the prevalence of these molecular alterations between colorectal adenomas and cancers.

Main Methods:

  • Analysis of K-ras/BRAF mutations and RASSF1/RASSF2 promoter methylation status in 120 colorectal adenomas.
  • Correlation of molecular findings with clinicopathological data using multivariate analysis.
  • Comparison of alteration frequencies between adenomas and cancers, particularly in the proximal colon.

Main Results:

  • K-ras/BRAF mutations were found in 41% and RASSF2 methylation in 25% of adenomas; RASSF1 methylation was rare (2.5%).
  • RASSF2 methylation frequently co-occurred with K-ras/BRAF mutations (P<0.01).
  • This co-occurrence was significantly associated with serrated adenomas (OR 11.11) and inversely associated with sigmoid/descending colon location (OR 0.13).
  • Colorectal cancers showed a higher prevalence of these alterations than adenomas in the proximal colon (58% vs 27%, P=0.02).

Conclusions:

  • RAS pathway alterations, including K-ras/BRAF mutations and RASSF2 methylation, occur differentially based on colorectal neoplasia type and location.
  • The timing and frequency of these molecular events vary during colorectal tumorigenesis.
  • Serrated adenomas and proximal colon cancers represent specific contexts where these RAS pathway dysregulations are more prevalent.

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