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Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3

R Dammann1, C Li, J H Yoon

  • 1Department of Biology, Beckman Research Institute, City of Hope Medical Center, Duarte, California, USA.

Nature Genetics
|July 11, 2000
PubMed

Insights

Loss of the RASSF1A gene is common in lung cancer, particularly small-cell lung cancer. Restoring RASSF1A expression suppressed tumor growth, indicating its role as a lung tumor suppressor.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Allelic loss on chromosome 3p is a frequent early event in lung cancer pathogenesis.
  • The 3p21.3 region is critical for tumorigenesis, with homozygous deletions identified in lung cancers.

Purpose of the Study:

  • To clone and characterize a novel gene, RASSF1, within the critical 3p21.3 homozygous deletion region.
  • To investigate the role of RASSF1A as a potential tumor suppressor gene in lung cancer.

Main Methods:

  • Cloning and characterization of RASSF1 transcripts (A, B, C).
  • Analysis of RASSF1A expression in normal tissues, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) cell lines.
  • Assessment of RASSF1A promoter methylation and mutation in primary lung tumors.
  • Functional studies involving re-expression of RASSF1A in lung carcinoma cells.

Main Results:

  • RASSF1, a RAS effector homologue, was identified in the minimal homozygous deletion region of 3p21.3.
  • Major transcripts RASSF1A and RASSF1C were expressed in normal tissues, but RASSF1A was absent in SCLC cell lines.
  • RASSF1A loss of expression correlated with promoter methylation (40% of primary lung tumors) and mutations (4 out of 41 tumors).
  • Re-expression of RASSF1A suppressed colony formation, anchorage-independent growth, and tumor formation in vivo.

Conclusions:

  • RASSF1A functions as a lung tumor suppressor gene.
  • Epigenetic silencing (promoter methylation) and genetic alterations contribute to RASSF1A inactivation in lung cancer.

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