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Genome-based identification of cancer genes by proviral tagging in mouse retrovirus-induced T-cell lymphomas

Rachel Kim1, Alla Trubetskoy, Takeshi Suzuki

  • 1Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

Journal of Virology
|January 15, 2003
PubMed

Insights

Researchers identified 19 cancer-associated genes in mouse T-cell lymphomas using retroviral insertion site analysis. Overexpression of the unmutated Rras2 gene was strongly linked to tumor development, suggesting its role in human cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Retroviruses can induce tumors by integrating viral DNA near cellular oncogenes, altering gene expression.
  • Identifying tumor-inducing genes is crucial for understanding cancer mechanisms.
  • The mouse genome sequence enables retroviral insertion site analysis for cancer gene discovery.

Purpose of the Study:

  • To identify novel cancer genes using retroviral insertion site analysis in mouse models.
  • To investigate the role of specific genes and pathways in T-cell lymphomagenesis.
  • To provide genetic evidence for the oncogenic potential of gene overexpression.

Main Methods:

  • Analysis of retroviral common integration sites in murine T-cell lymphomas induced by the SL3-3 retrovirus.
  • Inverse PCR amplification of virus-host junction fragments.
  • Sequencing and mapping of amplified fragments to the mouse genome to identify target genes.

Main Results:

  • 19 candidate cancer genes were identified, including transcription factors (Fos, Gfi1, Lef1, Myb, Myc, Runx3, Sox3), D cyclins, and Ras signaling pathway components (Rras2/TC21, Rasgrp1).
  • Rras2 was the most frequent target, with insertions up to 57 kb away leading to significantly increased transcription without coding mutations.
  • No Ras activation mutations were detected, but overexpression of unmutated Rras2 was linked to tumorigenesis.

Conclusions:

  • Genome-based retroviral insertion site analysis is a powerful tool for cancer gene discovery.
  • Several newly identified genes and pathways implicated in lymphomagenesis warrant further investigation for roles in human cancer.
  • Overexpression of unmutated Rras2 contributes to tumorigenesis, suggesting its potential role in human tumor development.

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