Approaches To The Identification Of Human Oncogenes

No acutely transforming retroviruses have been observed in humans and even activation of cellular genes by retroviruses or related viruses such as HBV (^16.3) is exceptional. Two cases of iatrogenic oncogene activation may have happened when during attempted gene therapy of severely immunocompromised children retroviruses carrying a therapeutic gene integrated into the MLO2 proto-oncogene locus.

While such cases are clearly exceptional, the elucidation of the mechanisms by which retroviruses cause cancers in animals has been very instructive for the understanding of human cancers. Even if genes in the human genome are almost never activated by retroviruses to become oncogenes, many genes orthologous to the viral and animal oncogenes can be activated by other mechanisms in humans. Following rapidly on the discovery of cellular oncogenes, many human cancers were also screened for oncogenic alterations in these genes. Indeed, a large number of genes are now implicated as oncogenes in human cancers (Table 4.3). These candidates were obtained through several lines of research.

Analysis of human orthologs of retroviral oncogenes: An obvious approach was to investigate the human orthologs of viral oncogenes for their level of expression and for mutations in human cancers. A huge amount of literature has resulted from

Table 4.3. Some important oncogenes in human cancers

Oncogene

Tumor type

Activation

Cellular

Main biochemical

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