transformation is mediated by a genetic paradigm 2 . The major lesions detected 
in cancer cells occur in dominant oncogenes and tumor suppressor genes. 
Dominant oncogenes have alterations in a class of genes called proto- 
oncogenes, which participate in critical normal cell functions, including signal 
transduction and transcription. Primary modifications in the dominant 
oncogenes that confer the ability to transform include point mutations, 
translocations, rearrangements, and amplification. Tumor suppressor genes 
appear to require homozygous loss of function, by mutation, deletion, or a 
combination of these for transformation to occur. Some tumor suppressor 
genes appear to play a role in the governance of proliferation by regulation of 
transcription. It is possible that modification of the expression of dominant and 
tumor suppressor oncogenes may influence certain characteristics of cells that 
contribute to the malignant phenotype. 
Despite increasing knowledge of the mechanisms involved in oncogene- 
mediated transformation, little progress has occurred in developing therapeutic 
strategies that specifically target oncogenes and their products. Initially, 
research in this area was focused on dominant oncogenes, as these were the 
first to be characterized. DNA-mediated gene transfer studies showed 
acquisition of the malignant phenotype by normal cells following the transfer of 
DNA from malignant human tumors. Activated oncogenes of the ras family 
were identified by this technique with transfection of human DNA into mouse 
NIH 3T3 cells. 
Oncogene Mutations in Lung Cancer 
Activation of the K-ras oncogene occurs in human NSCLC 3,4 . Recent studies 
using the polymerase chain reaction (PCR) and specific oligonucleotide 
hybridization show that a third of NSCLC patients have ras family mutations 5,6 . 
However, Reynolds and coworkers, using a sensitive NIH 3T3 cotransfection- 
nude mouse tumorigenicity assay, found that 12 of 14 (86%). lung tumor DNAs 
from smokers contained activated proto-oncogenes related to the ras family 7 . 
K-ras mutations occur primarily in adenocarcinomas, and the K-ras proto- 
oncogene has a point mutation in 30% to 40% of adenocarcinomas of the 
lung 5,6 . Thus, a minimum of 32,000 patients per year are expected to develop 
ras-mutation-positive lung cancer. K-ras mutations are associated with a history 
of tobacco consumption and may contribute to tumor progression. 
The p53 gene is the most frequently mutated gene yet identified in human 
cancers. It is mutated in over 50% of human NSCLC 8 . The p53 gene encodes 
a 375-amino-acid phosphoprotein that can form complexes with host proteins 
such as large-T antigen and E1B a . Missense mutations are common for the 
p53 gene and are essential for the transforming ability of the oncogene. The 
wildtype p53 gene may directly suppress uncontrolled cell growth or indirectly 
activate genes that suppress this growth. Thus, absence or inactivation of 
wildtype p53 may contribute to transformation. However, some studies indicate 
Recombinant DNA Research, Volume 16 
