It has been well established that specific alterations in members of the ras gene family, H-ras, K-ras and N-ras, can convert them into active oncogenes. These alterations are either point mutations occurring in either codon 12, 13 or 61 or, alternatively, a 5- to 50-fold amplification of the wild-type gene. Activated ras oncogenes have been found in a significant proportion of all tumors but the incidence varies considerably with the tumor type: it is relatively frequent (20-40%) in colorectal cancer and acute myeloid leukemia, but absent or present only rarely in, for example, breast tumors and stomach cancer. No correlation has been found, yet, between the presence of absence of an activated ras gene and the clinical or biological features of the malignancy. The activation of ras oncogenes is only one step in the multistep process of tumor formation. The presence of mutated ras genes in benign polyps of the colon indicates that activation can be an early event, possibly even the initiating event. However, it can also occur later in the course of carcinogenesis to initiate for instance the transition of a benign polyp of the colon into a malignant carcinoma or to convert a primary melanoma into a metastatic tumor. Apparently, the activation of ras genes is not an obligatory event but when it occurs it can contribute to both early and advanced stages of human carcinogenesis.

The ras gene family and human carcinogenesis

To define the role of cellular oncogenes in human cancers, we studied the prevalence of mutational activation of ras oncogenes in untreated non-small-cell lung cancer. Genomic DNA was extracted from 39 tumor specimens obtained by thoracotomy and was examined for activating point mutations in codons 12, 13, and 61 of the H-ras, K-ras, and N-ras genes. A novel, highly sensitive assay based on oligonucleotide hybridization following an in vitro amplification step was employed. The K-ras gene was found to be activated by point mutations in codon 12 in 5 of 10 adenocarcinomas. Two of these tumors were less than 2 cm in size and had not metastasized. No ras gene mutations were observed in 15 squamous-cell carcinomas, 10 large-cell carcinomas, 1 carcinoid, 2 metastatic adenocarcinomas from primary tumors outside the lung, and 1 small-cell carcinoma. An approximately 20-fold amplification of the unmutated K-ras gene was observed in a tumor that proved to be a solitary lung metastasis of a rectal carcinoma. We conclude that mutational K-ras activation may be an important early event in the pathogenesis of adenocarcinoma of the lung but that amplification of ras genes or mutational activation of H-ras or N-ras does not play a major part in non-small-cell lung cancer.

Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung.

Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial.

Map kinase signaling pathways and hematologic malignancies

A dot-blot screening procedure for mutated ras oncogenes using synthetic oligodeoxynucleotides.

Mutations in N-ras predominate in acute myeloid leukemia

Of the 20–30 oncogenes presently known, the ras genes belong to the best studied genes that are thought to play a role in carcinogenesis (Weinberg, 1984). The ras family consists of 3 members the H-ras, K-ras and N-ras genes. They encode homologous proteins of 21kD whose cellular location is at the inner surface of the plasma membrane (Land et al., 1983b; Cooper, 1983). The 21kD H-ras protein has been found to bind guanine nucleotides and to exhibit GTPase activity (McGrath et al., 1984; Sweet et al., 1984). In this respect, the protein resembles the “G proteins”, which are known to be involved in the transduction of the receptor-mediated external signals into the cell. Recently, it was found that cells when injected with ras-specific monoclonal antibodies which presumably inactivate the H-ras protein cannot enter the S-phase of the cell cycle, this suggests that the H-ras protein plays an essential role in the G1 phase (Mulcahy et al., 1985).

L. P. Colly

Papers

Mutations in N-ras predominate in acute myeloid leukemia

Activated RAS Oncogenes in Acute Leukemia