Analysis of RAS oncogene mutations in human lymphoid malignancies

We investigated the frequency of mutations activating RAS oncogenes in human lymphoid malignancies, including B- and T-cell-derived acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. By the polymerase chain reaction/oligonucleotide hybridization method, DNA from 178 cases was analyzed for activating mutations involving codons 12 and 61 of the HRAS, KRAS and NRAS genes and codon 13 of the NRAS gene. Mutations involving codons 12 or 13 of the NRAS gene were detected in 6 of 33 cases of acute lymphoblastic leukemia (6/33, 18%), whereas no mutations were found in non-Hodgkin lymphoma or chronic lymphocytic leukemia. Direct nucleotide sequence analysis of polymerase chain reaction products showed that the mutations involved a G----A transition in five of the six cases of acute lymphocytic leukemia. In four cases the mutations seemed to occur in only a fraction of the neoplastic cells, and one case displayed two distinct NRAS mutations, most likely present in two distinct cell populations. These results indicate the following: (i) RAS oncogenes are not found in all types of human malignancies, (ii) significant differences in the frequency of RAS mutations can be found among subtypes of neoplasms derived from the same tissue, (iii) in lymphoid neoplasms the NRAS mutation correlates with the most undifferentiated acute lymphocytic leukemia phenotype, and (iv) NRAS mutations present in only a fraction of malignant cells may result from either the selective loss or the acquisition of mutated alleles during tumor development.