Ras gene mutations in patients with acute myeloid leukaemia and exposure to chemical agents

Abstract

Mutations of the N- and K-ras genes occur in approximately 15-30% of acute myeloid leukaemia patients. The role of the oncogenic ras in leukaemogenesis remains unclear. Few studies have revealed that mutations in the ras oncogene family are more probably found in acute myeloid leukaemia patients with previous exposure to toxic agents. A case-case study was conducted in the areas of Florence and Turin, Italy, to investigate whether the presence of N- and K-ras mutations in acute myeloid leukaemia patients was related to a higher frequency of exposure to chemicals. During a 3-year period, 111 acute myeloid leukaemia patients were enrolled. All the patients were interviewed using a semi-structured questionnaire collecting data on residential history, occupation, personal habits and pathological history. The presence of N- and K-ras mutations was analysed by amplification and synthetic oligonucleotide probes and by the so-called polymerase chain reaction amplification for specific alleles technique. A total of 34 (30.6%) patients were found to harbour ras mutations in N-ras and/or K-ras. Fourteen patients (12.6%) had a single ras mutation and 20 patients (18%) had two ras mutations. A positive association between a priori at risk jobs and ras mutations was found, based on nine exposed cases; the odds ratio, adjusted by age, sex and previous X-ray and/or chemotherapy was 2.8 (95% confidence intervals: 0.9-9.0). When considering only subjects with two ras mutations the odds ratio was 4.8 (95% confidence intervals: 1.2-18.8). The odds ratio for a previous X-ray and/or chemotherapy was 16.2 (95% confidence intervals: 1.8-755.9); when only subjects with two ras mutations were considered, the odds ratio was 26.1 (95% confidence intervals: 2.5-1248.9). In conclusion, our data suggest that ras oncogene mutations might identify a group of leukaemia in people with previous X-ray/chemotherapy or with exposure to chemical agents in the work environment.

RAS mutation is associated with hyperdiploidy and parental characteristics in pediatric acute lymphoblastic leukemia

“…Two epidemiologic studies have linked RAS mutation in adult myeloid leukemia with 'high risk' occupations for leukemogenesis. 6,7 Another case-case pediatric leukemia study (like the current one) suggested a role for parental hydrocarbon exposures including some specific for the father for leukemias with RAS mutations compared to those without. 30 In addition, mutagenic chemicals from maternal smoking cross the placenta enhancing the plausibility of an effect of parental smoking on pediatric leukemia risk.…”

“…3 RAS is not associated with prognostic outcome of leukemia in studies of childhood AML 4 and ALL, 5 but has been associated in etiology studies with occupational chemical exposures in adult AML. 6,7 The RAS genes are part of the small GTPase family and consist of three separate genes, NRAS, KRAS2, and HRAS. HRAS is rarely mutated in hematologic tumors and is expressed at a low level compared to the other two isoforms in leukemia and the hematopoietic cells from which they derive, 8 and hence is not further considered here.…”

Infant Acute Leukemia and Maternal Exposures during Pregnancy

“…A hospital-based case-control study was conducted to evaluate the magnitude of association between IAL exposure to selected environmental risk factors during pregnancy. The association between MLL rearrangements and selected environmental exposures was also explored using either a case-case study (12) or a case-only study approach (13).…”

Loss of heterozygosity of Kras2 gene on 12p12-13 in Chinese colon carcinoma patients

“…Activated Ras proto-oncogenes, especially Kras2, play an important role in the carcinogenesis of human and rodent tumors. Mutations of Kras2 gene have been found in tumor tissues of human organs, including bladder [11] , breast [12] , rectum [13] , kidney [14] , liver [15] , lung [16] , ovary [17] , pancreas [18] , stomach [19] and hematopoietic system [20] . In general, about 30% cancers display ras gene mutations, while the highest mutation rate is found in colonic and pancreatic cancer [21][22][23][24][25].…”