Document 3QykxvVN6d9dqgkza4Dy5xn4O

Downloaded from http://jnci.oxfordjournals.org by on March 30, 2010 EDITORIAL Chemical Exposure, ras Oncogene Activation, and Acute Myeloid Leukemia Martyn T. Smith,* Joseph Wiemels, Nathaniel Rothman, Martha S. Linet Interest in the association between mutations in the ras family of oncogenes and acute myeloid leukemia (AML) began with the description of a point mutation in N-ras (also known as NRAS) in a patient with AML (/). Since then, clinical reports suggest that 15%-30% of patients with AML exhibit ras oncogene activation, making it the single most common genetic perturbation in AML (2,3). The vast majority of these mutations occur in N-ras. Occasionally, K-ras (also known as KRAS2) mutations are found. Mutations in H-ras (also known as HRAS) are very rarely demonstrated (2,3). The role of ras oncogene activation in AML patients remains unclear and can occur either early or late in the development of the disease (2-4). Mutation in ras oncogenes probably represents one of many genetic events that occur in leukemia. This mutation, however, could be especially important in the early stages of leukemia development, because it may cause chromosomal instability and increase the probability of other genetic alterations (5,6). If ras mutations had no functional role in leukemia development, they would occur randomly and at similar frequencies in different leukemias. This situation is not the case. Although the incidence of these mutations in AML patients is 15%-30%, in patients with acute lymphocytic leukemia, it is lower--only 10%-18%. In patients with chronic myeloid leukemia, the incidence is less than 5%, and in those with chronic lymphocytic leukemia, it is 0% (3). The highest incidence of ras mutations occurs in patients with the myelodysplasia subtype of chronic myelomonocytic leukemia, where 68% of patients carry a mutation (3). Thus, such mutations may be particularly important in specific subcategories of the leukemias and less important or unimportant in others. To clarify relationships between specific exposures and disease occurrence in an epidemiological sense, it is important to classify disease outcomes into subgroups that are as homogeneous as possible. In this manner, exposure associations confined to a specific subtype can be clearly identified. In this issue of the Journal, Taylor and his co- workers (7) argue that, since AML appears to be a heterogeneous disease at the molecular and cytogenetic levels, it is possible that certain environmental agents might be linked to specific molecular subtypes. Using ras mutationpositive (ras-positive) AML as a molecular subtype, they go on to show that this form of leukemia is strongly associated with employment in any of 32 a priori occupations reported to be associated with increased leukemia risk (7). Patients with ras-positive AML had a significantly higher frequency of working 5 or more years in an a priori high-risk occupation than did population-based control subjects (odds ratio [OR] = 5.9). Furthermore, ras-positive AML patients were more likely than control subjects to have had dermal exposure (OR = 4.5) or to have breathed chemical vapors on the job (OR = 3.0), associations which became stronger after exposure status was reclassified on the basis of use of protective equipment. Similar results were obtained when exposure patterns among ras-positive and ras mutationnegative (ras-negative) patients were compared. Earlier studies (8-11) had shown a link between chemical exposures and cytogenetically characterized subtypes of AML, e.g., association of alkylating agents used in chemotherapy with aberrations in the -5/-5q and -7/-7q chromosomal regions; association of occupational exposure with these aberrations plus aberrations in t(8;21) and trisomy 8; and association of smoking with aberrations in +8 and inv(16). The study by Taylor et al. (7) is the first, however, to use mutations in a proto-oncogene, which lead to activation of the oncogene, to subclassify leukemia and relate the subtype of AML characterized by ras mutation activation with employment in an occupation associated with elevated leukemia occurrence and substantial chemical exposure. In an important paper in the American Journal of Epidemiology in 1989 (12), Taylor suggested that oncogene assays could become a powerful epidemiological tool for investigating tumor etiology. His group's article in this issue further advances that concept. It is interesting to note that the occupational associations observed in this study would not have been detected had ras-positive and ras-negative patients been analyzed as a single group. This observation suggests that the leukemogenic potential of some previously studied occupations and chemical exposures may have been underestimated. Moreover, ras mutations tend to be chemical specific (13,14); thus, a larger study of ras-positive leukemias may enable identification of associations between specific ras mutations and particular chemical exposures. Application of molecular genetics may, therefore, significantly enhance the potential for epidemiological studies to Received October 14, 1992; accepted October 14, 1992. M. T. Smith, J. Wiemels, Center for Occupational and Environmental Health, School of Public Health, University of California, Berkeley. N. Rothman, M. S. Linet, Epidemiology and Biostatistics Program, Division of Cancer Etiology, National Cancer Institute, Bethesda, Md. M. T. Smith thanks the National Foundation for Cancer Research for supporting his group's work on ras and leukemia. J. Wiemels is a trainee of the Health Effects Component of the University of California Toxic Substances Program. We thank Dr. Richard Hayes for helpful comments. ^Correspondence to: Martyn T. Smith, Ph.D., School of Public Health, 322 Warren Hall, University of California, Berkeley, CA 94720. 1614 Journal of the National Cancer Institute Downloaded from http://jnci.oxfordjournals.org by on March 30, 2010 identify risk factor associations with higher sensitivity and 307:476-^78, 1984 specificity. (2) NEEDLEMAN SW: ras protooncogene activation in acute myeloid leukemia and related disorders. Leukemia and Lymphoma 5:85-91, The ORs described in the study by Taylor et al. (7) are 1991 large and the study is, indeed, noteworthy and suggestive. The findings are, however, based on relatively small numbers of patients, and the exposure assessment is confined (3) Liu ET: ras gene mutations in acute myelogenous leukemia. In Acute Myelogenous Leukemia: Progress and Controversies (Gale, RP, ed). New York: Wiley-Liss, 1990, pp 107-115 (4) RADICH JP, KOPECKY KJ, APPELBAUM F, ET AL: N-ras mutations in to job title and general types of exposure information acute myelogenous leukemia: A review of the current literature and an derived from questionnaires. Since exposures among workers update of the Southwest Oncology Group experience. Leukemia and Lymphoma 6:325-334, 1992 with the same job titles may be heterogeneous and no (5) BURNS PA, BREMNER R, BALMAIN A: Genetic changes during mouse detailed information was obtained about the specific skin tumorigenesis. Environ Health Perspect 93:41-44, 1991 chemical exposures, the findings from this study need to be (6) ROWLEY JD: Chromosome changes in leukemia cells as indicators of mutagenic exposure. In Chromosome and Cancer (Rowley JD, followed up in future studies with detailed, validated Ultmann JE, eds). New York: Academic Press, 1983, pp 139-157 exposure assessment. For example, Siemiatycki et al. (75) (7) TAYLOR JA, SANDLER DP, BLOOMFIELD CD, ET AL: ras oncogene have developed a particularly effective method of obtaining activation and occupational exposures in acute myeloid leukemia. J Natl Cancer Inst 84:1626-1632, 1992 exposure data in case-control studies. Questionnaires are (S) MITELMAN F, NILSSON PG, BRANDT L, ET AL: Chromosome pattern, reviewed by chemists and engineers who determine pertinent occupation, and clinical features in patients with acute nonlymphocytic detailed occupational exposure questions to be asked in a leukemia. Cancer Genet Cytogenet 4:197-214, 1981 (9) GOLOMB HM, ALIMENA G, ROWLEY JD, ET AL: Correlation of second interview and who make follow-up visits to selected occupation and karyotype in adults with acute nonlymphocytic places of employment. Another option is to analyze archived leukemia. Blood 60:404-411, 1982 material obtained from cohorts of occupationally exposed (10) NAROD SA, DUBE ID: Occupational history and involvement of chromosomes 5 and 7 in acute nonlymphocytic leukemia. Cancer workers with well-defined exposure. With larger numbers of Genet Cytogenet 38:261-269, 1989 leukemia cases characterized as ras positive or ras negative (//) CRANE MM, KEATING MJ, TRUJILLO JM, ET AL: Environmental and with state-of-the-art exposure assessment, we hope that investigators will be able to find exposure-specific abnor- exposures in cytogenetically defined subsets of acute nonlymphocytic leukemia [published erratum appears in JAMA 263:662, 1989]. JAMA 262:634-639, 1989 malities of oncogene activation. (12) TAYLOR JA: Oncogenes and their applications in epidemiologic Finally, it should be noted that ras-positive AML is found studies. Am J Epidemiol 130:6-13, 1989 (13) REYNOLDS SH, PATTERSON RM, MENNEAR JH, ET AL: ras gene with equal prevalence in children and adults (16,17). The activation in rat tumors included by benzidine congeners and derived pattern of ras mutation activation is also very similar-- dyes. Cancer Res 50:266-272, 1990 mainly G to A transitions (76). Obviously, occupational (14) MANAM S, STORER RD, PRAHALADA S, ET AL: Activation of Ha-, Ki- and N-ras genes in chemically induced liver tumors from CD-I mice. chemical exposures cannot directly account for ras mutations Cancer Res 52:3347-3352, 1992 found in childhood AML and must only account for a (15) SIEMIATYCKI J, RICHARDSON L, GERIN M, ET AL: Associations portion of those found in adult AML. However, it is between several sites of cancer and nine organic dusts: Results from an hypothesis-generating case-control study in Montreal, 1979-1983. interesting to speculate that the ras mutations found in Am J Epidemiol 123:235-249, 1986 childhood AML and other leukemias may be due to chemical (16) VOGELSTEIN B, CIVIN CI, PREISINOER AC, ET AL: RAS gene exposures either in utero or in early life or, perhaps, even to mutations in childhood acute myeloid leukemia: A Pediatric Oncology Group study. Genes Chromosom Cancer 2:159-162, 1990 parental exposure to occupational chemicals. Parental ex- (17) FARR C, GILL R, KATZ F, ET AL: Analysis of ras gene mutations in posure has been suggested as a source of increased risk of childhood myeloid leukaemia. Br J Hamatol 77:323-327, 1991 childhood leukemia (18). (18) LOWENGART RA, PETERS JM, CICIONI C, ET AL: Childhood leukemia and parents' occupational and home exposures. JNCI 79:39-46, 1987 References (/) GAMBKE C, SIGNER E, MORONI S: Activation of N-ras gene in bone marrow cells from a patient with acute myeloblastic leukemia. Nature European Organization for Research and Treatment of Cancer U.S. National 1 Cancer Institute The European Organization for Research and Treatment of Cancer (EORTO and the U.S. National Cancer Institute (NCI) are offering an exchange program to enable cancer researchers to work at NCI or EORTC-related institutions for one to three years. Ceneral Conditions Awardees will receive an annual subsistence allowance of S30,000. Half of this amount will be provided by U.S. sources, the remainder by European sources. European awardees will receive the U.S. contribution either from the NCI or from their extramural host institution. The European contribution of mthe exchangeship will be provided either by the scientist's home institution or by a European granting agency. For American awardees, the host institution must be affiliated with the EORTC. Documentation The following documents are required, in English, from all applicants: Completed application form. Description of the research to be undertaken, not to exceed three typewritten pages. Letter of invitation from the prospective host. Agreement to release the applicant from the home institution for the duration of the exchangeship. Assurance of intention to return to the home institution at the end of the exchangeship. Statement concerning the provision of 50 percent of financial support by European sources. NonEORTC member country candidates must continue at full salary at the home institution for the duration of the exchangeship. Three letters of recommendation mailed directly to the NCI Liaison Office by the recommending individuals. For More Information Contact: EORTC/NCI Exchange Program NCI Liaison Office 83, Avenue E. Mounier 1200 Brussels, Belgium Telephone: (321(2)772-22-17 Telefax: (32) (2) 770-47-54 Vol. 84, No. 21, November 4, 1992 EDITORIAL 1615