P53 MUTATIONS IN LUNG CANCERS FROM JAPANESE MUSTARD GAS WORKERS

Mustard gas (MG) is a mutagenic and carcinogenic alkylating agent, and is a known risk factor for occupational lung cancer. Our hypothesis i s that lung cancers from MG workers contain mutations (G:C to A:T tran sitions)as the result of MG-produced DNA promutagenic adducts in the p 53 tumor suppressor gene, We analyzed 12 primary lung cancers from Jap anese MG factory workers and 12 lung cancers from non-exposed individu als. Genomic DNA was isolated from archival paraffin-embedded tissues. Exons 5-8 were amplified by polymerase chain reaction using p53-speci fic primers, and sequenced by dideoxy. termination methods. Six out of 12 lung cancers from MG workers contained a total of eight somatic po int mutations: two cases had double G:C to A:T transitions; one had a G:C to T:A transversion; one case had an A:T to G:C transition; and tw o cases had single base deletions. Four of the six mutated purines occ urred on the non-transcribed, DNA-coding strand. Out of 12 unexposed c ases, there were six single base mutations in six cancers, and no doub le mutations. The p53 mutational frequency in the MG-exposed cases is similar to the non-exposed controls and the usual smoking-related lung cancers reported previously. However, the distinctive double mutation s (G:C to A:T transition) observed in two cases are unusual and may be related to MG exposure.