A higher frequency of ras mutations, in particular K-ras mutations, was detected in isoprene-induced neoplasms than in 1,3-butadiene-induced or control HG neoplasms. All of the isoprene-induced HG neoplasms exhibited activated K-ras (60%) or H-ras (40%) mutations. In contrast, ras mutations were detected in 69% of HG neoplasms from 1,3-butadiene exposed mice (14% K-ras and 55% H-ras) and in 56% of HG neoplasms obtained from control B6C3F1 mice (8% K-ras and 48% H-ras). The predominant mutations in isoprene-induced HG neoplasms, but not in previously or newly analyzed 1,3-butadiene-induced HG neoplasms, consisted of A-T transversions (CCC-CTA) at K-ras codon 61 (15/30) and C-A transversions (CAA-AAA) at H-ras codon 61 (8/30). Two thirds of the K-ras CTA mutations were detected in HG neoplasms from the 2200 ppm exposure group while one third was present in the 7000 ppm group. Compared to the surrounding non-tumor HG tissue, HG neoplasms with K-ras or H-ras mutations had an elevated proliferating cell nuclear antigen (PCNA) index. The high frequency and specificity of the ras mutation profile suggest that ras protooncogene activation contributes to isoprene-induced HG tumorigenesis.
