Over half of the angiosarcomas (n = 18, 53%) harbored genetic alterations affecting the MAPK pathway, involving mutations in KRAS, HRAS, NRAS, BRAF, MAPK1 and NF1, or amplifications in MAPK1/CRKL, CRAF or BRAF.
Chemical-specific alterations in ras, p53, and beta-catenin genes in hemangiosarcomas from B6C3F1 mice exposed to o-nitrotoluene or riddelliine for 2 years.
Although p14 inactivation or overexpression of the human murine double minute homolog (HDM2) were frequent in LMS and UPS and could substitute for TP53 mutation or deletion, such alterations were rare in angiosarcomas.
Our data indicated that p53 and beta-catenin mutations in the o-nitrotoluene-induced hemangiosarcomas and K-ras mutations and p53 protein expression in riddelliine-induced hemangiosarcomas most likely occurred as a result of the genotoxic effects of these chemicals.
Methylated p14(ARF) appeared in the context of a methylated p16(INKa) promoter in 3 cases of the 5 angiosarcomas methylated at p14(ARF). p14(ARF) aberrant methylation was not related to the presence of p53 mutations, which was detected in 6 of 19 (32%) cases.
In vivo, mice doubly deficient for p16(INK4a) and p53 showed an increased rate of tumor formation with particular susceptibility to aggressive angiosarcomas.
Our data indicate that K-ras, H-ras, and p53 mutations in these hemangiosarcomas most likely occurred as a result of the genotoxic effects of BD and that these mutations may play a role in the pathogenesis of BD-induced cardiac hemangiosarcomas in the B6C3F1 mouse.
The nature of these cells and the abnormalities of the p53 gene and the karyotype, suggest that: i) they were a component of the tumor stroma, and ii) they could have been involved in angiosarcoma development.
The pattern of modification followed the pattern of p53 mutations found in vinyl chloride-associated liver angiosarcomas in humans and rats, but only in regions that showed 100% homology with the human sequence.