In a Ni-caused malignant fibrous histiocytomas moue model, tumors had a down-regulated expression of p16Ink4a and hypermethylation of its DNA, and activation of the MAPK signaling pathway was observed, suggesting a role of synergistic interactions between MAPK activation and p16Ink4a silence in Ni carcinogenesis [104]. The gene discussed is CDKN2A; the disease is undifferentiated pleomorphic sarcoma.