Mutations of the ING1 tumor suppressor gene detected in human melanoma abrogate nucleotide excision repair

Proc Amer Assoc Cancer Res, Volume 45, 2004 1542 Malignant melanoma is a life-threatening skin cancer for which there is still no effective treatment. Epidemiological evidence indicates that ultraviolet radiation is the primary environmental cause of the rapid increase in the incidence of human cutaneous melanoma observed in the past decades. However, the genetic changes caused by ultraviolet radiation that lead to melanoma formation remain unclear. The ING1 (inhibitor of growth 1) tumor suppressor plays an important role in cellular stress response to UV radiation, such as cell cycle arrest, DNA repair and apoptosis. To further investigate whether ING1 is involved in melanoma development, we examined the mutational status of ING1 in 46 human cutaneous melanoma biopsies. Single-strand conformation polymorphism (SSCP) and DNA sequencing revealed that 20% of the melanoma primaries contained missense mutations in the ING1 gene. Missense mutations affecting codons 102 and 260 of the p33ING1 protein were observed in more than one patient. Furthermore, our data indicates that patients that harbor ING1 mutations in the tumors have a higher risk to die from the disease within 5 years (50%) compared to patients with no ING1 mutation (18%). Using a host-cell-reactivation assay and a radioimmunoassay, we demonstrated that missense mutations at codon 102 or 260 as well as the deletion of the PHD finger motif are detrimental to p33ING1-mediated enhancement of DNA repair. Taken together, our data indicates that ING1 mutations abrogate its enhancement in nucleotide excision repair, which leads to increased genomic instability, tumor progression and a poorer 5-year patient survival.