AN ABUNDANCE OF P53 NULL MUTATIONS IN OVARIAN-CARCINOMA

Ovarian cancers from 64 midwestern US women were screened for p53 dysf unction both by immunohistochemical staining (IHCS) and single strand conformation polymorphism (SSCP) analysis of the entire open reading f rame (ORF), Forty SSCP abnormalities in 39 tumors included nine deleti on, one insertion, two splice junction, two nonsense, one silent and 2 5 missense mutations were confirmed by direct genomic sequencing, Eigh t of the insertion/deletion defects may have occurred due to slippage during the course of DNA replication, This observation suggests that g enomic instability may play an important role in ovarian carcinogenesi s, Fifteen percent of the mutations encountered were located outside e xons 5-9 and four of these were null, The sensitivity of IHCS was 96% for missense mutations but only 14% for null mutations, This contraste d with 100% sensitivity of the SSCP screening methodology, The 21% ove rall incidence of null mutations in the present study far exceeds the reported 6.8% incidence in the world literature (P=0.0003). Explanatio ns for this difference include: (1) our complete analysis of the entir e ORF of the p53 gene; (2) the tendency of others to rely upon IHCS to screen tumors prior to mutation analysis; and (3) environmental or en dogenous genetic influences.