P53 GENE-MUTATIONS IN BREAST CANCERS IN MIDWESTERN US WOMEN - NULL ASWELL AS MISSENSE-TYPE MUTATIONS ARE ASSOCIATED WITH POOR-PROGNOSIS

We determined the pattern of mutations in exons 2-11 and adjacent intr onic regions in breast cancers from Midwestern US white women. Twenty- one mutations were detected in 53 tumors (39.6%). Comparisons of the p attern of mutations within exons 5-9 showed that the frequency of miss ense mutations (44%) was lower in breast cancers of US Midwestern wome n than in most tumor types including breast cancers in other populatio ns. Compared to breast cancers reported in a Scottish population, US w omen had a high frequency of microdeletion mutations (P = 0.006) and a low frequency of G:C-->T:A transversions (P = 0.046). These findings suggest that environmental or endogenous factors contribute to p53 mut agenesis in mammary tissue to different extents among different popula tions. With a median follow-up of 19 months, the presence of a mutatio n was associated with shorter time to disease recurrence (P = 0.05) an d shorter survival (P = 0.003). Putative dominant negative missense-ty pe mutations (missense and in-frame microdeletions; P = 0.001) and nul l mutations (hemizygous nonsense and frameshift mutations; P = 0.007) were equally ominous. Thus, tumors with missense p53 mutations resulti ng in overexpression of a dysfunctional but otherwise intact protein h ave a clinical outcome similar to tumors with null mutations resulting in a truncated or garbled protein.