P53 GENE-MUTATIONS AND STEROID-RECEPTOR STATUS IN BREAST-CANCER - CLINICOPATHOLOGICAL CORRELATIONS AND PROGNOSTIC ASSESSMENT

Background. There is increasing evidence linking development and progr ession of cancer to an accumulation of mutations at the genomic level. The most frequently mutated gene known to date in sporadic breast can cer appears to be the tumor suppressor gene p53. This study was design ed to determine the frequency of p53 gene mutations in primary breast cancer, to correlate the presence of p53 mutations with established cl inicopathologic parameters, including the estrogen receptor (ER) and p rogesterone receptor (PR) status, and to assess the prognostic signifi cance of p53 mutations regarding patient survival. Methods. We examine d the p53 gene in genomic DNA samples from 192 primary breast cancers. Using denaturant gradient gel electrophoresis, the authors analyzed e xons 5-9 in all tumors for mutations and performed DNA sequencing in 2 0 tumors to identify the exact nature of the p53 mutations. Results. p 53 gene alterations were identified in 43 of the 192 tumors (22%), the majority localized in exons 5 and 6. DNA sequencing showed mostly mis sense mutations resulting from G or C substitutions. p53 mutations wer e found more often in tumors of younger women (P = 0.002), Afro-Americ an women (P = 0.05), and in tumors lacking ER (P = 0.03), PR (P = 0.04 ), or both (P = 0.06). There were no significant correlations with fam ily history, tumor size, histologic grade or type, nodal status, or di sease stage. The overall survival rates showed no significant differen ce between patients with mutant and wildtype p53 tumors. The same was true when the comparison was limited to node-negative patients or pati ents with ER-positive or ER-negative tumors. Finally, there was no sig nificant difference in survival between patients with tumors harboring mutations in exons 5 and 6 versus exons 7-9. Conclusions. The results of this and other studies demonstrate a consistent relationship betwe en ER-positive tumors and wild-type p53 on one hand and ER-negative ca ncers and p53 mutations on the other. Our data do not support a signif icant prognostic role for p53 mutations in predicting survival.