DETECTION OF C-MYC ONCOGENE AMPLIFICATION AND CHROMOSOMAL-ANOMALIES IN METASTATIC PROSTATIC-CARCINOMA BY FLUORESCENCE IN-SITU HYBRIDIZATION

The role of c-myc in prostatic carcinogenesis is poorly understood, Th e pathogenetic relationship between high-grade prostatic intraepitheli al neoplasia (PIN), prostatic carcinoma, and metastases is not well-de fined, We used fluorescence in situ hybridization (FISH) with a region -specific probe for c-myc (band 8q24) and chromosome enumeration probe s for chromosomes 7, 8, 10, 12, and Y to evaluate genetic changes in m atched PIN (48 foci), localized prostatic carcinoma (71 feci), and lym ph node metastases (23 foci) in 25 totally embedded whole-mount stage D1 (T(2-3)N(1-3)M(0)) radical prostatectomy and pelvic lymphadenectomy specimens. The c-myc protein expression in these lesions was evaluate d by immunohistochemistry. Foci with extra copies of c-myc could be di vided into three groups: (a) those with simple gain of a whole chromos ome 8 (no increase in c-myc copy number relative to the chromosome 8 c entromere), which was identified in 42, 25, and 46% of foci of PIN, ca rcinoma, and metastases, respectively; (b) those with an intermediate increase in c-myc copy number relative to the chromosome 8 centromere, which was found in 8, 11, and 25% of foci of PIN, carcinoma, and meta stases, respectively; and (c) those with substantial amplification of c-myc (large increases in c-myc copy number relative to the chromosome 8 centromere), which was detected in 0, 8, and 21% of foci of PIN, ca rcinoma, and metastases, respectively, Substantial amplification of c- myc was strongly correlated with increasing cancer nuclear grade and i mmunohistochemic al evidence of c-myc protein overexpression. Numeric chromosomal anomalies were found in 67, 68, and 96% of foci of PIN, ca rcinoma, and metastases, respectively, The most frequent anomaly in PI N and carcinoma was a gain of chromosome 8, and the presence of this a nomaly strongly correlated with Gleason score. Carcinoma foci usually contained more FISH anomalies than paired PIN foci, but three prostate s contained one or more PIN foci with more anomalies than carcinoma, T hirteen primary tumor foci exhibited intratumor genetic heterogeneity by FISH. One or more foci of the primary tumor usually shared FISH ano malies with the matched metastases. Our FISH results indicate that: (a ) gain of chromosome 8 and amplification of c-myc are potential marker s of prostate carcinoma progression; (b) PIN is likely a precursor of carcinoma; (c) intraglandular and intratumoral genetic heterogeneity i s relatively common; and (d) usually a single focus of cancer gives ri se to metastases.