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R B Jenkins

Publications and source records attributed to R B Jenkins.

At least 55 records · Page 3Linked to original sources
PubMed1999

Detection of p16, RB, CDK4, and p53 gene deletion and amplification by fluorescence in situ hybridization in 96 gliomas.

Inactivation of the p53 gene is a common early event of astrocytoma tumorigenesis. Alternatively, since the p16, retinoblastoma (RB), and CDK4 genes have been implicated in malignant progression, detection of losses or amplifications of these genes in gliomas could be diagnostically, prognostically, and therapeutically important. We obtained smear preparations from 96 diffuse gliomas and 10 nonneoplastic specimens. Dual-color fluorescence in situ hybridizations using paired probes for CEN9/p16, CEN8/RB, CEN17/p53, and CEN12/CDK4 were performed and revealed expected frequencies of abnormalities, except for p53 losses, which were low (7%). The latter supports the concept that p53 inactivation usually occurs by mitotic recombination. Detected abnormalities of the p16/RB/CDK4 pathway were highly associated with astrocytic differentiation and were univariately associated with decreased patient survival. However, only patient age and histologic classification retained statistical significance on multivariate analysis. We conclude that in diffuse gliomas, p16/RB/CDK4 abnormalities are markers of astrocytic phenotype. Thus, their detection by fluorescence in situ hybridization may have diagnostic usefulness in cases with equivocal morphologic features. Although our numbers are small, we find no additional prognostic significance to these genetic abnormalities one age, grade, and oligodendroglial histology are taken into account.

Adult↗
PubMed1999

Genetic and chromosomal alterations in prostatic intraepithelial neoplasia and carcinoma detected by fluorescence in situ hybridization.

OBJECTIVE: In this review, we discuss the utility of fluorescence in situ hybridization (FISH) in the determination of genetic and chromosomal alterations in prostate cancer specimens. We also discuss the genetic association between prostatic intraepithelial neoplasia (PIN) and adenocarcinoma as detected by FISH and other techniques. METHODS AND RESULTS: FISH is a commonly used technique for the determination of gene and chromosome dosage. In tissue sections, FISH allows precise histopathologic correlation of multiple foci of normal epithelium, premalignant lesions, and carcinoma within a single specimen, including study of intratumoral heterogeneity. PIN and prostatic carcinoma foci have a similar proportion of genetic changes, but foci of carcinoma usually have more alterations. This supports the hypothesis that PIN is the most likely precursor of prostatic carcinoma. The most common genetic alterations in PIN and carcinoma are: (1) gain of chromosome 7, particularly 7q31; (2) loss of 8p and gain of 8q, and (3) loss of 10q, 16q and 18q. Inactivation of tumor suppressor genes and/or overexpression of oncogenes in these regions may be important for the initiation and progression of prostate cancer. CONCLUSIONS: FISH is a useful technique to determine genetic relationships between cancer and its precursors. PIN and prostatic carcinoma foci have a similar proportion of genetic alterations, suggesting that PIN is often a precursor of prostatic carcinoma. Genes on chromosomes 7, 8, 10, 16 and 18 may play an important role in both initiation and progression of prostatic carcinoma.

Adenocarcinoma↗
PubMed1999

Tumor suppressor gene alterations in malignant gliomas: histopathological associations and prognostic evaluation.

We have examined a series of 135 gliomas for alterations of the p53, CDKN2A (p16) and PTEN tumor suppressor genes (TSGs) in order to evaluate the incidence of their inactivation as a function of tumor malignancy and cellular differentiation, and to examine potential associations with patient outcome. The composition of this series, classified using WHO criteria, is as follows: 27 grade 2 tumors (11 astrocytomas, 12 oligoastrocytomas, 4 oligodendrogliomas), 42 grade 3 tumors (22 astrocytomas, 16 oligoastrocytomas, 4 oligodendrogliomas), and 66 grade 4 tumors (63 astrocytomas and 3 oligoastrocytomas). Similar frequencies of p53 mutation were observed among grade 2 (37.0%), and grade 3 tumors (38.1%), as well as between astrocytomas and mixed tumors. CDKN2A and PTEN mutations were clearly associated with increasing tumor malignancy (occurring in 0% of grade 2 tumors, 14.3% and 4.8% respectively of grade 3 tumors, and 27.3% and 30.3% respectively of grade 4 tumors) and were observed at substantially higher rates among astrocytomas. For the tumor suppressor genes examined, there was no relationship between the occurrence of any two TSG inactivation events. With regard to outcome, the p53 genetic status showed no significant relationship with patient survival. The CDKN2 and PTEN alterations were negative prognostic indicators of survival when evaluated in all 135 gliomas, but failed to predict outcome when evaluated in either of the high grade (3 or 4) tumor groups.

Adolescent↗
PubMed1999

Fluorescence in situ hybridization aneuploidy as a predictor of clinical disease recurrence and prostate-specific antigen level 3 years after radical prostatectomy.

OBJECTIVE: To determine if fluorescence in situ hybridization (FISH) analysis of fresh-tissue biopsy specimens obtained at the time of radical prostatectomy is able to predict prospectively clinical disease progression or prostate-specific antigen (PSA) level in patients 3 to 4 years after surgery. MATERIALS AND METHODS: FISH analysis was performed on fresh-tissue touch preparations obtained from 90 randomly selected radical prostatectomy specimens. Cut surface touch preparations from 40 specimens resected in 1992 were analyzed with DNA probes for chromosomes 4, 6-12, 17, 18, X, and Y. Needle-biopsy specimens were obtained from 50 tumors resected in 1993, and touch preparations from these specimens were studied with DNA probes for chromosomes 7, 8, 11, and 12. Serum PSA levels and clinicopathologic data were recorded, and each patient was followed up from the time of surgery to determine cancer progression. RESULTS: Of 90 patients undergoing radical prostatectomy in 1992 and 1993, 89 returned for follow-up. Three patients received preoperative hormonal therapy, and in 2 patients, antiandrogen therapy was continued postoperatively. Fifteen patients underwent intraoperative orchiectomy immediately after radical prostatectomy, while 9 patients had postoperative adjuvant hormonal therapy. Six patients underwent postoperative radiation therapy. Fourteen patients (15.7%) demonstrated systemic, local, or PSA progression. Only 2 (4.7%) of 43 patients with FISH diploid tumors demonstrated cancer progression. Conversely, 10 (30.3%) of 33 FISH aneuploid and 12 (26.1%) of 46 FISH nondiploid tumors demonstrated cancer progression (P=.004 and P=.006, respectively). Unlike FISH, flow cytometric aneuploidy was not associated with early cancer progression. Elevated preoperative PSA concentration, increased preoperative and postoperative Gleason score, and increased preoperative and postoperative T or N stage were not statistically significantly associated with cancer progression. While chromosome 7 and 8 aneusomies were not statistically associated with cancer progression, 2 of 5 (P=.04) chromosome 12 aneusomic tumors demonstrated cancer progression. CONCLUSION: Early (within 4 years) local, systemic, or PSA progression occurred more frequently (P<.05) in radical prostatectomy patients with FISH aneuploid, nondiploid, and chromosome 12 aneusomic tumors. Flow cytometric ploidy status, preoperative serum PSA concentration, and clinical or pathologic grade or stage, including seminal vesicle involvement, margin status, and capsular perforation status, were not associated with early prostate cancer progression in this group of 89 patients. FISH analysis appears to be a useful preoperative tool for predicting aggressive vs indolent prostate cancer.

Aged↗
PubMed1999

Analysis of oncogene and tumor suppressor gene alterations in pediatric malignant astrocytomas reveals reduced survival for patients with PTEN mutations.

Although common among adult intracranial neoplasms, pediatric malignant astrocytomas (PMAs) comprise a relatively small proportion of the brain tumors that occur in children. The scarcity of such cases generally requires that molecular analyses of PMAs are based on the utilization of paraffin-embedded material, and here we have used 39 such specimens to examine the incidence and prognostic significance of oncogene and tumor suppressor gene alterations (including amplifications of EGFR, CDK4, and MDM2 as well as inactivating mutations of CDKN2A, TP53, and PTEN) in these tumors. In general, the frequency of alteration for the genes we have studied fell within ranges that have been reported for adult astrocytomas. However, EGFR amplification, which is usually observed in approximately 40% and 15% of adult grade 4 and grade 3 astrocytomas, respectively, was not detected in any member of this series. With regard to prognosis, PTEN mutations were significantly associated with decreased survival among grade 3 and grade 4 PMA patients, a potentially important observation because neither patient age nor tumor malignancy grade was correlated with outcome for these individuals. In total, our data suggest at least one significant distinction between the genetic etiology of pediatric and adult astrocytomas and additionally reveal that analysis of PTEN mutations in PMA patients may be useful in the differential diagnosis of these tumors.

Adolescent↗
PubMed1998

Independent origin of multiple foci of prostatic intraepithelial neoplasia: comparison with matched foci of prostate carcinoma.

BACKGROUND: Prostate carcinoma usually is heterogeneous and multifocal, with diverse clinical and morphologic manifestations. Understanding of the molecular basis for this heterogeneity is limited, particularly for the putative precursor, high grade prostatic intraepithelial neoplasia (PIN). In this study, the authors attempted to determine the genetic relation between multiple foci of PIN and matched foci of carcinoma, and whether they are independent in origin. METHODS: The distribution and prevalence of allelic imbalance at 6 microsatellite polymorphic markers on chromosomes 7q, 8p, 8q, and 18q were examined in 84 microscopically excised PIN foci (mean, 1.6 foci/case) and 95 foci of prostate carcinoma (mean, 1.8 foci/case) from 52 completely embedded, mapped whole mount prostates. RESULTS: PIN contained a lower overall proportion of allelic imbalance than matched prostate carcinoma foci for the 6 polymorphic microsatellite markers (65% vs. 82%), but this difference was not significant. The rate of allelic imbalance in PIN was similar to that in prostate carcinoma at 5 of 6 loci studied; the exception, D18S34 (18q12.2-12.3), had a significantly lower rate of allelic imbalance in PIN than in prostate carcinoma (19% vs. 52%), suggesting that genetic alterations in this chromosomal region may be important in carcinogenesis. Of 22 cases with allelic imbalance in at least 1 focus of PIN and 1 focus of prostate carcinoma, 21 informative cases (95%) showed a similar pattern of allelic imbalance at > or = 1 markers in the matched PIN and prostate carcinoma foci. Significant genetic heterogeneity was observed in both PIN and prostate carcinoma. Allelic imbalance was observed in at least 1 focus in 11 of 25 cases with multiple foci of PIN (44%) and 20 of 25 cases with multiple foci of prostate carcinoma (80%). There was no significant correlation between allelic imbalance and pathologic stage or tumor grade. CONCLUSIONS: Our findings indicate that multiple foci of PIN arise independently within the same prostate. This observation suggests that a field effect underlies prostatic neoplasia. Multiple foci of prostate carcinoma also often arise independently, lending additional support for this hypothesis. The strong genetic similarities between PIN and prostate carcinoma strongly suggest that evolution and clonal expansion of PIN may account for the multifocal etiology of carcinomas.

Aged↗
PubMed1998

Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors.

Joint predisposition to malignant melanoma and nervous system tumors (NSTs) is a puzzle. Several melanoma susceptibility genes have been identified, including p16, a clustered tumor suppressor. However, the molecular bases of inherited proclivity to NSTs in the absence of a recognizable genetic syndrome are unknown. We analyzed two families with joint proneness to melanoma and NSTs in view of genetic linkage and identification of the causal molecular lesions. Highly informative linkage markers were used for segregation analyses of the predisposition alleles in the two pedigrees. Characterization of the molecular lesions required hemizygosity mapping based on microsatellite markers physically mapped to contigs of the 9p21 region and a Southern blot approach using several PCR-generated probes. Both families were found to be allelic and linked to p16 markers. In the family segregating the melanoma/NST syndrome, a large germ-line deletion ablated the whole p16, p19, and p15 gene cluster (or INK4 locus), whereas a more circumscribed molecular lesion disrupting p16 and p19 but leaving p15 unaltered segregated with the melanoma-astrocytoma syndrome (MIM 155755). Our results suggest that multiple cancer susceptibility in these two families ensues from contiguous tumor suppressor gene deletion. Indeed, known phenotypes associated with germ-line p16 mutations and an apparent correlation between the deletion span and tumor spectrum in the two families suggest a new model of cancer pathogenesis based on the inactivation of contiguous tumor suppressor genes, an alternative to the established pleiotropic effects of single-gene disruption.

Adult↗
PubMed1998

A molecular cytogenetic analysis of 7q31 in prostate cancer.

Gains of chromosome 7 and alterations of the 7q-arm have been frequently observed in multiple cancers using various cytogenetic and molecular genetic techniques. Using PCR analysis of microsatellite markers, we have previously reported that allelic imbalance of 7q31 is common in prostate cancer and is associated with higher tumor grade and advanced pathological stage. In an effort to better understand the chromosome 7 alterations in prostate cancer, we undertook a molecular cytogenetic study of 25 prostate specimens using fluorescence in situ hybridization (FISH) with DNA probes for the chromosome 7 centromere and for 5 loci mapped to 7q31 (D7S523, D7S486, D7S522, D7S480, and D7S490) and 1 locus at 7q11.23 (ELN). Six tumors had no apparent anomaly for any chromosome 7 probe. Nine tumors showed apparent simple gain of a whole chromosome 7, whereas one tumor had apparent simple loss of a whole chromosome 7. Four tumors had gain of the chromosome 7 centromere and additional overrepresentation of the 7q-arm. One tumor had overrepresentation of 7q31 without any apparent anomaly of the chromosome 7 centromere, and one tumor had apparent loss of the chromosome 7 centromere with no apparent anomaly of the 7q-arm. Three tumors had gain of the chromosome 7 centromere and loss of the 7q31 region. Gain of 7q31 was strongly correlated with tumor Gleason score. Multiplex PCR studies of these specimens supported these FISH observations. Mutation screening and DNA sequencing of the MET gene, which is mapped to 7q31, revealed only the presence of simple sequence polymorphisms but no apparent acquired disease-associated mutations. FISH analysis of metaphases from an aphidicolin-induced, chromosome 7 only, somatic cell hybrid demonstrated that the DNA probe for D7S522 spans the common fragile site FRA7G at 7q31. Our data indicate that the 7q-arm, particularly the 7q31 region, is genetically unstable in prostate cancer, and some of the gene dosage differences observed may be due to fragility at FRA7G.

Chromosome Aberrations↗
PubMed1998

Biological characterization of human epithelial ovarian carcinoma cells in primary culture: the insulin-like growth factor system.

Little is known about the factors regulating epithelial ovarian cancer cell growth. This is due, in large part, to the difficulty in obtaining and culturing human ovarian cells for relevant in vitro studies. We recently developed a method for culturing epithelial carcinoma cells derived from fresh, untreated epithelial ovarian cancer specimens. The cell populations are free of fibroblasts and reflect the primary tumor as determined by chromosomal analysis. In this study we report on the cells' growth in serum-free medium and their secretion of CA-125, a glycoprotein marker for ovarian cancer. Furthermore we characterize the insulin-like growth factor (IGF) system in these primary ovarian carcinoma cell cultures. The cells secrete IGF peptides and IGF-binding proteins, possess specific type I IGF receptors, and respond to exogenous IGFs. The culture system reported here provides the basis for further study and manipulation of the IGF system as well as other regulators of epithelial ovarian cancer. Greater understanding of the cellular and molecular mediators of primary human ovarian cancer cell growth may translate into relevant clinical interventions.

Adenocarcinoma↗
PubMed1998

Comparative genomic hybridization: a comparison with molecular and cytogenetic analysis.

Comparative genomic hybridization (CGH) is a powerful technique for detecting copy number changes throughout the genome. We describe the development of a versatile image analysis program for CGH studies. Several methods for the production of metaphases which give optimum hybridization signals have also been assessed. CGH analysis was performed on DNA samples from several different and clinically relevant specimens: amniotic fluid cells trisomic for a single chromosome, lymphoblastoid cell lines with abnormalities involving single chromosome bands, malignant cell lines and biopsy material from primary ovarian carcinomas. The results were compared with those derived from G-banding, chromosome painting, and molecular genetic techniques. Our data demonstrate that CGH was able to detect a wide range of quantitative genetic alterations including duplication or deletion of single chromosome bands. CGH analysis also indicated the presence of genetic abnormalities that were not detected by other cytogenetic or molecular approaches. Moreover, our CGH methodology allowed the ready comparison of CGH results from different tumors, a process which greatly facilitated identification of shared genetic changes.

Amniotic Fluid↗
PubMed1998

Fish mapping of YAC clones at human chromosomal band 7q31.2: identification of YACS spanning FRA7G within the common region of LOH in breast and prostate cancer.

Loss of DNA sequences within human chromosomal band 7q31.2 is frequently observed in a number of different solid tumors including breast, prostate, and ovarian cancer. This chromosomal band also contains the common fragile site, FRA7G. Many of the common fragile sites occur within chromosomal regions that are frequently deleted during tumor formation but their precise position, relative to the chromosome breakpoints and deletions, has not been defined for the majority of the fragile sites. Because the frequency of expression of FRA7G is low, we analyzed the expression of FRA7G in a chromosome 7-only somatic cell hybrid (hamster-human). YAC clones defining a contig spanning 7q31.2 were then used as FISH probes against metaphase spreads prepared from the hybrid cells after aphidicolin induction. This analysis quickly revealed whether a specific YAC clone mapped proximal, distal, or actually spanned the region of decondensation/breakage of FRA7G. By using this approach, we have identified several overlapping YAC clones that clearly span FRA7G. Interestingly, these clones map precisely to the common region of LOH in breast cancer and prostate cancer. In addition, the MET oncogene is contained within the three YACs that span FRA7G.

Animals↗
PubMed1998

Clinical outcome of gliosarcoma compared with glioblastoma multiforme: North Central Cancer Treatment Group results.

OBJECT: Gliosarcoma, a rare malignancy of the central nervous system, consists of gliomatous and sarcomatous elements. There are conflicting reports regarding its aggressiveness and cell line of origin compared with those of glioblastoma multiforme (GBM). The goal of this study was to compare clinicopathological features such as disease-free survival time and actual survival time in patients with gliosarcoma with a matched group of patients with GBM as well as with the entire group of patients with GBM. METHODS: The authors report on 18 cases of gliosarcoma derived from a series of 748 Grade 4 astrocytoma cases that were part of four consecutive randomized Phase III trials conducted between 1979 and 1996. In this series the gliosarcoma group represented only 2.4% of all GBMs and included 11 men and seven women with a median age of 61.5 years (range 31-81 years). The median tumor size was 5 cm (range 2-8 cm). The locations, all supratentorial, included temporal in 44%, parietal in 28%, frontal in 17%, and occipital in 11%. The 18 patients with gliosarcomas, all Grade 4 (World Health Organization classification), were compared with the entire group of 730 patients with GBM and a control group of 18 patients with GBM matched for known prognostic factors including patient age, randomization date, performance status, extent of resection, and protocol number. Patients in all treatment groups received radiation and nitrosourea-based chemotherapy. The median time to progression and the median survival times for the patients with gliosarcoma were 28.0 and 35.1 weeks as compared with 24.7 and 41.6 weeks for the entire group of patients with GBM (log rank test, p = 0.94 and 0.27, respectively) and 16.7 and 34.4 weeks in the control group (p = 0.20 and 0.84, respectively). In previous molecular cytogenetic analyses of gliosarcoma these authors have shown similar genetic changes in the gliomatous and sarcomatous components. CONCLUSIONS: The data obtained in this study support the conclusion that gliosarcoma shares significant clinical and genetic similarities with GBM and that the same principles should be applied for patient enrollment in research protocols and treatment for these two kinds of tumor.

Adult↗
PubMed1998

Mutation analysis of the putative tumor suppressor PTEN/MMAC1 in human ovarian cancer.

A putative tumor suppressor, PTEN/MMAC1 gene was recently identified at 10q23 and was found to be frequently altered in several types of human tumors. To determine the possible role of this gene in human ovarian tumors, we screened 31 unselected primary epithelial ovarian cancers with matched normal tissues and 7 ovarian cancer cell lines. Two homozygous deletions (4.8%) were detected in primary ovarian tumors by a semi-quantitative multiplex polymerase chain reaction. However, no point mutations were observed in any of the PTEN/MMAC1 coding sequences as determined by denaturing high-performance liquid chromatography and DNA sequencing. These data indicate that PTEN/MMAC1 mutations are rare in ovarian cancers.

Alternative Splicing↗
PubMed1998

Determination of gene and chromosome dosage in prostatic intraepithelial neoplasia and carcinoma.

OBJECTIVE: To review the utility of fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR) and comparative genomic hybridization (CGH) in the determination of gene and chromosome dosage in cancer specimens and to discuss the genetic association between prostatic intraepithelial neoplasia (PIN) and adenocarcinoma as detected by these three techniques. STUDY DESIGN: FISH, PCR, and CGH were applied to the same specimens to clarify discrepancies observed by a single technique alone and to further understand prostate carcinogenesis. RESULTS: The most common genetic alterations in PIN and carcinoma were (1) gain of chromosome 7, particularly 7q31; (2) loss of 8p and gain of 8q; and (3) loss of 10q, 16q and 18q. CONCLUSION: Using different techniques on the same specimen was useful to determine genetic relationships between cancer and its precursors. PIN and prostatic carcinoma foci have a similar proportion of genetic changes, but foci of carcinoma usually have more alterations. This supports the hypothesis that PIN is the most likely precursor of prostatic carcinoma.

Adenocarcinoma↗
PubMed1997

PTEN/MMAC1 mutations and EGFR amplification in glioblastomas.

Loss of heterozygosity (LOH) from chromosome 10 is a hallmark of glioblastoma, the most malignant (grade IV) form of glioma. A candidate tumor suppressor gene, PTEN/MMAC1, that may be targeted for deletion in association with chromosome 10 LOH has recently been identified. Here we have investigated 63 glioblastomas for PTEN/MMAC1 alterations and identified DNA sequence changes that would affect the encoded protein in 17 (27%) tumors. Microsatellite analyses of normal-tumor DNA pairs were performed on 14 of these cases and revealed LOH at locations flanking and/or near PTEN/MMAC1 in all but 1 instance, suggesting that deletion of the remaining wild-type allele had occurred in the large majority of tumors with PTEN/MMAC1 mutations. Competitive PCR assays were developed to address the possible occurrence of PTEN/MMAC1 homozygous deletions in glioblastomas, and this analysis identified three samples having loss of both PTEN/MMAC1 alleles. EGFR amplification was determined to occur at similar frequencies among cases with or without PTEN/MMAC1 homozygous deletions or mutations, suggesting that a growth-promoting effect resulting from amplification-associated increases in epidermal growth factor receptor signaling is not necessarily dependent on the inactivation of PTEN/MMAC1.

Alternative Splicing↗
PubMed1997

Sporadic medulloblastomas contain PTCH mutations.

Nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin's syndrome, is an autosomal dominant disorder that predisposes to developmental defects and various forms of cancer. PTCH was recently proposed as a candidate gene for NBCCS due to its frequent mutation in basal cell carcinomas, the cancer most often associated with this syndrome. Another NBCCS-associated cancer is medulloblastoma, a common central nervous system tumor in children. Most medulloblastomas, however, occur without indication of an inherited predisposition. We have examined 24 sporadic medulloblastomas for loss of heterozygosity (LOH) at loci flanking as well as within PTCH. In cases with LOH, single-strand conformational polymorphism and sequencing analysis were performed to determine the status of the remaining PTCH allele. Microsatellite analysis indicated LOH of PTCH in 5 of 24 tumors, and in three of these cases a mutation of the remaining allele was identified. Two of the mutations were duplication insertions, and the third consisted of a single base deletion. It is interesting that all three mutations occur in exon 17 of the PTCH gene. These data suggest that inactivation of PTCH function is involved in the development of at least a subset of sporadic medulloblastomas.

Chromosomes, Human, Pair 9↗
PubMed1997

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. The pathogenetic relationship between high-grade prostatic intraepithelial neoplasia (PIN), prostatic carcinoma, and metastases is not well-defined. We used fluorescence in situ hybridization (FISH) with a region-specific probe for c-myc (band 8q24) and chromosome enumeration probes for chromosomes 7, 8, 10, 12, and Y to evaluate genetic changes in matched PIN (48 foci), localized prostatic carcinoma (71 foci), and lymph node metastases (23 foci) in 25 totally embedded whole-mount stage D1 (T2-3 N1-3 M0) radical prostatectomy and pelvic lymphadenectomy specimens. The c-myc protein expression in these lesions was evaluated by immunohistochemistry. Foci with extra copies of c-myc could be divided into three groups: (a) those with simple gain of a whole chromosome 8 (no increase in c-myc copy number relative to the chromosome 8 centromere), which was identified in 42, 25, and 46% of foci of PIN, carcinoma, 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 metastases, 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, carcinoma, and metastases, respectively. Substantial amplification of c-myc was strongly correlated with increasing cancer nuclear grade and immunohistochemical evidence of c-myc protein overexpression. Numeric chromosomal anomalies were found in 67, 68, and 96% of foci of PIN, carcinoma, and metastases, respectively. The most frequent anomaly in PIN and carcinoma was a gain of chromosome 8, and the presence of this anomaly strongly correlated with Gleason score. Carcinoma foci usually contained more FISH anomalies than paired PIN foci, but three prostates contained one or more PIN foci with more anomalies than carcinoma. Thirteen primary tumor foci exhibited intratumor genetic heterogeneity by FISH. One or more foci of the primary tumor usually shared FISH anomalies with the matched metastases. Our FISH results indicate that: (a) gain of chromosome 8 and amplification of c-myc are potential markers of prostate carcinoma progression; (b) PIN is likely a precursor of carcinoma; (c) intraglandular and intratumoral genetic heterogeneity is relatively common; and (d) usually a single focus of cancer gives rise to metastases.

Aged↗