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Results for “amplification”

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PubMed1990

Protooncogene amplification and tumor ploidy in human ovarian neoplasms.

DNA from 24 ovarian tumors, including 16 carcinomas, was examined for amplification of the proto-oncogenes c-myc, int-2, and rc-erbB-2. All cases of carcinoma were also examined by flow cytometry for DNA ploidy and cell cycle analysis, and eight cases of carcinoma were examined for estrogen and progesterone receptors. Protooncogene amplification was not detected in the DNA of benign ovarian neoplasms, or of ovarian carcinomas with low malignant potential. Amplification of c-myc was detected in six of 12 cases of invasive carcinoma, int-2 amplification was present in one case, and c-erbB-2 amplification was not detected in any case. Among the seven cases evidencing protooncogene amplification, three cases showed aneuploidy in tumor DNA, while four showed diploidy. Two cases which showed aneuploidy in tumor DNA did not demonstrate any degree of protooncogene amplification. Protooncogene amplification was frequently associated with morphologic nuclear anaplasia and high mitotic count. Six of the seven cases demonstrating c-myc or int-2 were of the serous type or showed some degree of serous differentiation, while none of the four cases of purely mucinous carcinoma had evidence of amplification. While the total number of cases in the study was limited, it would appear from the trend demonstrated by the data that protooncogene amplification (particularly c-myc) may be involved in the pathogenesis of aggressive common epithelial tumors of the ovary.

Adenocarcinoma, Mucinous↗

PubMed1995

Gene amplification in Chinese hamster DNA repair deficient mutants.

In order to study the possible relationship between gene amplification and DNA repair we analyzed the amplification of the CAD gene in four mutants hypersensitive to UV light (CHO43RO, CHO7PV, UV5 and UV61) isolated in vitro from Chinese hamster cell lines (CHO-K1 and AA8). These mutants are characterized by different defects in the nucleotide excision repair mechanism and represent complementation groups 1, 9, 2, and 6 respectively. To evaluate the amplification ability of each cell line we measured the rate of appearance of PALA resistant clones with the Luria and Delbrück fluctuation test. Resistance to PALA is mainly due to amplification of the CAD gene. In the mutants CHO43RO, UV5 and CHO7PV we reproducibly found an amplification rate lower than in the parental cell lines (2-5 times), while in UV61 the amplification rate was about 4 times higher. This result indicates that each mutant is characterized by a specific amplification ability and that the unefficient removal of UV induced DNA damage can be associated with either a higher or a lower amplification rate. However, the analysis of randomly isolated CHO-K1 clones with normal UV sensitivity has shown variability in their amplification ability, making it difficult to relate the specific amplification ability of the mutants to the DNA repair defect and suggesting clonal heterogeneity of the parental population.

Animals↗

PubMed2007

Androgen receptor amplification is associated with increased cell proliferation in prostate cancer.

Mechanisms of prostate cancer progression during hormonal therapy and the pathobiologic consequences of androgen receptor (AR) gene amplification are inadequately known. To further investigate the hypothesis that AR gene amplification is associated with increased cell proliferation, we analyzed 123 paraffin-embedded prostate cancer specimens from men who experienced tumor relapse during androgen withdrawal therapy. We used fluorescence in situ hybridization to quantify AR gene copy number and Ki-67 immunohistochemistry to determine cell proliferation. One third of the tumors showed AR gene amplification. Among tumors with AR amplification, the mean cell proliferation rate was 19.8 (SD, 12.3; 95% confidence interval [CI], 15.4-24.1), whereas it was 13.0 (SD, 15.9; 95% CI, 9.1-16.8) in tumors without amplification (P = .032). In the best fitting logistic regression model, only proliferation remained significant (P = .040). When the median Ki-67 labeling index (6.7%) of all tumors was used as a cutoff point, the tumors with AR amplification were more frequently highly proliferating than tumors with no amplification (P = .010; odds ratio, 3.4; 95% CI, 1.4-8.3). Our results imply that progression of prostate cancer during androgen withdrawal therapy is associated with AR gene amplification and increased cell proliferation rate in one third of tumors. We suggest that AR gene amplification is an important molecular mechanism underlying the increase in proliferation rate of a substantial fraction of recurrent prostate carcinomas. However, efforts should be targeted to develop prostate cancer cell lines to study causal relationships between AR gene amplification and various biologic variables.

Androgen Antagonists↗

PubMed2004

MDM2 gene amplification: a new independent factor of adverse prognosis in non-small cell lung cancer (NSCLC).

The prognostic impact of MDM2 amplification in non-small cell lung cancer (NSCLC) remains unknown. In this study, we investigated the occurrence of MDM2 amplification in surgically treated NSCLC patients. Molecular data were correlated with clinicopathological factors and evaluated for their prognostic value. The study group included 116 NSCLC patients who underwent pulmonary resection between 1996 and 1999. MDM2 amplification was assessed by real-time PCR using hybridization probe format on a LightCycler (Roche). The calculated ratio was a MDM2 value normalized to the amplification of the housekeeping gene phenylalaninhydroxylase (PAH). Survival curves were drawn according to the Kaplan-Meier method and compared with the use of the log-rank test. Multivariate analysis was based on Cox regression analysis. MDM2 amplification was found in 24 patients (21%). There was no relationship between MDM2 amplification and clinicopathological factors, such as sex, age and stage of disease, pT, pN, histology and tumor differentiation. Median disease-free survival (DFS) in patients with and without MDM2 amplification was 3 and 31 months, and 5-year DFS 24 and 33%, respectively (log-rank, P = 0.02). Likewise, median overall survival (OS) in patients with and without MDM2 amplification was 9 and 33 months, respectively, and 5-year OS 24 and 39%, respectively (log-rank, P = 0.01). The strong prognostic relevance of MDM2 amplification for both DFS and OS was confirmed in multivariate analysis (P < 0.01 for both comparisons). Our results suggest that MDM2 gene amplification analysis provides additional prognostic information in surgically treated NSCLC patients.

Adenocarcinoma↗

PubMed2001

Amplification of EIF3S3 gene is associated with advanced stage in prostate cancer.

Gain of the long arm of chromosome 8 (8q) is one of the most common gains found in the advanced prostate cancer by comparative genomic hybridization. We have previously identified a putative target gene for the 8q gain, EIF3S3, that encodes a p40 subunit of eukaryotic translation initiation factor 3 (eIF3). Here, we studied the frequency of the EIF3S3 amplification in different stages of prostate cancer and co-amplification of EIF3S3 and oncogene MYC. In addition, prognostic utility of the EIF3S3 copy number alteration was evaluated. The analyses were done with fluorescence in situ hybridization and tissue microarray technology. High-level amplification of EIF3S3 was found in 11 of 125 (9%) of pT1/pT2 tumors, 12 of 44 (27%) of pT3/pT4 tumors, and 8 of 37 (22%) of lymph node metastases as well as in 26 of 78 (33%) and 15 of 30 (50%) of hormone refractory locally recurrent tumors and metastases, respectively. The amplification was associated with high Gleason score (P < 0.001). One of the 79 tumors with EIF3S3 amplification had only two copies of MYC, whereas all tumors with amplification of MYC had also amplification of EIF3S3 indicating common co-amplification of the genes. Gain of EIF3S3 was associated with poor cancer-specific survival in incidentally found prostate carcinomas (P = 0.023). In the analyses of prostatectomy-treated patients, the amplification was not statistically significantly associated with progression-free time. In conclusion, amplification of EIF3S3 gene is common in late-stage prostate cancer suggesting that it may be functionally involved in the progression of the disease.

Aged↗

PubMed2002

Amplification of the 3q26.3 locus is associated with progression to invasive cancer and is a negative prognostic factor in head and neck squamous cell carcinomas.

Amplification of the 3q26-q27 has a high prevalence in squamous cell carcinomas of mucosal origin, including those originating in the head and neck region. To elucidate its role as a prognostic tool in head and neck squamous cell carcinoma, a yeast artificial chromosome (YAC) contig spanning the entire 3q26-27 region was constructed. The minimal region of amplification was refined within a 1- to 2-Mb genomic segment contained within three overlapping, nonchimeric YAC clones using sequential fluorescent in situ hybridization analysis. These YAC clones containing the apex of amplification were used to develop a two-color fluorescence in situ hybridization assay and applied to the detection of 3q copy numbers in interphase nuclei on archival tumor tissue from 29 cases of normal mucosa, 20 of premalignant mucosa, and 50 of invasive head and neck squamous cell carcinomas. The presence of 3q amplification increased from 3% in normal mucosa to 25% in premalignant mucosa and 56% in invasive cancers (P < 0.01). In invasive tumors, low-level 3q amplification (3 to 4 X copy number) was identified in 18 of 50 primary head and neck cancers and high-level amplification (>4 X copy number) in 10 of 50 cases. With a median follow-up of 82.5 months, an increasing proportion of recurrences (32%, 72%, and 90%; P = 0.003) and cancer-related deaths (14%, 44%, and 70%; P = 0.006) were seen in patients with normal 3q copy number, low-level amplification, and high-level amplification, respectively. The 3-year disease-free (69%, 56%, and 10%; P = 0.001) and cause-specific (94%, 83%, and 40%; P = 0.01) survivals also decreased from normal copy number to low-level and high-level amplification. Only high-level amplification at 3q remained a significant prognostic variable on multivariate analysis including common prognostic predictors for both disease-free (relative risk, 5.1; 95% confidence interval = 1.9 to 13.9) and cause-specific survival (relative risk, 7.6; 95% confidence interval = 1.9 to 29.6). The findings suggest that the 3q copy number status is an important marker for tumor progression and prognostication in patients with head and neck squamous cell carcinoma.

Aged↗

PubMed2003

Infrequent but high-level amplification of 17p11.2 approximately p12 in human glioma.

We reported previously the amplification of DNA markers in 17p12 in 3 of 60 high-grade gliomas. To detect additional cases, we screened in total 104 gliomas of various types and grades by Southern blot analysis using marker 745R, which is within the commonly amplified region. However, no other caseswith significant amplification (amplification level > 4) were found. To investigate in detail the extent of the amplifications in the three tumors, which were all glioblastomas, we determined 17p11.2 approximately p12 amplification profiles by semiquantitative polymerase chain reaction using 15 microsatellite markers and seven candidate genes. Distinct and high-level amplifications, with maximum levels ranging from 15 to 38, were found in these tumors. The 0.8 Mb-region between D17S1525 and MAP2K4 in 17p12 proved to be commonly amplified in these tumors. In one tumor, a heterogeneous distribution of the amplification in 17p12 was found, suggesting that it is a late event during glioma tumorigenesis. Another tumor showed additional high-level amplification of PMP22 and D17S1843 in 17p11.2. From the high-level amplifications we conclude that at least one, but possibly more, putative oncogenes are present in 17p11.2 approximately p12 whose amplifications and/or overexpressions contribute to glioma tumorigenesis.

Blotting, Southern↗

PubMed2001

Cyclin D1 amplification correlates with early recurrence of squamous cell carcinoma of the tongue.

Amplification of CCND1 was studied in 23 tongue carcinoma patients by fluorescence in situ hybridization (FISH) using a paraffin embedded specimen. All the patients received complete resection of the primary site with or without neck dissection. CCND1 amplification was positive in 13 (56.5%) out of 23 cases. Correlations between CCND1 amplification and histological grading, T category, N category, and Stages were not significant. The 5-year disease-free survival rate, which was 23.1% for CCND1 amplification positive patients and 80.0% for negative patients, was significantly better for the CCND1 amplification negative patients (P=0.0070). Nine patients were examined by dual-color FISH with the probe for centromere of chromosome 11 and 11q13. In five patients, who had positive amplification for CCND1, cell numbers with a larger number of signals for 11q13 than the centromere of chromosome 11 were significantly higher than those of CCND1 amplification negative patients (P=0.013). This indicates that amplification of 11q13 occurs more frequently than aberration of chromosome 11 in CCND1 amplification positive patients. From these results, the amplification of CCND1 is a key factor in predicting the aggressiveness of tongue cancer. Furthermore, FISH proved to be a useful method for such evaluation.

Carcinoma, Squamous Cell↗

PubMed1996

A comparison of the propensity for gene amplification between near-tetraploid and near-diploid V79 clones resistant to 150 nM methotrexate.

Among various 150-nM methotrexate-resistant (MTXr) V79 clones isolated, we found that two near-tetraploid clones as well as a near-diploid clone with amplification in the dihydrofolate reductase (dhfr) gene readily developed resistant to 40 000 nM MTX within 3 months during stepwise increased MTX selection, while two near-diploid clones without gene amplification could not acquire resistance beyond 5000 nM MTX. Then, we studied how the clones increased the resistance to MTX, and compared the propensity for gene amplification among three types of clones. Dot blot analysis showed that the acquisition of the high levels of resistance to MTX observed in two near-tetraploid clones and a near-diploid clone with gene amplification was associated with amplification in the dhfr gene. The amplified dhfr gene was overexpressed at mRNA and protein levels in the clones. Southern blot analysis of Hind III- and Eco RI-digested DNA in the clones at the time when they became resistant to 10 000 nM MTX indicated that they amplified the dhfr gene fragments which existed in low amounts in parental V79 cells, and that no gross rearrangement of the amplified dhfr gene was detected. Furthermore, fluorescence in situ hybridization analysis showed that the amplified dhfr gene was located on one chromosome as cluster(s). On the other hand, two near-diploid clones without gene amplification did not show any amplification of the dhfr gene even at 5000 nM-MTX resistant stage. These combined results suggest that the near-tetraploid clone as well as the near-diploid clone with the dhfr gene amplification have genomic instability with the propensity for gene amplification during stepwise MTX selection, and have a similar process for the development of the dhfr gene amplification.

Animals↗

PubMed2006

Inhibition of gene amplification in telomerase deficient immortalized mouse embryonic fibroblasts.

Mutations in genes important for the preservation of genome stability can increase the frequency of gene amplification, a process relevant to tumor development. To investigate whether telomerase, the enzyme deputed to telomere maintenance, also plays a role in gene amplification, we studied the amplification of the carbamyl-P-synthetase, aspartate transcarbamilase, dihydro-orotase (CAD) gene in immortalized embryonic fibroblasts derived from telomerase knockout mice (mTERC(-/-)) of the first and of the sixth generation. As expected, in 9 out of 10 N-(phosphonacetyl)-L-aspartate (PALA) resistant clones derived from wild-type cells, CAD was amplified; in contrast, in none of the 30 PALA resistant clones isolated from the three mTERC(-/-) cell lines we could detect CAD amplification, indicating that, in the absence of telomerase activity, gene amplification is inhibited. The causal relationship between mTERC deficiency and lack of gene amplification was demonstrated by the restoration of CAD gene amplification in two of the three deficient cell lines transfected with mTERC. The lack of amplification in mTERC deficient cells could be related to a defect in the stabilization of the ends of the amplified chromosomes in the absence of telomerase, to a more general effect of telomerase in the regulation of gene expression, including genes involved in amplification, or to a possible interaction of the telomerase RNA with proteins involved in gene amplification.

Animals↗

PubMed1993

Relationship of c-myc amplification to progression of breast cancer from in situ to invasive tumor and lymph node metastasis.

BACKGROUND: Amplification of the c-myc gene (also known as MYC) occurs in up to 20%-30% of breast cancers and has been associated with poor prognosis. PURPOSE: The purpose of this study was to define the relationship between c-myc amplification and breast cancer progression in order to better understand the biological significance of c-myc amplification. METHODS: We identified invasive tumors with grossly detectable c-myc amplification by using Southern blot analysis to examine frozen tissue from 135 breast carcinomas and polymerase chain reaction (PCR) analysis to examine archival paraffin-embedded tissue from an additional 19 invasive tumors. These 19 tumors were selected on the basis of histologically identifiable in situ and invasive components within the primary tumor and associated lymph node metastases. Amplification of c-myc in these areas was then assessed by quantitative PCR assay. RESULTS: We detected gross c-myc amplification in 10 of the tumors examined--eight of the 135 frozen tissue specimens and two of the 19 archival specimens. We selected five of these 10 invasive tumors for further regional analysis. In all four cases where an in situ component was present, amplification of c-myc was present in both the in situ and the invasive components. However, c-myc amplification was present in the corresponding nodal metastases in only two of the four cases where this could be examined. CONCLUSION: These results suggest that c-myc amplification can occur at an early stage in tumor progression and that amplification does not always persist in the nodal metastasis.

Adult↗

PubMed1988

Gene amplification in malignant human gliomas: clinical and histopathologic aspects.

Gene amplification occurs in 45-50% of malignant human gliomas (MHG). In the present study, 64 genetically characterized gliomas were evaluated to determine if tumors with amplification of the epidermal growth factor receptor (EGFR), N-myc, c-myc, or gli genes had distinctive histopathologic features. There was no significant difference in age (p = 0.10) or gender (p = 0.78) between patients whose tumors contained amplified genes and those whose tumors did not exhibit this characteristic. Although the patients with amplified genes in their tumors survived slightly longer than patients whose tumors had no detectable gene amplification, these differences were not statistically significant (p = 0.21). The 28 tumors with amplification included 24/48 (50%) glioblastoma multiforme, 2/6 (33%) anaplastic astrocytomas and 2/5 (40%) gliosarcomas. No amplification was seen in one oligodendroglioma, three anaplastic mixed gliomas or one giant cell glioblastoma multiforme. Necrosis and endothelial proliferation were equally prevalent among tumors with and without amplification. Comparison of tumors with gene amplification and tumors without this characteristic revealed similar distributions of most morphologic cells types. Although prominent perivascular lymphocytic infiltrates were more frequent in tumors without amplification, this association was of borderline significance statistically. In situ hybridization of tumors with amplification using an EGFR mRNA probe showed intense labeling of different neoplastic cell types including fibrillary and protoplasmic astrocytes, gemistocytes, anaplastic cells, and multinucleated giant cells. Non-neoplastic cells such as hyperplastic endothelium within the tumors did not express detectable EGFR mRNA. These studies demonstrate that (a) cells with quite different morphology within the same tumor can contain the same genetic alteration; (b) tumors of identical histological appearance may have arisen and evolved by different molecular mechanisms; and (c) molecular analyses are necessary to evaluate gene amplification in MHG since this characteristic cannot be accurately predicted by the morphologic or clinical criteria used in this study.

Adult↗

PubMed2002

Comparison of HER-2/neu oncogene amplification detected by fluorescence in situ hybridization in lobular and ductal breast cancer.

BACKGROUND: Abnormal expression of the HER-2/neu oncogene, a tyrosine kinase-type transmembrane growth factor receptor localized to chromosome 17q, has been associated with poor prognosis and the prediction of therapy response in invasive breast cancer. The comparative incidence and significance of HER-2/neu gene amplification for lobular and ductal breast cancer have not been previously characterized. DESIGN: Formalin-fixed, paraffin-embedded primary breast cancer tissue sections from 71 women diagnosed with invasive lobular carcinoma were tested for HER-2/neu gene amplification by fluorescence in situ hybridization (FISH) method using the Ventana unique sequence probe (Ventana Medical Systems, Tucson, AZ). A series of 106 cases of invasive ductal carcinoma was similarly processed and tested. Lymph node status was available for 155 (88%) of the 177 cases and 82 (46%) were lymph node-negative (LN-) and 73 (41%) were lymph node-positive (LN+). Patients were treated for a mean of 65 months (range 1-169 months). RESULTS: 9 of 71 (13%) cases of lobular cancer featured HER-2/neu gene amplification, whereas 51 (48%) of 106 cases of ductal cancer showed amplification (P < 0.0001). On univariate analysis of combined lobular and ductal cases, HER-2/neu gene amplification detected by FISH predicted disease-related death (P < 0.0001). HER-2/neu gene amplification also predicted disease-related death in lobular cases alone (P = 0.003), LN+ lobular cases separately (P = 0.019), and LN- and LN+ ductal cases separately and alone (P < 0.0001). Multivariate analysis of the lobular group alone revealed that LN+ status (P = 0.015) and stage (P = 0.01) were independent predictors of disease-related death, and HER-2/neu gene amplification reached near significance (P = 0.086). In the ductal carcinoma group alone, HER-2/neu gene amplification (P = 0.03), lymph node status (P = 0.0001), tumor stage (P = 0.0001), and tumor grade (P = 0.044) were independent predictors of overall disease survival. CONCLUSIONS: HER-2/neu gene amplification detected by FISH was identified at a significantly lower rate in lobular compared with ductal breast cancer. HER-2/neu gene amplification when present in lobular breast cancer is a significant adverse prognostic factor.

Breast Neoplasms↗

PubMed1992

The Drosophila ACE3 chorion element autonomously induces amplification.

The Drosophila chorion genes amplify in the follicle cells by repeated rounds of reinitiation of DNA replication. ACE3 (amplification control element from the third chromosome) has been identified by a series of deletion experiments as an important control element for amplification of the third-chromosome chorion cluster. Several elements that quantitatively enhance amplification also have been defined. We show that a single 440-bp ACE3 sequence is sufficient to regulate amplification with proper developmental specificity autonomously from other chorion DNA sequences and regulatory elements. Although ACE3 is sufficient for amplification, the levels of amplification are low even when ACE3 is present in multiple copies. When controlled solely by ACE3, amplification initiates either at ACE3 or within closely linked sequences. Amplification of an ACE3 transposon insertion produces a gradient of amplified DNA that extends into flanking sequences approximately the same distance as does the amplification gradient at the endogenous chorion locus. The profile and extent of the amplified gradient imply that the low levels of amplification observed are the result of limited rounds of initiation of DNA replication. Transposon inserts containing multiple copies of ACE3 in a tandem, head-to-tail array are maintained stably in the chromosome. However, mobilization of the P-element transposons containing ACE3 multimers results in deletions within the array at a high frequency.

Animals↗

PubMed2006

Does MYCN amplification manifested as homogeneously staining regions at diagnosis predict a worse outcome in children with neuroblastoma? A Children's Oncology Group study.

PURPOSE: MYCN amplification in neuroblastoma tumor cells is manifested primarily as double minutes (dmins), whereas in cell lines it often appears in the form of homogeneously staining regions (HSR), suggesting that HSRs are associated with a more aggressive tumor phenotype and worse clinical outcome. The aim of this study was to determine whether children with neuroblastoma in which MYCN oncogene amplification is manifested as HSRs at diagnosis have a worse prognosis than those whose tumors exhibit dmins. EXPERIMENTAL DESIGN: A retrospective analysis of primary neuroblastomas analyzed for MYCN amplification by the Children's Oncology Group between 1993 and 2004 was done. Tumors with MYCN amplification were defined as having dmins, HSRs, or both (dmins + HSRs), and associations with currently used risk group stratification variables and patient outcome were assessed. RESULTS: Of the 4,102 tumor samples analyzed, 800 (19.5%) had MYCN amplification. Among the 677 tumors for which the pattern of amplification was known, 629 (92.9%) had dmins, 40 (5.9%) had HSRs, and 8 (0.1%) had dmins + HSRs. Although MYCN amplification is associated with older age, higher stage, and unfavorable histology, whether the amplification occurred as dmins or HSRs did not significantly affect these risk factors. There were no differences in the event-free survival (EFS) or overall survival in patients with MYCN amplification manifested as either dmins or HSRs (5-year EFS, 35 +/- 3% versus 38 +/- 15%; P = 0.59). Although the eight patients with dmins + HSRs fared worse than either of the individual subgroups (EFS, 18 +/- 16% versus 35 +/- 3% for dmins and 38 +/- 15% for HSRs), these differences were not significant. CONCLUSIONS: MYCN amplification in any form (HSRs or dmins) is associated with a poor outcome.

Cell Nucleus↗

PubMed1999

Amplification of c-myc in hepatocellular carcinoma: correlation with clinicopathologic features, proliferative activity and p53 overexpression.

Expression of the proto-oncogene c-myc has been implicated in liver regeneration and hepatocarcinogenesis. The biologic significance of c-myc gene amplification in human hepatocellular carcinoma, however, is unconfirmed. We correlated c-myc gene amplification with clinicopathologic features, proliferative activity, and p53 expression in 42 resected tumors. c-myc amplification in tumor tissue was determined using a differential polymerase chain reaction, a useful procedure for the evaluation of gene amplification in archival formalin-fixed paraffin-embedded tissues, in comparison with a dopamine D2 receptor gene. Proliferative activity was estimated by numbers of argyrophilic nucleolar organizer regions and immunohistochemical nuclear labeling rates using a monoclonal antibody against Ki-67. The c-myc gene was amplified in 14 of 42 tumors (33.3%). Amplification of c-myc was more frequent in younger patients and in larger tumors, and less differentiated tumors. No correlation was noted with alpha-fetoprotein level or viral hepatitis state. The amplification showed positive correlation with both proliferative activity and p53 overexpression. Disease-free survival in patients showing c-myc amplification was significantly shorter than in those without amplification. These results suggest that c-myc amplification is an indicator of malignant potential and poor prognosis in hepatocellular carcinoma. c-myc amplification and p53 alteration may be coparticipating events in the progression of these tumors.

Adult↗

PubMedDate not supplied

Amplification and overexpression of cyclin D1 in aggressive human esophageal cancer.

Cyclin D1 is a cell-cycle regulator essential for G1 phase progression and a candidate proto-oncogene implicated in pathogenesis of several human tumor types including esophageal cancers. Association between cyclin D1 gene amplification and clinical outcome was examined using southern blotting in 45 patients with primary esophageal cancer. In cases showing gene amplification, expression levels of mRNA and gene product were further examined by northern blotting, western blotting and immunohistochemical analyses. Amplification of cyclin D1 gene was found in 14 of 45 patients (31. 1%). There was no association between gene amplification and clinicopathological parameters but the frequency of hematogenous recurrence in cases with gene amplification was significantly higher than that in cases without amplification in 30 patients undergoing curative surgery (70.0% vs 25.0%, p<0.05). Furthermore, cumulative survival rate of cases with gene amplification was significantly lower than that of cases without amplification (p<0.05). Overexpression of cyclin D1 mRNA was observed in 12 of 14 cases (85. 7%) showing gene amplification but overexpression of its protein was found in only four cases (28.6%). Amplification of the cyclin D1 gene is a reliable prognostic factor and post-translational modification of this gene may play a functionally important role in development of primary esophageal cancer.

Aged↗

PubMed2000

Androgen receptor gene amplification at primary progression predicts response to combined androgen blockade as second line therapy for advanced prostate cancer.

PURPOSE: Amplification of the androgen receptor gene has been found in a third of hormone refractory prostate carcinomas. It is possible that amplification facilitates cell growth ability in low concentrations of androgens remaining in the serum after androgen deprivation therapy. We evaluate whether androgen receptor gene amplification at primary progression is associated with response to second line combined androgen blockade for prostate cancer. MATERIALS AND METHODS: A total of 77 patients with prostate cancer were treated initially with androgen deprivation monotherapy followed by combined androgen blockade after the first progression. After initiation of second line combined androgen blockade patients were followed every 3 months to evaluate treatment responses. Biopsies were taken from the prostate at the first progression under endocrine monotherapy. Androgen receptor gene copy number was determined by fluorescence in situ hybridization. RESULTS: Androgen receptor gene amplification was found in 10 of the 77 cases (13%) at the primary disease progression, and was associated with a favorable response to second line combined androgen blockade. Only 1 of 34 (3%) patients classified as nonresponders had androgen receptor gene amplification, whereas 9 of 41 (21%) classified as having either stable disease or response had amplification (p = 0.016). Patients with androgen receptor gene amplification also had a decrease in prostate specific antigen more often after combined androgen blockade than those with no amplification (p = 0.079). However, androgen receptor gene amplification was not associated with patient survival after the first progression. CONCLUSIONS: Androgen receptor gene amplification detected in tumors progressing during androgen deprivation monotherapy is associated with favorable treatment response to second line combined androgen blockade. This finding suggests that at least some androgen receptor amplified tumors retain a high degree of dependency on residual androgens remaining in serum after monotherapy.

Adult↗