RESUMEN
Array comparative genomic hybridization was used to identify copy number alterations in clear cell renal cell carcinoma (ccRCC) patient tumors to identify associations with patient/clinical characteristics. Of 763 ccRCC patients, 412 (54%) provided frozen biopsies. Clones were analyzed for significant copy number differences, adjusting for multiple comparisons and covariates in multivariate analyses. Frequent alterations included losses on: 3p (92.2%), 14q (46.8%), 8p (38.1%), 4q (35.4%), 9p (32.3%), 9q (31.8%), 6q (30.8%), 3q (29.4%), 10q (25.7%), 13q (24.5%), 1p (23.5%) and gains on 5q (60.2%), 7q (39.6%), 7p (30.6%), 5p (26.5%), 20q (25.5%), 12q (24.8%), 12p (22.8%). Stage and grade were associated with 1p, 9p, 9q, 13q and 14q loss and 12q gain. Males had more alterations compared with females, independent of stage and grade. Significant differences in the number/types of alterations were observed by family cancer history, age at diagnosis and smoking status. Von Hippel-Lindau (VHL) gene inactivation was associated with 3p loss (P
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Renal-cell carcinomas (RCC) are frequent in central and eastern Europe and the reasons remain unclear. Molecular mechanisms, except for VHL, have not been much investigated. We analysed 361 RCCs (334 clear-cell carcinomas) from a multi-centre case-control study for mutations in TP53 (exons 5-9 in the whole series and exons 4 and 10 in a pilot subset of 60 tumours) and a pilot 50 tumours for mutations in EGFR (exons 18-21) or KRAS (codon 12) in relation to VHL status. TP53 mutations were detected in 4% of clear-cell cases, independently of VHL mutations. In non-clear-cell carcinomas, they were detected in 11% of VHL-wild-type tumours and in 0% of tumours with VHL functional mutations. No mutations were found in EGFR or KRAS. We conclude that mutations in TP53, KRAS, or EGFR are not major contributors to the RCC development even in the absence of VHL inactivation. The prevalence of TP53 mutations in relation to VHL status may differ between clear-cell and other renal carcinomas.
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Carcinoma de Células Renales/genética , Genes erbB-1 , Genes p53 , Genes ras , Neoplasias Renales/genética , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/patología , Estudios de Casos y Controles , Europa (Continente) , Femenino , Silenciador del Gen , Humanos , Neoplasias Renales/patología , Estilo de Vida , Masculino , Persona de Mediana Edad , Factores de Riesgo , Células Tumorales CultivadasRESUMEN
Immune escape describes a critical event whereby tumor cells adopt an immunoresistant phenotype to escape adaptive surveillance. We show that expression of a pivotal negative regulator of T-cell function, B7-H1, correlates with PI(3) kinase activation in breast and prostate cancer patients. B7-H1-mediated immunoresistance can be attenuated by inhibitors of the PI(3) kinase pathway, and is dependent on S6K1-mediated translational regulation of B7-H1 protein. Breast and prostate carcinoma cells with activated PI(3) kinase lose the immunoresistant phenotype after treatment with B7-H1 siRNA. Conversely, breast and prostate carcinoma cells with minimal PI(3) kinase activation adopt an immunoresistant phenotype when engineered to overexpress B7-H1 protein. These observations describe a mechanism for immune escape from tumor dormancy in humans that relates to oncogenesis.
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Adenocarcinoma/enzimología , Antígenos CD/fisiología , Neoplasias de la Mama/enzimología , Proteínas de Neoplasias/fisiología , Fosfatidilinositol 3-Quinasas/fisiología , Neoplasias de la Próstata/enzimología , Escape del Tumor/inmunología , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Antígenos CD/genética , Antígeno B7-H1 , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/enzimología , Línea Celular Tumoral/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Fosfohidrolasa PTEN/fisiología , Fenotipo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Inhibidores de Proteínas Quinasas/farmacología , ARN Interferente Pequeño/farmacología , Proteínas Recombinantes de Fusión/fisiología , Proteínas Quinasas S6 Ribosómicas/fisiología , Linfocitos T Citotóxicos/inmunología , Escape del Tumor/efectos de los fármacos , Escape del Tumor/genéticaRESUMEN
BACKGROUND: Amplification of 20q13 is a frequent chromosomal alteration in solid tumors and harbors a number of putative oncogenes (CAS/CSE1-L, NABC1, or Aurora2). Amplifications on 20q13 have been identified as an independent prognostic marker indicating worse survival in breast and ovarian cancer. However, little is known about the prognostic significance of 20q13 gains in sporadic colorectal cancers. The aim of this study was to correlate 20q13 gains in sporadic colorectal cancers with other known prognostic factors, tumor progression, and overall survival. METHODS: Nuclei were extracted from 146 paraffin-embedded colorectal cancers of different UICC stages and used for fluorescence in situ hybridization (FISH) with a directly labeled probe for 20q13.2 (VYSIS). Signals were counted in 120 nuclei per sample. 20q13 was considered gained when > or =40% of the nuclei showed 3 or more FISH signals. Statistical correlations were tested with log-rank tests and Kaplan-Meier survival curves. RESULTS: Signal numbers for 20q13.2 were gained in 78 cases (53%). Cases with gains on 20q13.2 showed worse outcome than cases without: the gain of 20q13.2 was an independent prognostic marker for overall survival (P=0.006) as well as tumor progression (P=0.012) in univariate and multivariate analyses. Gains on 20q13.2 did not correlate with tumor stage. However, there was a significant association between 20q13.2 gains and tumor location in the left-sided colon and an inverse correlation between histologic grade and 20q13.2 gains. CONCLUSION: These data indicate that gains on 20q13.2 correlate with faster tumor progression and worse patient survival independent from tumor size and lymph node involvement. Therefore, alterations on 20q13 are an important biological event in colorectal tumor progression with independent prognostic relevance.
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Cromosomas Humanos Par 20/genética , Neoplasias Colorrectales/genética , Amplificación de Genes , Adenoma/genética , Neoplasias Colorrectales/química , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Pronóstico , Proteína p53 Supresora de Tumor/análisisRESUMEN
The role of the HER2 receptor remains uncertain in the pathogenesis and progression of human prostate cancer. Previous studies have reported widely divergent rates for HER2 expression in primary prostate tumors, probably owing to significant methodologic differences in the studies. Few data exist about the frequency of HER2 protein overexpression and gene amplification in androgen-independent prostate cancer (AIPC), although recent xenograft models suggest HER2 expression may be up-regulated in the transition from androgen-dependent to androgen-independent disease. We studied the role of HER2 protein in AIPC by immunohistochemical and fluorescence in situ hybridization (FISH) analyses on AIPC specimens using well-characterized and validated reagents. Fourteen (36%) of 39 specimens expressed HER2; however, only 2 (5%) had moderate (2+) expression, and 2 (5%) had high-level (3+) expression. Two (6%) of 36 specimens had gene amplification by FISH. These data suggest that HER2 protein overexpression and gene amplification are relatively uncommon in AIPC.
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Andrógenos/farmacología , Amplificación de Genes , Expresión Génica , Neoplasias de la Próstata/química , Receptor ErbB-2/análisis , Receptor ErbB-2/genética , Adenoma/química , Adenoma/patología , Adenoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/uso terapéutico , Anticuerpos Monoclonales , Biopsia , Neoplasias Óseas/química , Neoplasias Óseas/secundario , Humanos , Técnicas para Inmunoenzimas , Hibridación Fluorescente in Situ , Metástasis Linfática , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Prostatectomía , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapiaRESUMEN
PURPOSE: Breast cancer is thought to develop from noninvasive precursor lesions, although the earliest steps of neoplastic transformation are still undefined. Usual ductal hyperplasia (UDH) is considered to represent a benign proliferation of ductal epithelial cells, whereas atypical ductal hyperplasia (ADH) may represent the first clonal neoplastic expansion of these cells. The aim of this study was to examine genetic alterations in UDH and ADH and to determine the relationship between these lesions in the same breast biopsy. EXPERIMENTAL DESIGN: Comparative genomic hybridization analysis was used to define copy number alterations in DNA extracted from archival sections of 18 patients. Nine patients showed ADH with adjacent UDH, and nine showed pure UDH. None showed evidence of invasive cancer or ductal carcinoma in situ. RESULTS: Five of the nine ADH lesions showed chromosome copy number alterations. 16q loss (five cases) and 17p loss (two cases) were the most frequent changes. The associated UDH lesions in these five patients also showed copy number alterations, always a subset of the changes present in the paired ADH. In one other patient, the UDH showed eight chromosomal alterations, whereas the paired ADH showed no changes. Only one of nine cases with pure UDH showed comparative genomic hybridization abnormalities. CONCLUSIONS: These data support the likelihood that UDH is a precursor of ADH, at least in some cases representing neoplastic growth. The frequencies of 16q and 17p losses suggest that alterations of candidate genes located in these chromosomal regions may play a role early in breast carcinogenesis.
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Neoplasias de la Mama/patología , Mama/patología , Adulto , Anciano , Anciano de 80 o más Años , Mama/metabolismo , Neoplasias de la Mama/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 17/genética , ADN de Neoplasias/genética , Humanos , Hiperplasia , Persona de Mediana Edad , Hibridación de Ácido Nucleico/métodos , Células Tumorales CultivadasRESUMEN
Lobular carcinoma in situ (LCIS) and infiltrating lobular carcinoma may represent different forms of the same disease based on their frequent clinical association and similar histologic features. Patients with LCIS are at increased risk of multicentric and bilateral disease. Thus, LCIS may represent both a precursor to infiltrating lobular carcinoma and a marker of risk for breast cancer. To identify genomic alterations in LCIS, comparative genomic hybridization was performed on 17 cases without concurrent invasive carcinoma. Loss involving chromosome 16q was present in 88% of cases and was the sole detected alteration in 29%. Gain involving 1q was second in frequency, occurring in 41% of tumors, and in all cases was associated with loss of 16q. Other recurrent changes were loss involving 17p (18%), 8p (12%), and 12q24 (12%). E-cadherin immunohistochemistry was performed on all LCIS cases to evaluate the correlation of loss involving 16q22, the site of the E-cadherin gene, and altered protein expression. Most cases with 16q22 loss showed altered E-cadherin expression (12 of 13). These results in LCIS are similar to changes reported in infiltrating lobular cancer, confirming a genetic relationship between them. HUM PATHOL 32:292-296.
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Neoplasias de la Mama/genética , Carcinoma in Situ/genética , Carcinoma Lobular/genética , Cromosomas Humanos Par 16 , Cadherinas/análisis , Cadherinas/genética , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 12 , Cromosomas Humanos Par 17 , Eliminación de Gen , Humanos , Inmunohistoquímica , Hibridación de Ácido Nucleico , Reacción en Cadena de la PolimerasaRESUMEN
Tubular carcinoma of the breast is a well-differentiated variant of invasive ductal carcinoma and has been shown to have an exceptionally favorable prognosis, as manifested by a low incidence of lymph node metastases and an excellent overall survival. It is unknown whether this subtype represents an early step along the continuum of development to a more aggressive, poorly differentiated ductal cancer, or whether these cancers are destined to remain well differentiated with limited metastatic potential. We undertook an analysis of 18 pure tubular carcinomas of the breast using comparative genomic hybridization to evaluate the chromosomal changes in these tumors. An average of 3.6 chromosomal alterations of the genome were identified per case. The most frequent change involved loss of 16q (in 78% of tumors) and gain of 1q (in 50% of tumors). All but one case with 1q gain also exhibited a concomitant 16q loss. Other frequent changes involved 16p gain in 7 of 18 cases (39%) and distal 8p loss in 5 of 18 cases (28%). Comparison with known genomic alterations in a mixed group of invasive cancers shows tubular cancer to have fewer overall chromosomal changes per tumor (P <.01), higher frequency of 16q loss (P <.001), and lower frequency of 17p loss (P =.007). These results strongly suggest that tubular carcinomas are a genetically distinct group of breast cancers.
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Adenocarcinoma/genética , Neoplasias de la Mama/genética , Hibridación de Ácido Nucleico , Adenocarcinoma/química , Adenocarcinoma/patología , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Cadherinas/análisis , ADN de Neoplasias/análisis , Disección , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Terapia por Láser , Micromanipulación , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
The beta-catenin pathway plays a central role in transcriptional signaling and cell-cell interactions in colonic epithelium. Alterations of the expression of beta-catenin, and its binding partners E-cadherin and the adenomatous polyposis coli protein (APC), are frequent events in sporadic colorectal cancer. Ulcerative colitis (UC)-related cancers originate in a field of chronic inflammation and therefore may have different alterations in the beta-catenin pathway than sporadic cancers. To test this hypothesis, expression and subcellular localization of beta-catenin, E-cadherin, and APC were detected by immunohistochemistry in paraffin sections from 33 UC-related and 42 sporadic colorectal cancers. Although beta-catenin and E-cadherin expression were predominantly limited to the lateral cell membrane in normal colonic epithelium, both tumor groups showed an overall shift from membranous to cytoplasmic expression for these proteins. An increase in nuclear localization of beta-catenin and a decrease in cytoplasmic APC expression also were seen in both cancer groups compared with normal epithelium. Abnormal beta-catenin expression was more closely linked to E-cadherin alterations in UC-related cancers than in sporadic cancers. In contrast, abnormal beta-catenin expression was more closely linked to APC alterations in sporadic cancers than in UC-related cancers. These data suggest that alterations of the beta-catenin pathway are important in both UC-related and sporadic colorectal cancers. However, differences in the expression patterns of beta-catenin, E-cadherin, and APC between UC-related and sporadic colorectal cancers suggest that the specific alterations in this pathway may differ in these two cancer groups.
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Cadherinas/metabolismo , Carcinoma/metabolismo , Colitis Ulcerosa/metabolismo , Neoplasias Colorrectales/metabolismo , Proteínas del Citoesqueleto/metabolismo , Proteínas de Neoplasias/metabolismo , Transactivadores , Proteína de la Poliposis Adenomatosa del Colon , Carcinoma/complicaciones , Carcinoma/patología , Membrana Celular/metabolismo , Membrana Celular/patología , Núcleo Celular/metabolismo , Núcleo Celular/patología , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/patología , Colon/anatomía & histología , Colon/patología , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/patología , Citoplasma/metabolismo , Citoplasma/patología , Femenino , Humanos , Inmunohistoquímica , Mucosa Intestinal/anatomía & histología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Estadificación de Neoplasias , beta CateninaRESUMEN
Comparative Genomic Hybridization (CGH) is a powerful molecular cytogenetic technique that permits assessment of DNA copy number on a genome-wide scale. Of note, this methodology uses tumor DNA as a probe for fluorescence in situ hybridization (FISH) to normal metaphase chromosomes and does not require dividing cells from the tumor specimen. This unit provides protocols for CGH, for preparation of metaphase chromosomes, tumor and normal DNAs for FISH and for the microscopy and image analysis of CGH experiments.
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Análisis Citogenético/métodos , ADN/genética , ADN/aislamiento & purificación , Sondas de ADN , ADN de Neoplasias/genética , ADN de Neoplasias/aislamiento & purificación , Genética Médica , Humanos , Hibridación Fluorescente in Situ , Metafase , Microscopía FluorescenteRESUMEN
Organ transplant recipients have an increased tumor incidence owing to their immunocompromised state. The origin of such tumors, whether donor or recipient, will have a clinical impact on decision-making concerning immunosuppressive therapy, retransplantation, and for recipients of other organs from the same donors. We report molecular cytogenetic determination of donor origin in 2 cases of small-cell neuroendocrine carcinoma developing in sex-mismatched transplant recipients (kidney and liver). Fluorescence in situ hybridization (FISH) analysis was performed on liver core needle biopsy material from the liver transplant patient and on liver fine needle aspiration cytopreparations from the kidney transplant patient. The results for the liver transplant patient were confirmed with microsatellite allelic analysis and with comparative genomic hybridization. In both cases, FISH showed the presence of only X chromosomes within the tumor cells, indicating the donor origin of the neoplasms. FISH is an excellent method to determine neoplastic origin in sex-mismatched transplant patients. HUM PATHOL 31:1425-1429.
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Carcinoma Neuroendocrino/etiología , Carcinoma de Células Pequeñas/etiología , Neoplasias Renales/etiología , Neoplasias Hepáticas/etiología , Trasplante de Órganos/efectos adversos , Donantes de Tejidos , Adulto , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/patología , ADN de Neoplasias/análisis , Humanos , Hibridación Fluorescente in Situ , Neoplasias Renales/genética , Neoplasias Renales/patología , Trasplante de Riñón/efectos adversos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Trasplante de Hígado/efectos adversos , Masculino , Repeticiones de Microsatélite , Reacción en Cadena de la Polimerasa , Cromosoma XRESUMEN
The development of bladder tumors has been associated with a number of causative agents, including schistosomiasis. Schistosome-related cancers show different clinical and pathological features compared with non-schistosome-related bladder cancers, occurring in younger patients, and being predominantly of squamous cell type. This study addresses the difference between squamous and transitional tumor types in the presence of schistosome infection as a measure of the relationship between tumor genotype and phenotype. We have used comparative genomic hybridization to analyze primary muscleinvasive schistosome-related bladder tumors in 54 patients. Twenty-six of these tumors were squamous cell carcinomas; the remaining 28 were of transitional cell type. On average, transitional cell tumors showed 1.8 times the number of chromosomal aberrations as squamous cell tumors (14.4 versus 8.2, P: < 0.001). For both groups combined, the most prevalent genetic alterations were losses of 8p and 18q, and gains of 8q. Transitional cell cancers also showed frequent losses involving 5q, 9p, 10q, 11p and 11q, and gains at 1q and 17q. Loss of 11p was significantly more frequent in TCC than in SCC tumors (50 versus 4%, P: = 0.01). Squamous cell cancers showed more frequent losses of 17p and 18p than transitional tumors, which was clearly significant given the overall reduced frequency of changes in squamous cancers (P: = 0.001 and P: = 0.03, respectively). These data show that different histologic subgroups of bladder tumors are characterized by distinct patterns of chromosomal alterations. The genetic changes found in the transitional cell group are similar to those reported in non-schistosome-related transitional cell tumors, but differ from tumors exhibiting squamous differentiation.
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Carcinoma de Células Escamosas/genética , Carcinoma de Células Transicionales/genética , Esquistosomiasis/complicaciones , Neoplasias de la Vejiga Urinaria/genética , Animales , Carcinoma de Células Escamosas/parasitología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Transicionales/parasitología , Carcinoma de Células Transicionales/patología , Aberraciones Cromosómicas , Amplificación de Genes , Humanos , Estadificación de Neoplasias , Hibridación de Ácido Nucleico , Schistosoma , Neoplasias de la Vejiga Urinaria/parasitología , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Proliferation indices are intended to help patients and clinicians make treatment decisions. We have previously demonstrated that a proliferation index based on in vivo labeling of S-phase cells with bromodeoxyuridine (BrdUrd) correlates with Ki-67 labeling index (LI). We now compare the prognostic value of these indices. With written consent, we gave 129 women with biopsy confirmed breast cancer 200 mg/M2 BrdUrd during 30 min immediately preceding surgery. We used IU-4 anti BrdUrd antibody to count the immunohistochemical labeling index (LI) of DNA-incorporated BrdUrd in 2,000 cells and MIB-1 to count Ki-67 (118 cases). Patients received standard surgical and adjuvant treatment. No patients were lost to follow-up and patients were followed a minimum of 2 (median 5.1) years. We compared survival and recurrence in tumors with high vs low labeling indices. We found that women in the low BrdUrd LI group had better disease free survival (92% vs 67% 5-yr DFS p = 0.001) and overall survival (94% vs 70% 5-yr OS, p = 0.0001) than those with a high LI. In comparison, a low Ki-67 index predicted better OS (87% vs 80% 5-yr OS, p = 0.020) and a trend for better DFS (84% vs 72% DFS p = 0.055). The apparent superiority of BrdUrd LI over Ki-67 LI is likely due to chance (p = 0.18). In multivariate survival analyses we found that BrdUrd LI proliferative index significantly improves prediction of DFS or OS even when node status, age or tumor size is in the model. We conclude that markers of proliferation are useful adjuncts in predicting patient prognosis.
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Neoplasias de la Mama/patología , Antígeno Ki-67/análisis , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Bromodesoxiuridina , Ciclo Celular/fisiología , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico , Fármacos Sensibilizantes a Radiaciones , Radioterapia AdyuvanteRESUMEN
We have developed a fluorescence-based single strand conformation polymorphism (SSCP) method that offers fast and sensitive screening for mutations in exons 5-8 of the human p53 gene. The method uses an ABI 377 DNA sequencer for unique color detection of each strand, plus accurate alignment of lanes for better detection of mobility shifts. To validate the method, 21 cell lines with reported mutations in p53 exons 5-8 were analyzed by SSCP using various gel conditions. The sensitivity for mutation detection was 95% for all cell lines studied, and no false positives were seen in 10 normal DNA samples for all four exons. Experiments mixing known amounts of tumor and normal DNA showed that mutations were detected even when tumor DNA was mixed with 80% normal DNA. Fluorescent SSCP analysis using the ABI sequencer is a useful tool in cancer research, where screening large numbers of samples for p53 mutations is desired.
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Análisis Mutacional de ADN/métodos , Análisis Mutacional de ADN/normas , Polimorfismo Conformacional Retorcido-Simple , Proteína p53 Supresora de Tumor/genética , Línea Celular , Color , Cartilla de ADN , ADN de Neoplasias/análisis , ADN de Neoplasias/genética , Exones , Colorantes Fluorescentes , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Humanos , Mutación , Reacción en Cadena de la Polimerasa , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
The National Cancer Institute Bladder Tumor Marker Network conducted a study to evaluate the reproducibility of immunohistochemistry for measuring p53 expression in bladder tumors. Fifty paraffin blocks (10 from each of the five network institutions) were chosen at random from among high-grade invasive primary bladder tumors. Two sections from each block were sent to each laboratory for staining and scoring, and then all sections were randomly redistributed among the laboratories for a second scoring. Intra- and interlaboratory reproducibility was assessed with regard to both staining and scoring. For overall assessments of p53 positivity, the results demonstrated that intralaboratory reproducibility was quite good. Concordance across the five participating laboratories was high for specimens exhibiting no or minimal nuclear immunostaining of tumor cells or high percentages of tumor cells with nuclear immunoreactivities. However, there was a reduced level of concordance on specimens with percentages of stained tumor cells in an intermediate range. The discordancies were due mainly to staining differences in one of the five laboratories and scoring differences in another laboratory. These results indicate that some caution must be used in comparing results across studies from different groups. Standardization of staining protocols and selection of a uniform threshold for binary interpretation of results may improve assay reproducibility between laboratories.
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Proteína p53 Supresora de Tumor/biosíntesis , Neoplasias de la Vejiga Urinaria/metabolismo , Análisis de Varianza , Humanos , Inmunohistoquímica , Reproducibilidad de los Resultados , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Ductal carcinoma in situ (DCIS) recurs in the same breast following breast-conserving surgery in 5%-25% of patients, with the rate influenced by the presence or absence of involved surgical margins, tumor size and nuclear grade, and whether or not radiation therapy was performed. A recurrent lesion arising soon after excision of an initial DCIS may reflect residual disease, whereas in situ tumors arising after longer periods are sometimes considered to be second independent events. The purpose of this study was to determine the clonal relationship between initial DCIS lesions and their recurrences. METHODS: Comparative genomic hybridization (CGH) was used to compare chromosomal alterations in 18 initial DCIS lesions (presenting in the absence of invasive disease) and in their subsequent ipsilateral DCIS recurrences (detected from 16 months to 9.3 years later). RESULTS: Of the 18 tumor pairs, 17 showed a high concordance in their chromosomal alterations (median = 81%; range = 65%-100%), while one case showed no agreement between the paired samples (having two and 20 alterations, respectively). Morphologic characterization of the DCIS pairs showed clear similarities. The mean number of CGH changes was greater in the recurrent tumors than in the initial lesions (10.7 versus 8.8; P =.019). The most common changes in both the initial and the recurrent in situ lesions were gains involving chromosome 17q and losses involving chromosomes 8p and 17p. The degree of concordance was independent of the time interval before recurrence and of the presence of positive surgical margins. CONCLUSIONS: In this study, DCIS recurrences were clonally related to their primary lesions in most cases. This finding is consistent with treatment paradigms requiring wide surgical margins and/or postoperative radiation therapy.
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Neoplasias de la Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Aberraciones Cromosómicas/genética , ADN de Neoplasias/genética , Adulto , Anciano , Neoplasias de la Mama/patología , Sondas de ADN , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Hibridación de Ácido Nucleico , Reacción en Cadena de la PolimerasaRESUMEN
Both ulcerative colitis (UC)-related and sporadic colorectal cancers are thought to evolve through a multistep process of genomic instability, accumulation of genomic alterations, and clonal expansion. This process may involve different genomic changes in UC-related cancers than in sporadic cancers because of the origin of UC-related cancers in an inflammatory field. This study was designed to define the specific genomic events occurring in UC-related cancers. Comparative genomic hybridization (CGH) was performed on 32 UC-related and 42 stage-matched sporadic colorectal cancers. The mean number of chromosomal alterations per case was similar in the UC-related and sporadic tumor groups (8.6 in UC, 8.1 in sporadic). The 2 tumor groups shared many chromosomal alterations: losses on 18q (78% UC v69% sporadic), 8p (53% v50%), 17p (44% v57%), and gains on 8q (63% v45%), 20q (44% UC v67%), and 13q (44% UC v38%). However, differences in the frequency and timing of specific alterations were observed. Chromosome 5q was lost in 56% of UC-related but in only 26% of sporadic cancers. Alterations of chromosome 8 were associated with stage progression in UC-related, but not in sporadic cancers. In contrast, 18q loss was associated with stage progression in sporadic cancers only. Thus, differences in the frequency and timing of individual chromosomal alterations suggest that genetic progression in these 2 tumor groups may follow multiple pathways.
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Aberraciones Cromosómicas , Colitis Ulcerosa/genética , Neoplasias Colorrectales/genética , Adulto , Anciano , Mapeo Cromosómico , Colitis Ulcerosa/patología , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Hibridación de Ácido NucleicoAsunto(s)
Biomarcadores de Tumor/análisis , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/fisiopatología , Proteínas de Ciclo Celular/análisis , Genes Supresores de Tumor , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/fisiopatología , Carcinoma de Células Transicionales/genética , Ciclo Celular , División Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/genética , Genes de Retinoblastoma , Genes p53 , Humanos , Pronóstico , Neoplasias de la Vejiga Urinaria/genéticaRESUMEN
Therapists working with court-ordered clients from cultures differing from the mainstream face challenging issues of compulsory therapy in the context of cultural diversity. This article reviews the literature on court-ordered and multicultural counseling, highlighting central elements of both. It then suggests guidelines that blend these elements. The author illustrates how using these guidelines can enable therapists to engage these clients in the therapeutic process and focus on culture as the context for change.
Asunto(s)
Diversidad Cultural , Terapia Familiar/legislación & jurisprudencia , Terapia Familiar/métodos , Violencia , Adulto , Consejo , Cultura , Guías como Asunto , Humanos , Masculino , Relaciones Padres-HijoRESUMEN
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon associated with a high risk of colorectal cancer. This increased cancer risk is thought to result from the cellular damage induced by the inflammatory field. The aim of this study was to determine the pattern and time course of genomic instability occurring in UC-related neoplasia. Sites of cancer, dysplasia, and nondysplasia from 14 UC colectomy cases containing cancer were analyzed for chromosomal alterations by comparative genomic hybridization (CGH) and for microsatellite instability using a series of 10 microsatellite markers. Clonal chromosomal alterations were present in 85% of cancer sites, 86% of dysplasia sites, and 36% of nondysplasia sites. Losses of chromosome 18 or 18q and chromosome 5 or 5q were common in cancer and dysplasia and were occasionally detected in nondysplasia. High-level microsatellite instability was detected in the cancer and dysplasia of two cases. Samples that demonstrated high-level microsatellite instability were unlikely to have chromosomal alterations demonstrable by CGH. These studies suggest that the predominant type of genomic instability in UC-related neoplasia is associated with chromosomal alterations and that this type of genomic instability frequently occurs before the development of histologically defined dysplasia.