RESUMEN
Body fatness is a risk factor for colorectal cancer, and promotes an inflammatory environment. Indeed, inflammation in normal colorectal mucosa may be a factor linking body fatness to colorectal carcinogenesis. In this study, we evaluated myeloperoxidase (MPO)-positive cells infiltration of normal colorectal mucosa as a marker of cancer-promoting inflammation in overweight and obese subjects. One hundred and three subjects with normal colonoscopy entered the study. Waist circumference (WC) and body mass index (BMI) were measured, and MPO-positive cells on histological sections of biopsies of normal colorectal mucosa were counted under a light microscope. The occurrence of adenomas was then evaluated on follow-up colonoscopies. Mean MPO-positive cell count (±s.e.m.) was higher in subject with a WC equal or above the obesity cutoff values according to gender (2.63±0.20 vs 2.06±0.18, P=0.03), and in subjects with BMI equal or above 25 kg m-2 (2.54±0.18 vs 1.97±0.20, P=0.03). A Cox proportional hazard model showed that mean MPO-positive cell count in normal colorectal mucosa was the only factor independently related to occurrence of adenomas in follow-up colonoscopies. Though preliminary, these results show that MPO-positive cell infiltration in normal colorectal mucosa is related with body fatness, as evaluated by WC and BMI, and it may be considered a useful and simple marker to estimate adenoma occurrence risk.
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Adenoma/enzimología , Antígenos de Diferenciación Mielomonocítica/metabolismo , Neoplasias Colorrectales/enzimología , Inflamación/enzimología , Sobrepeso/fisiopatología , Peroxidasa/metabolismo , Adenoma/metabolismo , Biomarcadores de Tumor/metabolismo , Índice de Masa Corporal , Colonoscopía , Neoplasias Colorrectales/metabolismo , Detección Precoz del Cáncer , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Inflamación/metabolismo , Mucosa Intestinal , Italia , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Sobrepeso/complicaciones , Sobrepeso/metabolismo , Factores de Riesgo , Circunferencia de la CinturaRESUMEN
We report on stable, long-term immobilization and localization of a single colloidal Er(3+)/Yb(3+) codoped upconverting fluorescent nanoparticle (UCNP) by optical trapping with a single infrared laser beam. Contrary to expectations, the single UCNP emission differs from that generated by an assembly of UCNPs. The experimental data reveal that the differences can be explained in terms of modulations caused by radiation-trapping, a phenomenon not considered before but that this work reveals to be of great relevance.
RESUMEN
Germline mutations in BRCA1 and BRCA2 genes predispose to hereditary breast cancer, whereas carriers of mutations in any of the mismatch repair genes (MMR; hMLH1, hMSH2, hMSH6, hPMS2) are highly susceptible to Lynch syndrome. In the present study, we describe a woman affected by unilateral breast cancer at the age of 35 years. After 4 years, during the follow-up she developed synchronous (and asymptomatic) endometrial cancer, ovarian carcinoma and renal clear cell carcinoma. After 7 years (at age 46), the patient developed an infiltrating carcinoma of the contralateral breast and died in a few months of metastatic disease. Initial investigations led to the detection of a constitutional mutation in the BRCA1 gene. The extended genealogical tree disclosed a suspected history of colorectal carcinoma in the maternal branch. Endometrial cancer of the proband was investigated for microsatellite instability (MSI) and immunohistochemical expression of MLH1, MSH2 and MSH6 proteins. An high MSI status and lack of expression of MLH1 protein were detected. hMLH1 gene sequencing revealed the presence of a constitutional mutation, which was also found in the mother of the proband. Loss of the wild-type hMLH1 allele was detected in both breast tumors, thus suggesting that the MMR defect contributed to the development of the breast cancer.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias de la Mama/genética , Neoplasias Endometriales/genética , Genes BRCA1 , Neoplasias Renales/genética , Neoplasias Primarias Múltiples/genética , Proteínas Nucleares/genética , Neoplasias Ováricas/genética , Alelos , Neoplasias de la Mama/patología , Neoplasias Endometriales/patología , Resultado Fatal , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Heterocigoto , Humanos , Inmunohistoquímica , Neoplasias Renales/patología , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Clasificación del Tumor , Neoplasias Ováricas/patología , LinajeRESUMEN
BACKGROUND: Attenuated familial adenomatous polyposis (AFAP) is characterized by the presence of 10-99 colorectal adenomas. The disease may be associated with mutations in either APC or MUTYH genes. We purposed to evaluate the contribution of adenomatous polyposis coli (APC) and MutY homologue (MUTYH) germline alterations to the AFAP phenotype and to identify genotype/phenotype correlations. METHODS: During counselling for familial adenomatous polyposis (FAP), 91 probands (and 107 affected individuals) who met the criteria of AFAP were identified. Eighty-two families were screened for constitutional mutations of the APC and MUTYH genes. RESULTS: MUTYH mutations were detected in 21 families (25.6 % of the 82 tested), and APC mutations in 7 (8.5 %). Overall, constitutional alterations were found in 34.1 % of the probands. Patients with APC mutations were younger at cancer onset and had a higher mean number of polyps (48.5 ± 33.0 in APC+ individuals vs. 35.7 ± 24.9 in MUTYH+ individuals, and 33.2 ± 18.4 in the "no mutation" group). Clinical features rendered the "no mutation" group closer to MUTYH+ than to the APC+ group. Colorectal cancer at diagnosis was detected in 40 % of AFAP individuals. CONCLUSIONS: AFAP is a new clinical entity with its frequency in the general population still undefined. The number of adenomas varies greatly, with an average of 30-40 lesions. The molecular basis of AFAP can be established in approximately 1/3 of the patients. Both MUTYH and APC genes are implicated in AFAP, though the role of MUTYH is of considerably greater relevance.
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ADN Glicosilasas/genética , Síndrome de Gardner/genética , Síndrome de Gardner/patología , Genes APC , Adolescente , Adulto , Factores de Edad , Anciano , Femenino , Genotipo , Humanos , Italia , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Estadísticas no Paramétricas , Carga Tumoral/genética , Adulto JovenRESUMEN
MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression by targeting messenger RNAs and causing cleavage or translation blockage. miRNAs induced after parasitization of the lepidopteran host Lymantria dispar by the parasitoid wasp Glyptapanteles flavicoxis, which introduces a polydnavirus and other parasitoid factors, were examined to identify induced miRNAs that might regulate host genes and contribute to host immunosuppression and other effects. miRNA profiling of parasitized larval hemocytes versus non-parasitized ones by microarray hybridization to mature insect and virus miRNAs identified 27 differentially expressed miRNAs after parasitization. This was confirmed by real-time relative qPCR for insect miRNAs (dme-mir-1, -8, -14, -184, -276, -277, -279, -289, -let-7) using miRNA-specific TaqMan assays. Certain cellular miRNAs were differentially expressed in larval tissues, such as the potentially developmentally linked mir-277, signifying a need for functional studies.
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Lepidópteros/parasitología , MicroARNs/análisis , Polydnaviridae/genética , Avispas/virología , Animales , Regulación de la Expresión Génica , Larva/genética , Lepidópteros/genética , MicroARNs/fisiología , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Lanthanide-activated SrF2 nanoparticles with a multishell architecture were investigated as optical thermometers in the biological windows. A ratiometric approach based on the relative changes in the intensities of different lanthanide (Nd3+ and Yb3+) NIR emissions was applied to investigate the thermometric properties of the nanoparticles. It was found that an appropriate doping with Er3+ ions can increase the thermometric properties of the Nd3+-Yb3+ coupled systems. In addition, a core containing Yb3+ and Tm3+ can generate light in the visible and UV regions upon near-infrared (NIR) laser excitation at 980 nm. The multishell structure combined with the rational choice of dopants proves to be particularly important to control and enhance the performance of nanoparticles as NIR nanothermometers.
RESUMEN
Hereditary NonPolyposis Colorectal Cancer (Lynch syndrome) is an autosomal dominant disease caused by germline mutations in a class of genes deputed to maintain genomic integrity during cell replication, mutations result in a generalized genomic instability, particularly evident at microsatellite loci (Microsatellite Instability, MSI). MSI is present in 85-90% of colorectal cancers that occur in Lynch Syndrome. To standardize the molecular diagnosis of MSI, a panel of 5 microsatellite markers was proposed (known as the "Bethesda panel"). Aim of our study is to evaluate if MSI testing with two mononucleotide markers, such as BAT25 and BAT26, was sufficient to identify patients with hMLH1/hMSH2 germline mutations. We tested 105 tumours for MSI using both the Bethesda markers and the two mononucleotide markers BAT25 and BAT26. Moreover, immunohistochemical evaluation of MLH1 and MSH2 proteins was executed on the tumours with at least one unstable microsatellite, whereas germline hMLH1/hMSH2 mutations were searched for all cases showing two or more unstable microsatellites. The Bethesda panel detected more MSI(+) tumors than the mononucleotide panel (49.5% and 28.6%, respectively). However, the mononucleotide panel was more efficient to detect MSI(+) tumours with lack of expression of Mismatch Repair proteins (93% vs 54%). Germline mutations were detected in almost all patients whose tumours showed MSI and no expression of MLH1/MSH2 proteins. No germline mutations were found in patients with MSI(+) tumour defined only through dinucleotide markers. In conclusion, the proposed mononucleotide markers panel seems to have a higher predictive value to identify hMLH1 and hMSH2 mutation-positive patients with Lynch syndrome. Moreover, this panel showed increased specificity, thus improving the cost/effectiveness ratio of the biomolecular analyses.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Mutación de Línea Germinal/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Nucleótidos/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/enzimología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Enzimas Reparadoras del ADN/genética , Marcadores Genéticos , Humanos , Inestabilidad de Microsatélites , Homólogo 1 de la Proteína MutLRESUMEN
Polydnaviruses are rarely studied for their natural variation in immune suppressive abilities. The polydnavirus harboring braconid Cotesia sesamiae, a widespread endoparasitoid of Busseola fusca and Sesamia calamistis in sub-Saharan Africa exists as two biotypes. In Kenya, the western biotype completes development in B. fusca larvae. However, eggs of the coastal C. sesamiae are encapsulated in this host and ultimately, no parasitoids emerge from parasitized B. fusca larvae. Both biotypes develop successfully in S. calamistis larvae. Encapsulation activity by B. fusca larvae towards eggs of the avirulent C. sesamiae was detectable six hours post-parasitization. The differences in encapsulation of virulent and avirulent strains were associated with differences in nucleotide sequences and expression of a CrV1 polydnavirus (PDV) gene, which is associated with haemocyte inactivation in the Cotesia rubecula/Pieris rapae system. CrV1 expression was faint or absent in fat body and haemolymph samples from B. fusca parasitized by the avirulent C. sesamiae, which exhibited encapsulation of eggs. Expression was high in fat body and haemolymph samples from both B. fusca and S. calamistis larvae parasitized by the virulent C. sesamiae, encapsulation in the former peaking at the same time points as CrV1 expression in the latter. Non synonymous difference in CrV1 gene sequences between virulent and avirulent wasp suggests that variations in B. fusca parasitism by C. sesamiae may be due to qualitative differences in CrV1-haemocyte interactions.
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Glicoproteínas/genética , Hemocitos/fisiología , Mariposas Nocturnas/parasitología , Polydnaviridae/genética , Proteínas Virales/genética , Avispas/patogenicidad , Zea mays/parasitología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Secuencia Conservada , Cartilla de ADN , Femenino , Genes Virales , Geografía , Glicoproteínas/química , Kenia , Datos de Secuencia Molecular , Mariposas Nocturnas/genética , Oviposición , Óvulo/parasitología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia , Proteínas Virales/químicaRESUMEN
This study presents the characterization and antibacterial activity of nanostructured Si by plasma treatment method using a tetrafluoromethane (CF4) and hydrogen (H2) mixture. Nanostructured-Si is a synthetic nanomaterial that contains high aspect ratio nanoprotrusions on its surface, produced through a reactive-ion etching process. We have shown that the nanoprotrusions on the surfaces produce a mechanical bactericidal effect. Nanostructured-Si exhibited notable activity against three different microorganisms: Gram-negative (Escherichia coli), Gram-positive (Staphylococcus aureus) and spore-forming bacteria (Bacillus cereus) producing a > 5 log10 reduction after 24h of incubation. Scanning electron microscopy was used to analysis the structure and morphology character of different surfaces evidencing the physical bactericidal activity of the Nanostructured-Si. These results provide excellent prospects for the development of a new generation of antibacterial surfaces.
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Nanoestructuras , Antibacterianos , Bacillus cereus , Escherichia coli , Fluorocarburos , Pruebas de Sensibilidad Microbiana , Staphylococcus aureusRESUMEN
Foci of aberrant crypts (ACF) have been observed on the unsectioned, methylene blue-stained mucosal surface of the human colon. Experimental evidence and the histological features of the lesions suggest that they might be early events in colon cancer development. The main objective of the present study was to evaluate cell kinetic properties of ACF in the human colon. Five samples of colon mucosa were collected immediately after operation following the administration of 500 mg of 5'-bromo-2'-deoxyuridine prior to surgery. ACF were then identified on the fixed, unsectioned, methylene blue-stained mucosal surface under a light microscope. Some specimens containing ACF were serially sectioned perpendicular to the luminal surface of the intestine, along with specimens of normal-appearing mucosa. Several sections were prepared for the immunohistochemical identification of 5'-bromo-2'-deoxyuridine-incorporating cells (in the S phase of the cell cycle). The results of this study demonstrated that aberrant crypts have more cells per crypt than normal glands. Total labeling index and labeling index values in each of the five longitudinal compartments in which each crypt was divided showed an increased total proliferative activity in all ACF examined, although limited to the lower crypt compartments in almost all aberrant crypts evaluated. These findings are in keeping with previous cell kinetic studies and observations in experimental animals and provide evidence of the involvement of human aberrant crypts in the stepwise process leading from normal mucosa to colon cancer.
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Colon/patología , Mucosa Intestinal/patología , Anciano , Anciano de 80 o más Años , Bromodesoxiuridina/administración & dosificación , Bromodesoxiuridina/metabolismo , División Celular , Colon/metabolismo , Neoplasias Colorrectales/cirugía , Femenino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Persona de Mediana Edad , Fase SRESUMEN
Hereditary nonpolyposis colorectal cancer (HNPCC) is attributable to a deficiency of mismatch repair. Inactivation of DNA mismatch repair underlies the genesis of microsatellite instability in colorectal cancer. Germline mutations in three DNA mismatch repair genes, hMSH2, hMLH1, and hMSH6, have been found to segregate in HNPCC and HNPCC-like families. The two DNA mismatch repair genes hPMS1 and hPMS2 have also been suggested to predispose to HNPCC. In this study, 84 HNPCC and HNPCC-like kindreds without known mutations in the other three known DNA mismatch repair genes were screened for germline mutations in the hPMS1 or hPMS2 gene. No clear-cut pathogenic mutations were identified. Conversion technology was used to detect a large hMSH2 deletion in two affected members of the kindred in which the hPMS1 mutation was originally reported, whereas the hPMS1 mutation was only present in one of these two individuals. Since the hPMS1 and hPMS2 genes were first reported, germline mutations in hPMS2 have been demonstrated primarily in patients with Turcot's syndrome. However, no mutation in any of the two genes has been found to segregate in HNPCC families. Until there is better evidence for an increased colorectal cancer risk associated with germline mutations in these genes, a conservative interpretation of the role of mutations in these genes is advised.
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Adenosina Trifosfatasas/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Enzimas Reparadoras del ADN , Proteínas de Unión al ADN/genética , Proteínas de Neoplasias/genética , Adulto , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Masculino , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Proteínas MutL , Linaje , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Aberrant crypt foci (ACF) are microscopic clusters of altered colonic crypts considered premalignant lesions in the large bowel. Genomic instability at short tandem repeats in the DNA, referred to as microsatellite instability (MSI) is the hallmark of hereditary nonpolyposis colorectal carcinoma (HNPCC) caused by mutations in DNA mismatch-repair genes, mostly hMLH1 and hMSH2. In this study, we evaluated for MSI ACF (n = 16), adenomas (n = 18), carcinomas (n =22), and lymph node metastases (n = 3) from 17 patients with colorectal cancer positive for MSI. Ten patients were members of HNPCC families; 7 patients had no family history of cancer. MSI was found in 7 of 7 (100%) ACF and 11 of 12 (91%) adenomas from patients with HNPCC. MSI was not related to histology and size of ACF. A progressive increase in instability as estimated by the number of shifted bands was observed along the ACF-adenoma-carcinoma sequence. In contrast, two of nine (22%) ACF and none of six adenomas from patients with MSI sporadic carcinoma were unstable at microsatellite loci. hMLH1 or hMSH2 protein expression was altered only in MSI-positive premalignant lesions (ACF and/or adenomas), but not in all MSI-positive lesions in patients with HNPCC. These observations provide evidence of the premalignant nature of ACF in HNPCC and suggest that MSI is a very early event both in HNPCC and in sporadic colorectal carcinogenesis, although in the latter it seems infrequent.
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Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Proteínas de Unión al ADN , Proteínas de Neoplasias/biosíntesis , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Adaptadoras Transductoras de Señales , Adenoma/genética , Adenoma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Disparidad de Par Base , Proteínas Portadoras , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS , Proteínas de Neoplasias/genética , Proteínas Nucleares , Lesiones Precancerosas/genética , Lesiones Precancerosas/metabolismo , Proteínas Proto-Oncogénicas/genéticaRESUMEN
PURPOSE: Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a high-incidence area for colon cancer. PATIENTS AND METHODS: Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1. RESULTS: Twenty-eight cases (8.3% of the total) showed MSI. MSI cases differed significantly from microsatellite-stable (MSS) cases for their proximal location (P <.01), high mucinous component (P <.01), and poor differentiation (P =.002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) did not show germline mutations. CONCLUSION: We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.
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Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Proteínas de Unión al ADN , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Portadoras , Neoplasias Colorrectales Hereditarias sin Poliposis/metabolismo , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Mutación de Línea Germinal , Humanos , Inmunohistoquímica , Incidencia , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Proteínas Nucleares , Estudios Prospectivos , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas/genética , Sistema de RegistrosRESUMEN
Aberrant crypt foci (ACF) have been identified on the colonic mucosal surface of rodents treated with colon carcinogens and of humans after methylene-blue staining and observation under a light microscope. Several lines of evidence strongly suggest that ACF with certain morphological, histological, cell kinetics, and genetic features are precursor lesions of colon cancer both in rodents and in humans. Thus, ACF represent the earliest step in colorectal carcinogenesis. This paper has the main purpose of reviewing the evidence supporting this view, with particular emphasis on cell and crypt dynamics in ACF. ACF have been used as intermediate biomarkers of cancer development in animal studies aimed at the identification of colon carcinogens and chemopreventive agents. Recently, evidence has also shown that ACF can be effectively employed in chemopreventive studies also in humans.
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Neoplasias Colorrectales/patología , Animales , Apoptosis , División Celular , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/genética , Genes APC , Humanos , Mucosa Intestinal/patología , Cinética , Microscopía Electrónica de Rastreo , Lesiones Precancerosas/etiología , Lesiones Precancerosas/genética , Lesiones Precancerosas/patologíaRESUMEN
The count of argyrophilic nucleolar organizer regions (AgNORs) has been proposed as a useful method for evaluating cell replication in human tumours. The current study was undertaken to compare AgNOR values in colorectal cancers with two better established methods for investigating cell proliferation such as bromodeoxyuridine (BrdUrd) and 3[H]-thymidine (3[H]dT) labelling indices (LIs). Because some concern still exists regarding accuracy and reproducibility of AgNOR quantifying methods, we carried out a control study by independently repeating the same measurements (number, area and area per silver-stained NOR particle) in two centres with different operators and computer-assisted image analysers on 40 colorectal carcinomas. AgNOR values recorded in the two centres were strictly correlated (r = 0.75; P < 0.001 for number; r = 0.62, P < 0.01 for area; r = 0.63, P < 0.001 for area per silver-stained NOR particle) and the range of values were almost identical. Then, AgNOR values were compared with BrdUrd and 3[H]dT LIs, respectively obtained by in vivo incorporation and in vitro incubation in the same series of colorectal carcinomas. No correlation was found between AgNOR values and BrdUrd or 3[H]dT LIs. BrdUrd and 3[H]dT LIs were instead reciprocally significantly correlated. No evident correlation was seen between LIs or AgNOR values and clinico-pathological parameters of the tumour. In conclusion, in colorectal neoplasms, AgNOR values did not appear to relate with more direct parameters of cell proliferation. It follows that AgNOR reliability as a biomarker of cell proliferation remains questionable.
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Neoplasias Colorrectales/patología , Región Organizadora del Nucléolo/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Bromodesoxiuridina , División Celular/fisiología , Femenino , Humanos , Cinética , Masculino , Persona de Mediana Edad , Tinción con Nitrato de Plata , Timidina , TritioRESUMEN
Mutations affecting human mismatch repair (MMR) genes (MLH1, MSH2, PMS1, PMS2, and MSH6) cause tumour predisposition in hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, and an association has been demonstrated with the replication error (RER) phenotype in most colorectal and some extracolonic neoplasms. A pathogenetic model for RER+ tumours through inactivation of suppressor genes has been hypothesised, and TGF beta RII, BAX and IGFIIR genes have recently been proposed as targets of such inactivating mutations. In this study, a series of 47 tumours developed in patients with known MLH1/MSH2 status and a family history of HNPCC and/or early onset colorectal cancer were characterised for the RER phenotype through microsatellite analysis. The RER phenotype, displayed by 17 tumours, was then correlated with the presence of insertions/deletions at the TGF beta RII, IGFIIR and BAX gene stretches, confirming that the TGF beta RII inactivation may be particularly critical for the RER-associated tumorigenesis. RER+ colorectal cancers (CRCs) developed more frequently in patients from HNPCC families (72.7%) than in those from families not fulfilling the Amsterdam criteria (33.3% in suspected HNPCC and 20.8% in early onset CRC patients). A consistent fraction of either Amsterdam and non-Amsterdam patients developed RER- CRCs, pointing to the involvement of other genes not related to the MMR system. The RER phenotype was associated with younger age at diagnosis in familial cases, and there was a trend for an association with proximal CRC localisation and early Dukes' stages. The RER status was also correlated with the presence and type of MLH1 and MSH2 alteration.
Asunto(s)
Disparidad de Par Base/genética , Neoplasias Colorrectales/genética , Proteínas de Unión al ADN , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Proteínas Portadoras , Neoplasias Colorrectales/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Reparación del ADN , Humanos , Repeticiones de Microsatélite , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares , Fenotipo , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
The main aim of this study was, through the data of a population-based Registry, to establish the incidence of Dukes' A lesions by year of registration and the main clinical features, and to assess cancer-specific survival. One hundred and eighteen Dukes' A colorectal tumours were diagnosed (in 117 patients) out of 1337 registered between 1984 and 1992 in the Health Care District of Modena, Northern Italy; 94 patients were treated with surgery and 23 with endoscopic polypectomy. The frequency of Dukes' A tumours ranged between 4.8% and 18% by year of registration. Dukes' A carcinomas were significantly more frequent in the distal colon. Only 5 patients (4%) died of their cancer, and in all patients the tumour was localised in the rectum. Carcinomas associated with a poor prognosis did not show any of the biological variables usually associated with an unfavourable outcome, but, our data suggest the possibility of incomplete removal of tumours at surgery.
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Neoplasias del Colon/epidemiología , Neoplasias del Recto/epidemiología , Anciano , Neoplasias del Colon/patología , Neoplasias del Colon/cirugía , Endoscopía , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Italia/epidemiología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Neoplasias del Recto/patología , Neoplasias del Recto/cirugía , Tasa de SupervivenciaRESUMEN
Hereditary non-polyposis colorectal cancer (HNPCC) is a genetically heterogeneous disease for which PMS2 gene, a member of the human PMS gene family, is believed to have a marginal role. To better define the contribution of PMS2 to hereditary colorectal cancer, we investigated this gene in 22 unrelated Italian patients that, despite a positive family history and/or early onset and development of tumors with microsatellite instability (MSI), did not carry constitutional mutations of MLH1 and MSH2 genes. No mutations with clear-cut pathogenetic significance were detected in the coding regions of PMS2 gene, but only 8 polymorphisms (7 common and 1 rare, 3 silent and 5 missense) and 3 unique molecular variants (2 missense substitutions and one 3-nucleotide deletion) were seen. Lack of PMS2 truncating mutations in our study does not disagree with its supposed marginal involvement in hereditary colorectal cancer, but at the same time points out the need to investigate the phenotypic molecular and clinical characteristics more specifically associated with PMS2 mutations.
Asunto(s)
Adenosina Trifosfatasas , Proteínas Portadoras , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Enzimas Reparadoras del ADN , Mutación de Línea Germinal , Proteínas/genética , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , ADN de Neoplasias/genética , Proteínas de Unión al ADN/genética , Femenino , Proteínas Fúngicas/genética , Humanos , Masculino , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , Proteínas MutL , Proteína 2 Homóloga a MutS , Proteínas de Neoplasias/genética , Proteínas Nucleares , Proteínas Proto-Oncogénicas/genéticaRESUMEN
Mutations of the mismatch repair (MMR) genes MLH1 and MSH2 are associated with hereditary nonpolyposis colorectal cancer (HNPCC), a highly penetrant autosomal dominant condition characterized by hypermutability of short tandemly repeated sequences in tumor DNA. Mutations of another MMR gene, MSH6, seem to be less common than MLH1 and MSH2 defects, and have been mostly observed in atypical HNPCC families, characterized by a weaker tumor family history, higher age at disease onset, and low degrees of microsatellite instability (MSI), predominantly involving mononucleotide runs. We have investigated the MSH6 gene sequence in the peripheral blood of 4 HNPCC and 20 atypical HNPCC probands. Two frameshift mutations within exon 4 were detected in 2 patients. One mutation was found in a proband from a typical HNPCC family, who had developed a colorectal cancer (CRC), a gastric cancer and a rectal adenoma. The CRC and the adenoma showed mild MSI limited to mononucleotide tracts, while the gastric carcinoma was microsatellite stable. The other mutation was detected in an atypical HNPCC proband, whose CRC showed widespread MSI involving both mono- and dinucleotide repeats. The phenotypic variability associated with MSH6 constitutional mutations represents a complicating factor for the optimization of strategies aimed at identifying candidates to MSH6 genetic testing.
Asunto(s)
Disparidad de Par Base , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Reparación del ADN , Proteínas de Unión al ADN/genética , Mutación del Sistema de Lectura , Pruebas Genéticas , Adulto , Secuencia de Bases , Análisis Mutacional de ADN , ADN de Neoplasias/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Fenotipo , Reacción en Cadena de la Polimerasa , Neoplasias del Recto/genética , Neoplasias Gástricas/genética , Secuencias Repetidas en TándemRESUMEN
The identification of hereditary non-polyposis colorectal cancer (HNPCC) is important not only for the patient, but also for family members who are at increased risk of developing cancer. To determine if measuring various pathobiologic features of the colon carcinomas is useful in separating sporadic from HNPCC tumors, the authors studied tumor tissues from 46 patients with HNPCC and compared them to 70 with sporadic colorectal carcinoma. Parameters investigated included DNA ploidy (flow cytometry), AgNOR count (by silver staining), microvessel density (immunohistochemistry), p53 and K-ras expression, and grade-related parameters. Diploid tumors were more frequent in patients with HNPCC (65% vs 40%, P < .02), thus confirming previous observations concerning such an association. Higher AgNOR counts and greater AgNOR areas were observed in sporadic tumors than in HNPCC (5.2 +/- 1.5 vs 4.5 +/- 1.8, P < .01). Hereditary tumors tended to be less vascularized, whereas oncogene expression and grade-related parameters did not show appreciable differences between the two types of tumors. In conclusion, some of the investigated parameters may contribute to defining the biologic profile of HNPCC. In addition, these findings support the clinical impression of a more favorable outcome that is frequently seen in HNPCC patients.