RESUMEN
BACKGROUND: We compared relative survival rates of patients after various operative treatments for abdominal aortic aneurysm (AAA) to those for the general population. We calculated a point of "recovery," defined as the survival rate equal to that of the general population. METHODS: Survival data were collected from patients who underwent open repair for a ruptured AAA (rAAA), elective open repair of an AAA (OPEN), and endovascular repair (EVAR) in our hospital between 1995 and 2005. The cumulative relative survival rate and time-specific relative survival rate were calculated for these patients compared to those for the general population. The point of "recovery" was defined as the cumulative relative survival rate equaling the survival rate for the population, and the time-specific relative survival rate reaching 1.0. RESULTS: The cumulative relative survival rate of the patients immediately after OPEN was lower than for the comparison group at the time the cumulative relative survival rate was regained. The time-specific relative survival rate of the rAAA reached 1.0 at 16 months following emergency surgery, and for OPEN after 10 months. The cumulative relative survival rate in the EVAR group had no impairment following intervention. The relative long-term survival rate in all three surgical groups was the same as that for the general German population. CONCLUSIONS: Patients treated successfully for AAA have the same relative long-term survival as the general population. The time required to reach the same survival, however, differs between the treatment groups and is longest in the group with a rAAA. The variable survival rates should be taken into consideration when treating patients with an AAA.
Asunto(s)
Aneurisma de la Aorta Abdominal/mortalidad , Aneurisma de la Aorta Abdominal/cirugía , Rotura de la Aorta/mortalidad , Rotura de la Aorta/cirugía , Anciano , Anciano de 80 o más Años , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Tasa de SupervivenciaRESUMEN
Pancreatic intraductal papillary mucinous neoplasms (IPMNs) rank among the most common cystic tumors of the pancreas. For a long time they were misdiagnosed as mucinous cystadenocarcinoma, ductal adenocarcinoma in situ, or chronic pancreatitis. Only in recent years have IPMNs been fully recognized as clinical and pathological entities, although their origin and molecular pathogenesis remain poorly understood. IPMNs are precursors of invasive carcinomas. When resected in a preinvasive state patient prognosis is excellent, and even when they are already invasive, patient prognosis is more favorable than with ductal adenocarcinomas. Subdivision into macroscopic and microscopic subtypes facilitates further patient risk stratification and directly impacts treatment. There are main duct and branch duct IPMNs, with the main duct type including the intestinal, pancreatobiliary, and oncocytic types and the branch duct type solely harboring the gastric type. Whereas main duct IPMNs have a high risk for malignant progression, demanding their resection, branch duct IPMNs have a much lower risk for harboring malignancy. Patients with small branch duct/gastric-type IPMNs (<2 cm) without symptoms or mural nodules can be managed by periodic surveillance.
Asunto(s)
Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/terapia , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/terapia , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/metabolismo , Carcinoma Papilar/terapia , Humanos , Neoplasias Pancreáticas/metabolismo , PronósticoRESUMEN
This literature review briefly summarizes the epidemiology, pathophysiology, clinical management, and outcomes of patients with pancreatic neuroendocrine tumors (PNETs) and highlights recent advances in PNET research. PNETs are rare neoplasms, compared with carcinomas arising from pancreatic exocrine tissue. They, like other neuroendocrine tumor types, display variable malignant potential, hormone-related syndromes (functionality), localization, and genetic background. Although tumor origin and molecular pathogenesis remain poorly understood, recently established grading and staging systems facilitate patient risk stratification, and thereby directly impact clinical decision making. Although the optimal clinical management of PNETs involves a multidisciplinary approach, surgery remains the only curative treatment for early-stage disease. Surgery may also have a role in patients with advanced-stage disease, including those with hepatic metastases. Alternative therapeutic approaches applied to PNETs, including chemotherapy, radiofrequency ablation, transarterial chemoembolization, biotherapy, polypeptide radionuclide receptor therapy, antiangiogenic therapy, and selective internal radiotherapy, have failed to demonstrate a long-term survival benefit. Surgery remains the primary therapeutic option for patients with PNETs. Research on PNETs is desperately needed to improve the therapeutic options for patients with this disease.
Asunto(s)
Tumores Neuroendocrinos , Neoplasias Pancreáticas , Gastrinoma/diagnóstico , Gastrinoma/terapia , Humanos , Incidencia , Insulinoma/diagnóstico , Insulinoma/terapia , Estadificación de Neoplasias , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/etiología , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/etiología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , PronósticoRESUMEN
BACKGROUND: Patients suffering from locally advanced esophageal carcinoma are generally treated using multimodal therapies. This prospective, non-randomized trial was performed to evaluate the survival benefit of neoadjuvant radiochemotherapy prior to surgery in comparison with surgery only. PATIENTS & METHODS: Histopathological outcomes and survival were compared between 61 patients who underwent neoadjuvant radiochemotherapy and 64 comparable control patients who had been under-staged. After neoadjuvant therapy, tumor regression was assessed using the method described by Mandard in 1994. Survival curves for the two groups were estimated using the Kaplan-Meier method, and compared with the log-rank test. RESULTS: Median and 3-year recurrence-free survival for the entire group were 26 months and 39.7%, respectively. The median and 3-year overall survival reached 34 months and 48.1%. Patients who showed complete response to neoadjuvant therapy had significantly improved survival (35 months) compared to patients with residual tumor cells (28 months), patients with tumors unresponsive to radiochemotherapy (22 months), or patients who received surgery only (control group, 29 months). Patients with nodal-negative carcinomas showed significantly longer survival after surgery only and after neoadjuvant therapy compared to patients with lymph node-positive cancers. CONCLUSIONS: Complete response after neoadjuvant radiochemotherapy is associated with significantly improved survival. Negative nodal status is a major determinant of outcomes following primary operation or neoadjuvant treatment.
Asunto(s)
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/terapia , Esofagectomía , Selección de Paciente , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/radioterapia , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/cirugía , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/radioterapia , Neoplasias Esofágicas/secundario , Neoplasias Esofágicas/cirugía , Esofagectomía/efectos adversos , Esofagectomía/mortalidad , Femenino , Fluorouracilo/administración & dosificación , Humanos , Estimación de Kaplan-Meier , Escisión del Ganglio Linfático , Metástasis Linfática , Masculino , Terapia Neoadyuvante , Invasividad Neoplásica , Estadificación de Neoplasias , Neoplasia Residual , Estudios Prospectivos , Radioterapia Adyuvante , Factores de Tiempo , Resultado del TratamientoRESUMEN
Mononucleotide repeat sequences are particularly prone to frameshift mutations in tumors with biallelic inactivation of the mismatch repair (MMR) genes MLH1 or MSH2. In these tumors, several genes harboring mononucleotide repeats in their coding region have been proposed as targets involved in tumor progression, among which are also the MMR genes MSH3 and MSH6. We have analyzed the expression of the MSH3 and MSH6 proteins by immunohistochemistry in 31 colorectal carcinomas in which MLH1 was inactivated. Loss of MSH3 expression was identified in 15 tumors (48.5%), whereas all tumors expressed MSH6. Frameshift mutations at coding microsatellites were more frequent in MSH3 (16 of 31) than in MSH6 (3 of 31; Fisher's exact test, P < 0.001). Frameshift mutations and allelic losses of MSH3 were more frequent in MSH3-negative tumors compared with those with normal expression (22 mutations in 30 alleles versus 8 mutations in 28 alleles; chi(2), P = 0.001). Biallelic inactivation was evident or inferred for 60% of MSH3-negative tumors but none of the tumors with normal MSH3 expression. In contrast, we did not identify frameshift mutations in the (A)8 tract of MSH3 in a control group of 18 colorectal carcinomas in which the MMR deficiency was based on the inactivation of MSH2. As it has been suggested that mutations of MSH3 might play a role in tumor progression, we studied the association between MSH3 expression and disease stage assessed by lymph node and distant metastases status. Dukes stages C and D were more frequent in primary tumors with loss of MSH3 expression (9 of 13), compared with tumors with retained expression (1 of 14; Fisher's exact test, P = 0.001), suggesting that MSH3 abrogation may be a predictor of metastatic disease or even favor tumor cell spread in MLH1-deficient colorectal cancers.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Proteínas de Unión al ADN/biosíntesis , Proteínas de Neoplasias/deficiencia , Proteínas Adaptadoras Transductoras de Señales , Alelos , Proteínas Portadoras , Neoplasias Colorrectales/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Progresión de la Enfermedad , Mutación del Sistema de Lectura , Humanos , Inmunohistoquímica , Pérdida de Heterocigocidad , Metástasis Linfática , Homólogo 1 de la Proteína MutL , Proteína 3 Homóloga de MutS , Estadificación de Neoplasias , Proteínas NuclearesRESUMEN
Hereditary nonpolyposis colorectal cancer (HNPCC) is one of the most common hereditary cancer-susceptibility syndromes. Germline mutations in mismatch repair genes are associated with the clinical phenotype of HNPCC. We report ten novel germline mutations, three in MSH2 and seven in MLH1. All but one mutation have been found in families fulfilling criteria of the Bethesda guidelines; four of them additionally fulfilled the Amsterdam criteria I or II. Eight mutations were considered pathogenic and predictive diagnostics in healthy family members at risk shall be undertaken; these include five frameshift mutations leading to premature stop codons, in MSH2: c.1672delT (p.S558Xfs) and c.2466_2467delTG (p.C822X) and in MLH1: c.1023delG (p.R341Xfs), c.1127_1128dupAT (p.K377Xfs) and c.1310delC (p.P437Xfs); three mutations leading to splice aberrations, in MSH2: c.1661G>C (r.1511_1661del) and in MLH1: c.677+3A>C (r.589_677del) and c.1990-2A>G predicted to result in a splice site defect. The remaining two mutations are unclassified variants with assumed pathogenicity: one missense mutation in the highly conserved ATPase domain of MLH1 (c.122A>G [p.D41G]) and one in-frame insertion of twelve nucleotides in MLH1 (c.2155_2156insATGTGTTCCACA [p.I719delinsNVFHI]). These two mutations were not found in 102 alleles of healthy control individuals. The corresponding tumors from all patients showed a high level of microsatellite instability (MSI-H). Immunohistochemistry (IHC) revealed complete loss of expression of the affected protein in the tumor cells from all but three patients. The tumors from the patients with the mutations c.1127_1128dupAT and c.1990-2A>G showed a reduction of expression of the MLH1-protein, rather than complete loss. In the tumor from the patient with the missense mutation c.122A>G [p.D41G] a normal expression of the proteins coded by MLH1 and MSH2 was noticed.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Proteínas de Unión al ADN/genética , Mutación de Línea Germinal , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Alelos , Disparidad de Par Base , Proteínas Portadoras , Codón sin Sentido , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Femenino , Mutación del Sistema de Lectura , Alemania/epidemiología , Humanos , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS , Mutagénesis Insercional , Proteínas Nucleares , Sitios de Empalme de ARN/genéticaRESUMEN
Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent hereditary form of colorectal cancer and is caused by germline mutations in mismatch repair (MMR) genes. The majority of mutations occur in MLH1 and MSH2. We report hereby seven novel germline mutations in these two genes (five in MLH1 and two in MSH2). All mutations have been found in families fulfilling criteria of the Bethesda guidelines and four of which also fulfilled the Amsterdam criteria. We identified three insertions or deletions of 1 bp leading to premature stop codons (MLH1: c.341delC, c.1413-1414insA; MSH2: c.1119delG) and three nonsense mutations (MLH1: c.67G>T [E23X], c.436C>T [Q146X]; MSH2: c.1857T>G [Y619X]). The corresponding tumors showed a high level of microsatellite instability (MSI-H) and a complete loss of expression of the affected protein. In addition, a missense mutation in MLH1 was identified (c.1984A>C [T662P]). The respective tumor also showed a high level of microsatellite instability but a reduced, rather then lost, expression of the MLH1-protein. This missense mutation was not found in 107 healthy control individuals and in 54 HNPCC patients.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Proteínas de Unión al ADN , Mutación de Línea Germinal/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Adaptadoras Transductoras de Señales , Adulto , Edad de Inicio , Anciano , Proteínas Portadoras , Neoplasias Colorrectales Hereditarias sin Poliposis/secundario , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS , Proteínas Nucleares , Epiplón/patología , Neoplasias Peritoneales/patologíaRESUMEN
Germline mutations in mismatch repair genes are responsible for hereditary nonpolyposis colorectal cancer (HNPCC), the most common hereditary cancer-susceptibility syndrome. We report six novel germline mutations, three in MSH2 and three in MLH1. All but one mutation have been found in families fulfilling the criteria of the Bethesda guidelines; two of them additionally fulfilled the Amsterdam criteria. We identified two nonsense mutations in MSH2 (c.1764T>G [p.Y588X], c.2579C>A [p.S860X]), one duplication of four nucleotides causing premature stop codon (MLH1: c.821_824dupAAGC [p.A275fsX307]), one splice site mutation resulting in skipping of exon 8 from the MLH1 transcript (c.677+3A>G), one duplication of 18 nucleotides leading to duplication of six amino acids in the mismatch-binding domain of MSH2 (c.4_21dup [p.A2_E7dup) and one missense mutation in the PMS2 interaction domain of MLH1 (c.1756G>C [p.A586P]). The three latter mutations were not found in 73, 90 and 94 healthy control individuals, respectively. The corresponding tumors from all patients showed a high level of microsatellite instability (MSI-H). Immunohistochemistry (IH) revealed complete loss of expression of the affected protein in the tumor cells from the patients with the nonsense, splice-site and missense mutation. The tumor from the patient with the c.821_824dupAAGC mutation showed a reduced, rather than lost, expression of the MLH1-protein.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Proteínas de Unión al ADN , Mutación de Línea Germinal , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Adaptadoras Transductoras de Señales , Proteínas Portadoras , Femenino , Humanos , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS , Proteínas NuclearesRESUMEN
Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the folate metabolism, which affects DNA synthesis and methylation. Low enzyme activity may reduce the capacity of DNA methylation, and possibly reduce uracil misincorporation into DNA, which can result in double strand breaks. Both processes may be critical for the oncogenic transformation of human cells. Two common amino acid-changing and enzyme activity-reducing nucleotide polymorphisms (677C --> T/Ala222Val and 1298A --> C/Glu428Ala) have been described in MTHFR. We performed estimations of the relative risk associated with these two polymorphisms in samples from 287 colorectal cancer patients, compared to 346 healthy controls. Relative risk were further determined for subpopulations of cancer patients having sporadic (n = 227) or suspected/verified hereditary disease (n = 60) and tumours exhibiting high-level microsatellite instability (n = 41) or not (n = 246). No significant differences for the relative risk of colorectal cancer were observed for the MTHFR genotypes either alone or in combination in the analysed cohorts, although the frequency of the 1298AA + AC genotypes was increased among the 60 cases with hereditary disease. Whereas our results do not support an association of high enzyme activity and increased risk of colorectal cancer in general, we can not exclude an association of patients with hereditary disease and the MTHFR 1298A --> C variant.
Asunto(s)
Adenoma/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Polimorfismo Genético , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Metilación de ADN , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2) , Repeticiones de Microsatélite , Persona de Mediana Edad , Oportunidad Relativa , Reacción en Cadena de la Polimerasa , Factores de RiesgoRESUMEN
Investigations into the pathogenesis of type 2 diabetes and islets of Langerhans malfunction (1) have been hampered by the limited availability of type 2 diabetic islets from organ donors(2). Here we share our protocol for isolating islets from human pancreatic tissue obtained from type 2 diabetic and non-diabetic patients who have undergone partial pancreatectomy due to different pancreatic diseases (benign or malignant pancreatic tumors, chronic pancreatitis, and common bile duct or duodenal tumors). All patients involved gave their consent to this study, which had also been approved by the local ethics committee. The surgical specimens were immediately delivered to the pathologist who selected soft and healthy appearing pancreatic tissue for islet isolation, retaining the damaged tissue for diagnostic purposes. We found that to isolate more than 1,000 islets, we had to begin with at least 2 g of pancreatic tissue. Also essential to our protocol was to visibly distend the tissue when injecting the enzyme-containing media and subsequently mince it to aid digestion by increasing the surface area. To extend the applicability of our protocol to include the occasional case in which a large amount (>15g) of human pancreatic tissue is available , we used a Ricordi chamber (50 ml) to digest the tissue. During digestion, we manually shook the Ricordi chamber(3) at an intensity that varied by specimen according to its level of tissue fibrosis. A discontinous Ficoll gradient was then used to separate the islets from acinar tissue. We noted that the tissue pellet should be small enough to be homogenously resuspended in Ficoll medium with a density of 1.125 g/ml. After isolation, we cultured the islets under stress free conditions (no shaking or rotation) with 5% CO(2;) at 37 °C for at least 48 h in order to facilitate their functional recovery. Widespread application of our protocol and its future improvement could enable the timely harvesting of large quantities of human islets from diabetic and clinically matched non-diabetic subjects, greatly advancing type 2 diabetes research.
Asunto(s)
Técnicas Citológicas/métodos , Islotes Pancreáticos/citología , Páncreas/citología , Diabetes Mellitus Tipo 2/patología , Humanos , Páncreas/cirugía , PancreatectomíaRESUMEN
BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer deaths despite the fact that detection of this cancer in early stages results in over 90% survival rate. Currently less than 45% of at-risk individuals in the US are screened regularly, exposing a need for better screening tests. We performed two case-control studies to validate a blood-based test that identifies methylated DNA in plasma from all stages of CRC. METHODOLOGY/PRINCIPAL FINDINGS: Using a PCR assay for analysis of Septin 9 (SEPT9) hypermethylation in DNA extracted from plasma, clinical performance was optimized on 354 samples (252 CRC, 102 controls) and validated in a blinded, independent study of 309 samples (126 CRC, 183 controls). 168 polyps and 411 additional disease controls were also evaluated. Based on the training study SEPT9-based classification detected 120/252 CRCs (48%) and 7/102 controls (7%). In the test study 73/126 CRCs (58%) and 18/183 control samples (10%) were positive for SEPT9 validating the training set results. Inclusion of an additional measurement replicate increased the sensitivity of the assay in the testing set to 72% (90/125 CRCs detected) while maintaining 90% specificity (19/183 for controls). Positive rates for plasmas from the other cancers (11/96) and non-cancerous conditions (41/315) were low. The rate of polyp detection (>1 cm) was approximately 20%. CONCLUSIONS/SIGNIFICANCE: Analysis of SEPT9 DNA methylation in plasma represents a straightforward, minimally invasive method to detect all stages of CRC with potential to satisfy unmet needs for increased compliance in the screening population. Further clinical testing is warranted.
Asunto(s)
Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/diagnóstico , Metilación de ADN , GTP Fosfohidrolasas/genética , Tamizaje Masivo/métodos , Adulto , Anciano , Algoritmos , Estudios de Casos y Controles , Neoplasias Colorrectales/genética , Femenino , GTP Fosfohidrolasas/sangre , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Sensibilidad y Especificidad , Septinas , Resultado del TratamientoRESUMEN
True aneurysms of the epigastric artery are rare. We report a case of a 65-year-old female who was admitted for increasing upper abdominal pain. A leukocytosis, pyrexia, breathing stop on inspiration, and a palpable mass next to the right costal arch with severe local pain were suspicious for acute cholecystitis. Surprisingly, sonography and CT scan revealed a 5 x 4 cm structure limited to the abdominal wall directly above the gallbladder, which showed an arterial flow in the duplex scan. After resection and an uneventful postoperative course, the histological findings confirmed the diagnosis of a symptomatic true atherosclerotic aneurysm.
Asunto(s)
Aneurisma/diagnóstico , Aterosclerosis/complicaciones , Colecistitis Aguda/diagnóstico , Arterias Epigástricas , Anciano , Aneurisma/etiología , Aneurisma/cirugía , Aterosclerosis/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Ligadura , Tomografía Computarizada por Rayos X , Procedimientos Quirúrgicos Vasculares/métodosRESUMEN
BACKGROUND: The formation of a sporadic abdominal aortic aneurysm (AAA) is explained by the remodeling of the extracellular matrix (ECM) and breakdown of structural components of the vascular wall. Matrix metalloproteinases are the principal matrix-degrading proteases and are known to play a major role in the remodeling of the extracellular matrix in arterial vessels. Their activity is controlled by tissue inhibitors of metalloproteinases (TIMPs). Decreased TIMP-1 and TIMP-2 expression in the extracellular matrix of the walls of AAAs has been shown in several studies. This case control study was designed to investigate the possible impact of genetic variants of the TIMP-1 gene in the etiology of AAA. METHODS: TIMP-1 single nucleotide polymorphisms (SNPs) were analyzed in a primary study sample of 50 patients with AAA and 44 controls. Differences in genotype and allele frequencies of identified polymorphisms were determined after sequencing the entire coding region and selected parts of the promoter using the automated laser fluorescence technique. A second sample (96 patients vs. 89 controls) was investigated by single-base sequencing to confirm significant results. RESULTS: Three polymorphisms were identified, one of which, described for the first time in this article, is located in intron 4 (TIMP-1: 328 + 16C > T). A statistically significant difference in allele frequencies for SNP TIMP-1 372T>C was detected in the primary study group. The C allele was more frequent in male patients with AAA than in the control group [23 vs. 4, p = 0.029, OR (95% CI) 4.38 (1.13-20.47)]. However, this result could not be confirmed in a second sample of males [52 vs. 45, p = 0.624, OR (95% CI) 1.16 (0.65-2.06)]. There were no statistically significant differences in genotype or allele frequencies of the other detected SNPs between the two groups. CONCLUSIONS: Our analysis of the entire coding region and selected parts of the promoter of the TIMP-1 gene failed to show an association between genetic polymorphisms and AAA, suggesting that variations in the TIMP-1 gene do not contribute to the development of AAA.
Asunto(s)
Aneurisma de la Aorta Abdominal/genética , Polimorfismo de Nucleótido Simple , Inhibidor Tisular de Metaloproteinasa-1/genética , Anciano , Anciano de 80 o más Años , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Población Blanca/genéticaRESUMEN
Germline mutations in human mismatch repair (MMR) genes yield a predisposition for the hereditary nonpolyposis colon cancer (HNPCC) syndrome. In contrast to hMLH1 and hMSH2, little is known about the overall involvement of hMSH6 in colorectal cancer. We investigated 82 tumors from patients who fulfilled the Bethesda guidelines for HNPCC as well as 146 sporadic tumors, analyzing microsatellite instability and expression of the 4 MMR proteins hMSH6, hMSH2, hMLH1 and hPMS2. Four tumors with lost expression and 1 tumor with cytoplasmic expression of hMSH6 were identified. Sequence analysis revealed germline mutations in 4 of the 5 patients, including 1 patient with sporadic disease. The lost or reduced expression of hMSH2 and hMLH1 was always identical to its heterodimerization partners, hMSH6 and hPMS2, respectively. Furthermore, hMSH2 expression was reduced upon hMSH6 deficiency. Abnormal expression of 1 or more of the 4 proteins was always associated with a high level of microsatellite instability (MSI-H). Conversely, all but 1 of the 44 MSI-H tumors had abnormal expression of 1 or more of the proteins, basically excluding additional genes associated with the MSI-H phenotype. We conclude that the involvement of somatic or epigenetic hMSH6 inactivation in colorectal cancer is rare.
Asunto(s)
Neoplasias Colorrectales/genética , Enzimas Reparadoras del ADN , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Repeticiones de Microsatélite/genética , Proteínas Adaptadoras Transductoras de Señales , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Adulto , Proteínas Portadoras , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Análisis Mutacional de ADN , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/metabolismo , Silenciador del Gen , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares , Fenotipo , Valor Predictivo de las Pruebas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
OBJECTIVE: To describe a genotype-phenotype correlation in MEN2 families with germline mutations of codons 790/791 and discuss options for the therapeutic management of gene carriers. SUMMARY BACKGROUND DATA: Heredity of MEN2 syndromes is caused by a heterozygous germline mutation in the protooncogene. Rare mutations of codons 790/791 associated with incomplete penetrant MEN2A/FMTC phenotype were reported in five families, contraindicating the prophylactic thyroidectomy for the genetically affected children. METHODS: Forty-five patients with a putative sporadic MTC were screened for germline mutations by direct DNA sequencing. Family members of identified index cases underwent genetic analysis. Gene carriers were examined clinically and biochemically, and all gene carriers underwent prophylactic thyroidectomy. RESULTS: Five index patients were identified, four of whom harbored mutations in codons 790/791 and one in codon 634. In the kindreds, four L790F carriers and one Y791F carrier were detected. The thyroid gland histology of L790F carriers revealed medullary thyroid carcinoma in two patients (aged 29 and 50 years) and C-cell hyperplasia in two additional patients (aged 9 and 16 years). The Y791F carrier had a normal histology. CONCLUSIONS: Codon 790/791 mutations had diverse penetrance. Whereas prophylactic thyroidectomy in children is a justifiable approach for codon 790 mutation carriers, the indication for thyroidectomy should depend on the clinical course of codon 791 carriers.