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G Capella

Publications and source records attributed to G Capella.

At least 19 recordsLinked to original sources
PubMed2000

Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis.

O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair protein that removes mutagenic and cytotoxic adducts from the O6 position of guanine. O6-methylguanine mispairs with thymine during replication, and if the adduct is not removed, this results in conversion from a guanine-cytosine pair to an adenine-thymine pair. In vitro assays show that MGMT expression avoids G to A mutations and MGMT transgenic mice are protected against G to A transitions at ras genes. We have recently demonstrated that the MGMT gene is silenced by promoter methylation in many human tumors, including colorectal carcinomas. To study the relevance of defective MGMT function by aberrant methylation in relation to the presence of K-ras mutations, we studied 244 colorectal tumor samples for MGMT promoter hypermethylation and K-ras mutational status. Our results show a clear association between the inactivation of MGMT by promoter hypermethylation and the appearance of G to A mutations at K-ras: 71% (36 of 51) of the tumors displaying this particular type of mutation had abnormal MGMT methylation, whereas only 32% (12 of 37) of those with other K-ras mutations not involving G to A transitions and 35% (55 of 156) of the tumors without K-ras mutations demonstrated MGMT methylation (P = 0.002). In addition, MGMT loss associated with hypermethylation was observed in the small adenomas, including those that do not yet contain K-ras mutations. Hypermethylation of other genes such as p16INK4a and p14ARF was not associated with either MGMT hypermethylation or K-ras mutation. Our data suggest that epigenetic silencing of MGMT by promoter hypermethylation may lead to a particular genetic change in human cancer, specifically G to A transitions in the K-ras oncogene.

Adenine↗
PubMed2000

Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status.

The INK4a/ARF locus encodes two cell cycle-regulatory proteins, p16INK4a andp14ARF, which share an exon using different reading frames. p14ARF antagonizes MDM2-dependent p53 degradation. However, no point mutations in p14ARF not altering p16INK4a have been described in primary tumors. We report that p14ARF is epigenetically inactivated in several colorectal cell lines, and its expression is restored by treatment with demethylating agents. In primary colorectal carcinomas, p14ARF promoter hypermethylation was found in 31 of 110 (28%) of the tumors and observed in 13 of 41 (32%) colorectal adenomas but was not present in any normal tissues. p14ARF methylation appears in the context of an adjacent unmethylated p16INK4a promoter in 16 of 31 (52%) of the carcinomas methylated at p14ARF. Although p14ARF hypermethylation was slightly overrepresented in tumors with wild-type p53 compared to tumors harboring p53 mutations [19 of 55 (34%) versus 12 of 55 (22%)], this difference did not reach statistical significance. p14ARF aberrant methylation was not related to the presence of K-ras mutations. Our results demonstrate that p14ARF promoter hypermethylation is frequent in colorectal cancer and occurs independently of the p16INK4a methylation status and only marginally in relation to the p53 mutational status.

Carrier Proteins↗
PubMed1999

p53 and K-ras gene mutations correlate with tumor aggressiveness but are not of routine prognostic value in colorectal cancer.

PURPOSE: p53 gene and K-ras mutations are among the most common genetic alterations present in colorectal cancer. The prognostic utility of such mutations remains controversial. The purpose of this study was to prospectively evaluate the prognostic significance of p53 and K-ras gene mutations in colorectal cancer. PATIENTS AND METHODS: One hundred forty patients were analyzed. Tumors belonging to the microsatellite mutator phenotype were excluded (n = 8). Mutations at the K-ras and p53 genes were detected and characterized by restriction fragment length polymorphism, single-strand conformation polymorphism, and sequencing, as appropriate. RESULTS: p53 mutations were detected in 66 (50%) and K-ras mutations were detected in 54 (41%) of the 132 patients. In 26 cases (20%), ras and p53 mutations coexisted; in 38 cases (29%), neither mutation was found. Multivariate analysis of the whole population analyzed (n = 132) showed that survival was strongly correlated with the presence of p53 mutations alone or in combination with K-ras mutations (P = .002; log-rank test). When only patients undergoing a radical resection were considered (R0; n = 101), p53 mutations were no longer of prognostic significance. CONCLUSION: p53 mutations alone or in combination with K-ras mutations are correlated with a worse outcome. However, the routine use of these mutations as prognostic markers in the clinical setting is not recommended.

Adult↗
PubMed1997

Cancers of the papilla of vater: mutator phenotype is associated with good prognosis.

Cancer of the papilla (ampulla) of Vater is an uncommon disease that kills 60% of affected patients. There is general agreement that local spread of the tumor (T stage) is the only significant and independent prognostic factor for this cancer, whereas the predictive value of tumor grade and lymph node metastases is controversial. The genetic anomalies involved in this process have the potential to serve as additional prognostic markers. We explored 25 ampullary cancers for the occurrence of instability at simple repeat DNA sequences (microsatellites) of the type seen in replication error phenotype (RER-positive) cancers. Ten microsatellites from five different chromosomes were amplified by PCR from both normal and cancer tissue DNA of the same patients. A tumor was defined as RER-positive when microsatellite instability was found in the majority (>/=6) of the loci analyzed. Five cancers (20%) showed a RER phenotype and were associated with long survival of patients (32-96 months), whereas RER-negative cancers had a significantly poorer prognosis (Mantel-Cox test; P = 0.0084), with a median actuarial survival of 17 months. We also report that three (12%) patients belonged to cancer-prone families and four (16%) were cancer-prone individuals.

Actuarial Analysis↗
PubMed1996

Loss of sst2 somatostatin receptor gene expression in human pancreatic and colorectal cancer.

Five somatostatin receptor subtypes (sst1 to sst5) have been cloned. We demonstrated previously that sst2 and sst5 mediate the antiproliferative effect of the somatostatin analogues octreotide and vapreotide. Using reverse transcription-PCR, we investigated gene expression of the five receptors in 47 human normal and cancerous tissues or cell lines from pancreatic and colorectal origin. mRNAs of somatostatin receptor subtypes were detected in 98% of samples, with more than two mRNA subtypes being expressed in 55% of cases. sst1, sst4, and sst5 were heterogeneously expressed in both normal and cancerous tissues; sst3 was rarely or not expressed. sst2 was present in normal pancreatic tissues but was absent in exocrine pancreatic carcinomas and their metastases. sst2 mRNAs were detected in normal colon, sporadic polyadenomas, and 50% of Dukes' stage B and 20% of Dukes' stage C carcinomas but were undetectable in Dukes' stage D carcinomas, hepatic metastases, and adenomas from familial adenomatous polyposis. The loss of sst2 expression could represent a growth advantage in these tumors and provide an explanation for the lack of therapeutic effect of somatostatin analogues in such adenocarcinomas. A subtyping of somatostatin receptors should be carried out before considering a somatostatin analogue treatment in patients with colorectal or pancreatic cancer.

Cell Line↗
PubMed1996

p53 in a thyroid follicular carcinoma with foci of poorly differentiated and anaplastic carcinoma.

The clinical and pathologic features of a rare case of follicular carcinoma with small foci of poorly differentiated and anaplastic carcinoma are presented. Eight years after the removal of the primary neoplasm, the patient developed pulmonary and brain metastases that were predominantly composed of the poorly differentiated and anaplastic components. A comparative immunohistochemical and molecular analysis of p53 status in the follicular, poorly differentiated and anaplastic components of the tumor was performed. p53 immunostaining was restricted to the poorly differentiated and anaplastic areas. Single strand conformation polymorphism analysis (SSCP-PCR) from DNA obtained by microdissection demonstrated the presence of a mutation (TAT-->TGT; Tyr-->Cys) in codon 220, exon six of the p53 gene in the anaplastic component, that was absent in the well-differentiated follicular areas. The results of that study in this rare tumor support that p53 has a tumor progression role in thyroid tumorigenesis.

Adenocarcinoma, Follicular↗
PubMed1996

Ras oncogene mutations in thyroid tumors: polymerase chain reaction-restriction-fragment-length polymorphism analysis from paraffin-embedded tissues.

Ras mutations have been found in thyroid lesions. Different studies have shown different frequencies of mutations among benign and malignant lesions. The presence of point mutations in codons 12 and 13 of the c-K-ras, c-H-ras, and N-ras genes was studied in 58 thyroid lesions (10 nodular goiters, 10 follicular adenomas, and 15 papillary, 10 follicular, and 13 anaplastic carcinomas). DNA was extracted from formalin-fixed paraffin-embedded tissue, and target sequences were amplified in vitro by the polymerase chain reaction. Mutations were detected by the presence of restriction-fragment-length polymorphisms either occurring naturally or introduced artificially by the use of mutant primers. No characterization of the mutations was performed. Results were correlated with clinicopathologic features and patient follow-up. One goiter showed a mutation at codon 13, c-K-ras. All follicular adenomas, including three hyalinizing trabecular adenomas, were negative. Four papillary carcinomas presented mutations (one at codon 13, c-K-ras; three at codon 12, N-ras). Two follicular carcinomas showed mutations at codon 12, N-ras. Five anaplastic carcinomas showed mutations (two at codon 12 and two at codon 13, c-K-ras; one at codon 12, N-ras). In summary, the results confirm that ras oncogenes play a role in thyroid tumorigenesis, probably at an early step. Ras mutations appear not to be related to prognosis.

Adenoma↗
PubMed1995

[Low incidence of mutations in codon 12 of the c-K-ras gene in bladder cancer].

During vesical carcinogenesis a variety of genetic alterations such as oncogene mutation or loss of suppressor genes have been detected. Codon 12 mutation of the c-K-ras gene has been seen with a high frequency in several human neoplasias but its participation in the development of vesical cancers has not been fully dilucidated. Using the DNA restriction fragments polymorphism (RFLP) technique enhanced by a polymerase chain reaction (PCR) a study has been made of codon 12 mutation at the c-K-ras gene in 55 patient with vesical cancer undergoing surgery between 1991 and 1992. The tumoral stage was superficial (Ta-Tl) in 24 cases, infiltrant (T2-T4) in 28 cases and unknown in 3 cases. Two patients (3.6%) showed codon 12 mutation at the c-K-ras gene. One case was a fast evolving infiltrant tumour (T2-T3) which caused death of the patient after 4 months while the other case was a surface tumour (G2Ta) which relapsed early, the pathological anatomy revealing a stage T2-T3 squamous carcinoma. Our results suggest that codon 12 mutation at the c-K-ras gene is not a meaningful genetic change in the genesis of vesical cancer. Its emergence, however, appears to be related to a more aggressive tumoural behaviour.

Aged↗
PubMed1993

Genetic heterogeneity of the c-K-ras locus in colorectal adenomas but not in adenocarcinomas.

BACKGROUND: Previous molecular genetics studies of colorectal cancer have identified multiple mutations in the c-K-ras gene (also known as KRAS2) in all phases of its development. Because of technical difficulty, prior studies rarely focused attention on the detailed distribution of c-K-ras mutations in multiple regions of the same primary tumor specimen. However, with recent development of the selective UV radiation fractionation method, characterization of c-K-ras mutations in multiple regions of the same primary tumor specimen can be performed. PURPOSE: Our purpose was to describe how c-K-ras mutations were distributed among cells obtained from multiple regions of the same primary tumor in an attempt to describe differences between early and late colorectal carcinogenesis. METHODS: Formalin-fixed, paraffin-embedded tissue blocks were obtained. Seven adenocarcinomas and seven adenomas were selected for the presence of mutant c-K-ras genes and histologic transitions between normal and neoplastic tissue. Tissue sections were prepared for analysis by the selective UV radiation fractionation method by placing thin, fixed tissue sections on a plastic slide with no coverslip. Under the microscope, small ink dots from a felt-tip pen were manually placed directly on relatively pure cell subpopulations. The slides were placed with the tissue side exposed to a UV transilluminator for 2-4 hours to inactivate the DNA present in the unprotected ("undotted") cells. Individual dots were cut out of the plastic slide into 2 x 2-mm squares and placed into microfuge tubes. The DNA was extracted and supernatant used for polymerase chain reaction (PCR) analysis. Mutations at c-K-ras codons 12 and 13 were detected. RESULTS: The selective UV radiation fractionation method and PCR analysis revealed that c-K-ras mutations never extended into normal mucosa and were present in all neoplastic cells regardless of phenotypes in all seven adenocarcinomas and three of the seven adenomas. Further examination of two carcinomas for p53 (also known as TP53) mutations or loss of heterozygosity demonstrated that these additional mutations were also present in all tumor cells, suggesting that a single transformed clone was responsible for the majority of growth. However, in four other adenomas, tumor heterogeneity was demonstrated, since c-K-ras mutations were detected only in discrete portions. CONCLUSIONS: Adenoma formation may include a stage in which multiple and genetically distinct neoplastic clones are present, while most carcinomas appear to have a homogeneous composition that may result from the successful progression of one of these clones.

Adenocarcinoma↗
PubMed1992

Experimental study of the efficacy of the endoluminal prosthesis in colonic anastomoses.

Colorectal surgery is still associated with a significant morbidity and mortality rate, mostly related to suture failure. We have carried out a randomized experimental study in dogs on colonic anastomoses exposed to a number of anastomotic risk situations. A total of 42 dogs was used. They were divided into three study groups (control, occlusion and diverticulitis), with and without an endoluminal tube. The aim was to assess the efficacy of the endoluminal prosthesis using clinical and radiological assessment of anastomotic healing. Pre- and post-anastomotic intraluminal pressures were also measured to determine whether these might be a factor in suture failure. There were significant differences in suture failure in animals in which the endoluminal tube was used. Mean duration of placement was 10.5 days. In the colon healing study, no significant differences were found between the groups in the pathological examination or in the assay of hydroxyproline content. The presence of the endoluminal tube may increase the maximum pressure applied on the colon wall. No significant differences were found in the intracolonic pressure differentials between the different groups or after the inclusion of the endoluminal prosthesis. The results obtained establish the efficacy of the endoluminal prosthesis in protecting the colonic anastomosis, and could be a valuable technique in colonic anastomoses with a high risk of suture dehiscence.

Anastomosis, Surgical↗
PubMed1992

[Rebound hyperglycemia and peroperative normalization of insulinemia. Complete excision of insulinoma?].

Clinical usefulness of the hyperglycemic rebound and the normalization of plasma insulin level as intraoperative markers of complete removal of insulinoma was assessed. Surgical removal was curative (no clinical or biological recurrence) in six patients harboring a single adenoma (mean follow-up = 32.2 months). In these patients plasma glucose increased an average of 32 mg/dl 30 minutes after resection, 68 mg/dl after 60 minutes, and 91 mg/dl after 90 minutes. Sensitivity of hyperglycemic rebound (defined as a plasma glucose increment of at least 30 mg/dl after tumor removal) as a marker of complete resection of the insulinoma was 40% at 30 min and 83% at 60 minutes after resection. Preresectional values of plasma immunoreactive insulin were elevated in 3 out of 4 patients with adenoma. All postresectional values were within normal ranges. Two patients operated on because of malignant insulinoma, underwent partial tumor resection; hyperglycemic rebound was also present, and high preresectional insulin values became normal 30 minutes after partial tumor removal. We conclude that information provided by intraoperative monitoring of both plasma glucose and insulin cannot be used as the only markers of complete resection of all insulinomas. Only long term clinical and biological follow-up can guarantee the complete resection of an insulinoma.

Blood Glucose↗
PubMed1991

Frequency and spectrum of mutations at codons 12 and 13 of the c-K-ras gene in human tumors.

The frequency of point mutations at codons 12 and 13 of the c-K-ras gene has been determined in a panel of more than 400 human tumors. Mutant c-K-ras genes were detected in about 75% of adenocarcinomas of the pancreas (n = 84); 40% of adenomas (n = 72) and carcinomas (n = 244) of the colon end rectum; 30% of carcinomas of the bile duct (n = 19); 25% of carcinomas of the lung (n = 92), and in lower frequency in other carcinomas, including liver, stomach, and kidney. No mutations were found in carcinomas of the breast, prostate, esophagus, and gall bladder, among others. Comparative analysis of the spectrum of mutations show that while G to A transitions were the most frequent mutations in pancreatic and colo-rectal tumors, G to T transversions were more prevalent in lung carcinomas. The aspartic acid mutation at codon 13 (GGC----GAC) was relatively frequent in colo-rectal tumors but rare in pancreatic and lung carcinomas. The differences in the mutation spectrum of the c-K-ras gene in cancers of the gastrointestinal and respiratory tracts are suggestive of differential exposure to genotoxic agents.

Base Sequence↗
PubMed1991

[Gastric villous adenoma. 2 new cases].

Villous adenomas are extremely rare in the stomach. This type of lesion is characterized by its high capacity of malignant degeneration, as well as by its association with other tumors of the gastrointestinal tract. In this regard, we present two cases of villous adenoma of the stomach observed in our hospital, as well as a review of the characteristics of these tumors and of the treatment required.

Adenocarcinoma↗
PubMed1990

Mutational activation of the c-K-ras gene in human pancreatic carcinoma.

We have reported the presence of c-K-ras oncogenes activated by single point mutations at codon 12 in a vast majority of human pancreatic carcinomas. Formalin-fixed, paraffin-embedded specimens from surgical resections, autopsies and biopsies were used as well as snap frozen surgical specimens. The high oncogene incidence has been confirmed in other studies and indicate that somatic mutational activation of the c-K-ras gene is an important event in the development, maintenance or progression of cancer of the exocrine pancreas. While the role that these point mutations play in any or all of these processes remains to be determined, their presence is useful clinically for the diagnosis of pancreatic carcinoma at the molecular genetic level. The detection of mutated c-K-ras oncogenes in fine needle aspirates of pancreatic masses, that by cytomorphology may be suspicious but not diagnostic of malignant disease, increases the sensitivity of the diagnosis for this cancer. The identification of codon 12 mutations in the c-K-ras gene in pancreatic adenocarcinomas has been possible by advances in recombinant DNA techniques, especially by the development of in vitro gene amplification by the polymerase chain reaction (PCR). The possibility of analysing formalin-fixed, paraffin-embedded tissue for the presence of genetic alterations as small as single point mutations by PCR in concert with other mutation detection techniques, should facilitate the molecular genetic analysis of pancreatic carcinoma. Retrospective studies using stored specimens are now feasible with the technology described and should yield important information on the molecular epidemiology and aetiology of this and other diseases.

Adenocarcinoma↗
PubMed1989

[Laryngeal paraganglioma].

A case is reported of laryngeal paraganglioma observed among 49,959 patients. A comparison is made of the characteristics of paragangliomas in general to those of laryngeal paraganglioma, which are more common in males; the case presented is that of a woman. Microscopic dissection failed to reveal the paraganglia in the trajectories of the superior and inferior laryngeal nerves, but they were found in histological sections of these nerves and their images were equal to those of the tumor studied. The trajectory of these nerves was investigated in preparations of the Embrioteca de Bellaterra (Prof. Doménech Mateu) and the clumps of paraganglioma cells from which these tumors proceed have been found; we emphasize the concept of neural crest pathology to which they pertain.

Adult↗