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PubMedDate not supplied

Electroretinographic changes in eyes of patients with BRCA1 gene mutation.

AIM: To assess the retinal function in BRCA1 gene mutation carriers and to evaluate the clinical significance of its potential alterations. PATIENTS AND METHODS: Flash electroretinogram (ERG) was studied in 15 unaffected patients (30 eyes) with constitutional BRCA1 gene mutation. Routine ophthalmological examination was additionally performed in the oldest, unaffected 15 patients and in 15 breast cancer patients being carriers of BRCA1 mutation. RESULTS: In ERGs, in the maximal response, a-wave (p < 0.03) and b-wave (p < 0.05) amplitudes were reduced. In the cone single-flash response, the amplitude of a-wave (p < 0.007) was also reduced. In the oscillatory potentials (OPs), increased amplitude of OP2 (p < 0.03), and increased latencies of OP3 (p < 0.0009) and OP4 (p < 0.03) were obtained. BRCA1 carriers even at old age or after treatment of breast cancer have not presented increased frequency of abnormalities detectable by routine ophthalmological examination. CONCLUSION: It can be hypothesized that dysfunction of rods, cones and inner retinal layers is present in asymptomatic carriers of BRCA1 gene mutation; however, this does not have clinical consequences.

Adult↗
PubMed1997

Long-term follow-up of patients with chronic pancreatitis and K-ras gene mutation detected in pancreatic juice.

BACKGROUND & AIMS: Conflicting reports have raised the question whether K-ras gene mutations in chronic pancreatitis are related to the development of pancreatic neoplasm. The aim of the present study was to clarify this issue by surveying patients with chronic pancreatitis and K-ras gene mutation over 4 years. METHODS: K-ras point mutations at codon 12 in duodenal juices obtained during exocrine function tests were examined by enriched polymerase chain reaction-restriction fragment length polymorphism and direct DNA sequence analysis, and long-term follow-up of these patients was performed. RESULTS: K-ras gene mutation was found in 20 of 54 patients (37%) with chronic pancreatitis. The types of mutation were GAT in 7, GTT in 11, and TGT in 2 patients. Pancreatic neoplasm occurred in none of the mutation-positive patients over a mean follow-up period of 78 months. CONCLUSIONS: K-ras gene mutation in patients with chronic pencreatitis did not seem to be related to the development of pancreatic neoplasm during the follow-up period, and analysis of K-ras gene mutation seems of little use for diagnosing pancreatic neoplasm in patients with chronic pancreatitis.

Adult↗
PubMed2004

Impact of GSTT1, GSTM1, GSTP1 and NAT2 genotypes on KRAS2 and TP53 gene mutations in colorectal cancer.

Which carcinogens are of influence in the development of human colorectal cancers remains a question; one answer could be the finding that specific polymorphisms in xenobiotic metabolizing enzymes are related to particular mutations in cancer genes. KRAS2 and TP53 gene mutations as well as genotypes for GSTM1, GSTP1, GSTT1 and NAT2 were determined in an exploratory series of 165 stable colorectal cancers. Mutations in KRAS2 and TP53 were found in 34% and 57.5% of cases, respectively. The KRAS2 mutation frequency was significantly lower in patients with a GSTT1 null genotype than in those with a GSTT1 non-null genotype (18% vs. 38%, p = 0.03). The overall risk of KRAS2 mutation for patients with distal colorectal cancer and GSTT1 null genotype was 0.3 (95% CI 0.1-0.9) compared to patients with distal colorectal cancer and non-null GSTT1 genotype. The overall risk of KRAS2 mutation was similarly reduced (OR = 0.4, 95% CI 0.2-0.9) for patients with distal colorectal cancer and GSTP1 mutated genotypes compared to patients with distal colorectal cancer and wild-type genotype. Patients with GSTP1 wild-type genotype appeared to be at significantly lower risk for TP53 mutation compared to patients with mutated genotypes (p = 0.023). Our results suggest that GSTT1 and GSTP1 could play a role in the occurrence of KRAS2 and TP53 mutations in colorectal cancer and generate a hypothesis on the dietary factors that could be incriminated.

Adult↗
PubMed2006

Evaluation of the diagnostic value of serum tumor markers, and fecal k-ras and p53 gene mutations for pancreatic cancer.

OBJECTIVE: To evaluate the diagnostic value for pancreatic cancer of four serum tumor markers, carbohydrate antigen (CA) 199, CA242, CA50 and carcino-embryonic antigen (CEA), and fecal k-ras and p53 gene mutations. METHODS: From February 2002 to March 2004, 136 patients were consecutively diagnosed with pancreatic cancer in the three participating medical centers. The diagnosis was confirmed by pathology in 53 patients, of whom five were excluded because they did not have measurement of serum tumor marker. The remaining 48 patients comprised the case group in the study. Ninety-six patients with benign digestive diseases diagnosed during the same period were recruited as control subjects. They were matched by sex and age. In both groups, serum CA199, CA242, CA50 and CEA were measured by ELISA, and fecal k-ras and p53 gene mutations were measured by PCR-restriction fragment length polymorphism and PCR-single strand conformational polymorphism, respectively. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to compare their diagnostic value, as well as the sensitivity, specificity and likelihood ratio. Moreover, independent and sensitive tests from these non-invasive approaches were selected to form a parallel test that may have further improved sensitivity for diagnosis of pancreatic cancer. RESULTS: The AUC of serum CA199 and CA242 were 0.821 (95%CI 0.725-0.917) and 0.821 (95%CI 0.723-0.919), respectively. The optimal diagnostic value of serum CA199 for pancreatic cancer was 93 U/mL, with a sensitivity of 73.7% and specificity of 91.4%. The positive likelihood ratio of CA199 was 8.57, and the negative likelihood ratio was 0.29. The optimal diagnostic value of serum CA242 was 25 U/mL, with a sensitivity of 71.1% and specificity of 93.5%. The positive likelihood ratio of CA242 was 10.94, and the negative likelihood ratio was 0.31. The sensitivity of fecal k-ras gene mutation for diagnosis of pancreatic cancer was 77.4%, and the specificity was 81.2%. The positive and negative likelihood ratios of fecal k-ras gene mutation were 4.12 and 0.28, respectively. The sensitivity and specificity of fecal p53 gene mutation were 25.8% and 95.3%, respectively, and its positive and negative likelihood ratios were 5.49 and 0.78. The rate of fecal k-ras mutation was higher in patients with benign pancreatic diseases (57.14%) than that of controls with non-pancreatic disorders. The values of serum tumor markers and fecal k-ras and p53 gene mutation rates were not significantly different in subgroups according to site or stage of pancreatic cancer. The sensitivity and specificity of the parallel test of serum CA199 and fecal k-ras gene mutation were 94.06% and 74.22%, respectively, while the sensitivity and specificity of the parallel test of serum CA242 and fecal k-ras were 93.47% and 75.92%, respectively. CONCLUSIONS: Serum CA199 and CA242 are valuable diagnostic tools for pancreatic cancer. The diagnostic value is further improved when they are combined with fecal k-ras gene mutation measurement.

Aged↗
PubMed2005

Thrombophilic gene mutations in cirrhotic patients with portal vein thrombosis.

OBJECTIVE: Thrombophilic gene mutations have been reported to be associated with the formation of portal vein thrombosis (PVT). This study aimed to investigate the role of thrombophilic gene mutations in cirrhotic patients with PVT. PATIENTS AND METHODS: A total of 74 cirrhotic patients (17 with PVT, 57 without PVT), and 19 non-cirrhotic patients with PVT and 80 healthy controls were included. Factor V Leiden G1691A, prothrombin G20210A and methylenetetrahydrofolate reductase C677T mutations were analysed by restriction fragment length polymorphism. RESULTS: Aetiologies and Child-Pugh distribution of cirrhotic patients with and without PVT were similar. Five of 17 (29%) of cirrhotic patients with PVT but only two of 57 (3.5%) of cirrhotics without PVT, five of 80 (6%) of controls and none of the 19 non-cirrhotic patients with PVT had factor V Leiden G1691A mutation (P<0.05). Prothrombin G20210A mutation was found in five (29%) cirrhotic patients with PVT while only two (3.5%) cirrhotic patients without PVT, one (5%) non-cirrhotic patient with PVT and two (2.5%) controls had this mutation (P<0.05). The frequency of the homozygote methylenetetrahydrofolate reductase 677C-T mutation was similar in all four groups. CONCLUSIONS: Inherited thrombophilic gene mutations appear to increase the risk of PVT formation in cirrhotic patients but not in patients without liver disease in a cohort of Turkish patients.

Adult↗
PubMed2001

A novel WT1 gene mutation associated with wilms' tumor and congenital male genitourinary malformation.

WT1 is located on the short arm of human chromosome 11 and consists of 10 coding exons. Mutations of this gene have been reported to be the cause of Wilms' tumor, congenital male genitourinary malformations, and/or renal disorders. We describe here a novel WT1 gene mutation, i.e. a point mutation at intron 7 (+2) in both the tumor and the germline cells of a patient with Wilms' tumor and congenital male genitourinary malformation, but without renal disorder. The position of the mutation is at a splice donor site of intron 7, which causes the splicing out of exon 7 and generates a truncated protein. This type of mutation in the WT1 zinc finger domain has not been reported before. The mutation is of paternal origin and is heterozygous in the germline cells. In the tumor cells, however, the maternal allele is largely lost, from 11p12 to 11p15, which results in maternal loss of heterozygosity. These results, together with the data from previous reports, suggest that WT1 may function in gonadogenesis, nephrogenesis, and Wilms' tumor tumorigenesis.

Chromosomes, Human, Pair 11↗
PubMed1994

[Sequence analysis of N--ras and p53 gene mutation in the human lung adenocarcinoma cell lines].

Gene mutation and abnormal expression of ras oncogenes and p53 gene have a direct bearing on the carcinogenesis. Polymerase chain reaction (PCR), sequencing technique of ds DNA cycle and sequencing system were used to detect the gene mutation of N-ras as well as the exon 5 and 7 of p53 gene in hLA and LTEP-a2 cell lines of human lung adenocarcinoma. The result showed that mutation of both cell lines occurred on the 154th codon in exon5 of p53 gene, where GGC was displaced by GTC resulting a substitution of Val for Gly, nevertheless, N-ras oncogene and the exon7 of p53 gene are normal.

Adenocarcinoma↗
PubMed2001

Factor V Leiden and prothrombin gene mutation in inflammatory bowel disease in a Mediterranean area.

BACKGROUND: Thromboembolism has been reported to be associated with inflammatory bowel disease. AIM: To evaluate the association of factor V Leiden and prothrombin gene mutation with inflammatory bowel disease in a population of patients with thromboembolic events and inflammatory bowel disease and in a control population of patients with inflammatory bowel disease without thromboembolic events. PATIENTS AND METHODS: A series of 18 patients with inflammatory bowel disease and a history of arterial or venous thrombosis and 45 patients with inflammatory bowel disease without thromboembolic events were evaluated for the presence of factor V Leiden and prothrombin gene mutation. Frequency of gene mutation was compared with its occurrence in 100 healthy controls. RESULTS: One patient with inflammatory bowel disease without thromboembolic events was heterozygous for factor V Leiden mutation. whereas no patient with a thromboembolic event had factor V Leiden mutation. No patients (either cases or controls) had prothrombin gene mutation. In the healthy population the frequency of factor V Leiden and prothrombin mutation was 5% and 2%, respectively. CONCLUSIONS: Data emerging from the present study do not support any role of factor V Leiden and prothrombin gene mutation as the cause of thromboembolism in inflammatory bowel disease.

Colitis, Ulcerative↗
PubMed2006

The coincidence of chromosome 15 aberrations and beta2-microglobulin gene mutations is causative for the total loss of human leukocyte antigen class I expression in melanoma.

PURPOSE: Total loss of surface presentation of human leukocyte antigen (HLA) class I molecules, protecting tumor cells from the recognition by cytotoxic host CD8+ T cells, is known to be caused by mutations in the beta2-microglobulin (beta2m) gene. We asked whether abnormalities of chromosome 15, harboring the beta2m gene on 15q21, in addition to beta2m gene mutations, are causative for the HLA class I-negative phenotype of melanoma cells. EXPERIMENTAL DESIGN: To answer this, we established primary cell lines from the beta2m-negative metastatic melanoma tissues of four different patients and analyzed them for beta2m gene mutations and chromosome 15 aberrations, the latter by loss of heterozygosity analysis, fluorescence in situ hybridization (FISH), and multicolor FISH. RESULTS: Mutations at the beta2m gene level were detected in all cell lines. The loss of heterozygosity analysis of microsatellite markers located on chromosome 15 in three of the four cell lines pointed to an extensive loss of chromosome 15 material. Subsequent molecular cytogenetic analysis revealed the coexistence of apparently normal and rearranged versions of chromosome 15 in three cell lines whereas the fourth cell line solely showed rearranged versions. Two of the four cell lines exhibited a special type of intrachromosomal rearrangement characterized by FISH signals specific for the subtelomeric region of 15q at both ends of the chromosome and one centromeric signal in between. CONCLUSIONS: Our data indicate that the complete loss of HLA class I expression in melanoma cells is due to the coincidence of the following mutational events: (a) chromosome 15 instability associated with an extensive loss of genetic material and (b) beta2m gene mutations.

Cell Line, Tumor↗
PubMed2004

[The application of p53 gene mutation status in fecal specimen in the diagnosis of colorectal carcinoma].

OBJECTIVE: To explore the value of analysis of p53 gene mutation in fecal specimen in the diagnosis of colorectal carcinoma (CRC) in order to establish a non-invasive method for the screening of CRC. METHODS: The status of p53 gene mutation of the tumor tissues and corresponding fecal specimens was analyzed by polymerase chain reaction-single strand configuration polymorphism with EB staining in 40 CRC, 20 colorectal adenoma and 15 gastrocarcinoma. RESULTS: Amplification rates of fecal p53 gene were 90%, 85% and 93% in 40 CRC, 20 colorectal adenoma and 15 gastrocarcinoma, respectively. Total amplification rate was 89%. p53 gene mutation in tumor tissue was detected in 29 of 40 cases of CRC, 23 cases of which had p53 mutation in fecal specimens with the diagnostic sensitivity rate of 57.5%. Analysis of fecal p53 gene mutation had relatively higher diagnostic sensitivity rate than the detection of serum carcinoembryonic antigen and fecal occult blood (P < 0.05) for the diagnosis of CRC. 3 of 20 colorectal adenoma had p53 mutation both in tumor tissues and fecal specimens. 10 of 15 gastrocarcinoma had p53 mutation in tumor tissues but none in fecal specimens. CONCLUSIONS: Analysis of fecal p53 gene mutation has relatively higher diagnostic sensitivity rate for diagnosis of CRC and is expected to be a relatively sensitive, specific and effective method for early diagnosis of CRC, especially for CRC screening in large scale of the population.

Adult↗
PubMed2002

CFTR gene mutations in patients suffering from acute pancreatitis.

BACKGROUND: The aim of our study was to investigate the frequency of the CFTR gene mutation in a selected group of patients suffering from severe acute pancreatitis. MATERIAL/METHODS: DNA isolated from peripheral blood samples from forty-one subjects was analyzed for the eight most common CFTR gene mutations (deltaF508, G542X, G551D, R553X, 1717-1(G>A), W1282X, N1303K, deltaI507) by the reverse-hybridization technique, using INNO-LIPA CF2 test strips. The level of chloride ions in sweat samples was established using the pilocarpine iontophoresis method. RESULTS: In the study group, none of the patients harbored CFTR gene mutations. In these selected cases, the experiments were repeated twice to ensure the reliability of the results. All of the subjects had a normal level of chloride ions (range 8-38 mmol/l). Comparison with historical carriers revealed no differences between the frequency of carriers of the CFTR gene mutations in the general Polish population (4%) in comparison with the surgical patients with acute pancreatitis (p=0.26; Fisher exact test). CONCLUSIONS: We found no patients with severe acute pancreatitis who had CFTR gene mutations, suggesting that these alterations are not a risk factor for the disease in our population. Further studies are warranted to evaluate the frequency and role of rare ('mild') CFTR gene point mutations in subjects suffering from severe acute pancreatitis.

Adult↗
PubMed2001

[Study on p53 gene mutation in hepatocellular carcinoma patients in China].

OBJECTIVE: To study p53 gene mutation in human hepatocellular carcinoma (HCC) samples and the relationship between p53 gene mutation and hepatitis B virus (HBV) infection. METHODS: DNA samples were prepared from 50 specimens of HCC patients that had been infected with HBV. Exons 5-9 were amplified with polymerase chain reaction (PCR), and then detected by single strand conformation polymorphism (SSCP). RESULTS: Over 26% (13/50) of p53 DNA samples were found to be mutated, mainly in exons 5-8 relating to 3,3,4,3 cases respectively and along with 4 suspicious samples. CONCLUSION: p53 gene mutation might be one of the causes of HCC, and HBV infection may be associated with such mutation in China.

Adolescent↗
PubMed2001

Trypsinogen gene mutations in patients with chronic or recurrent acute pancreatitis.

Three-point mutations (R117H, N211, A16V) within the cationic trypsinogen gene have been identified in patients with hereditary pancreatitis (HP). A genetic background has also been discussed for idiopathic juvenile chronic pancreatitis (IJCP), which closely mimicks the clinical pattern of HP, and alcoholic chronic pancreatitis because only a small number of heavy drinkers develop pancreatitis. This prompted us to screen 104 patients in our well-defined pancreatitis cohort for the currently known cationic trypsinogen gene mutations. The R117H mutation was detected in seven patients (six patients of two clinically classified HP families, one patient with clinically classified IJCP) and the A16V mutation in one IJCP patient. No cationic trypsinogen gene mutations were found in the remaining 96 patients with chronic and recurrent acute pancreatitis of various etiologies. Our results demonstrate the need for genetic testing to exclude HP, particularly in the presence of an atypical or unknown family history. In addition, cationic trypsinogen gene mutations are no predisposing factor in patients with chronic and recurrent acute pancreatitis of different etiologies.

Acute Disease↗
PubMed1997

A frequent polymorphism of the gene mutated in ataxia telangiectasia.

The gene mutated in ataxia telangiectasia (AT), the ATM gene, has recently been cloned and shown to encode a multi-domain protein with homology to cell-cycle regulators. We report here an intragenic restriction fragment length polymorphism of the ATM gene that is common in the German population with allele frequencies of 0.56 and 0.44, respectively. Observed heterozygosity approximated 50% in healthy individuals as well as in 152 randomly selected breast cancer patients. We present a simple and rapid polymerase chain reaction (PCR)-based assay for this dimorphism that should be useful to trace the inheritance of ATM alleles in ataxia telangiectasia and breast cancer families and to study loss of heterozygosity in primary tumours.

Alleles↗
PubMed2004

[Experimental study on p53 gene mutation in keloid fibroblasts].

OBJECTIVE: To explore the significance and the role of the p53 gene mutation in the exon 4 to 8 in keloid fibroblasts. METHODS: Tissue samples from twelve patients with keloid and twelve hyperplastic scar respectively were harvested for in vitro culture of fibroblasts, and normal skin samples from the same patients were employed as the control. Polymerase chain reaction-based single-strained conformational polymorphism (PCR-SSCP) and DNA sequencing were employed to detect p53 gene mutations of the fibroblasts. RESULTS: The points and frameshift mutations in the exon 4, 5, 6, 7 of p53 gene were identified in 9 of the 12 keloid tissue samples. No p53 gene mutation was detected in all hyperplastic scar and normal skin samples. CONCLUSION: p53 gene mutation might play an important role in the formation and development of keloids.

Female↗
PubMed1999

Analyses of microsatellite instability and the transforming growth factor-beta receptor type II gene mutation in sporadic human gastrointestinal cancer.

Microsatellite instability (MSI) and transforming growth factor-beta receptor type II (RII) gene mutation have been reported in many types of tumors and their instance seem to vary among the tumors investigated. To determine the relation between MSI and RII gene mutation in sporadic gastrointestinal cancer development, 21 esophageal, 19 gastric, and 27 colorectal cancers were investigated. The presence of MSI was screened by single strand conformation polymorphism (SSCP) method using six microsatellite markers. RII gene mutations were detected by SSCP method and direct sequencing. MSI was detected in seven of 21 (33.3%) esophageal cancers, three of 19 (15.8%) gastric cancers and seven of 27 (25.9%) colorectal cancers. However, RII gene mutations were observed in only two of seven (28.6%) MSI-positive colorectal cancers. Our data suggest that among sporadic gastrointestinal cancers, colorectal cancers seem to be the most frequent target organ involved in carcinogenesis through RII gene mutation, which thus appears to be related to organ specificity.

Base Sequence↗
PubMed2005

[Analysis of gene mutation in Chinese patients with Reis-Bücklers corneal dystrophy].

OBJECTIVE: To identify the mutation of the TGFBI gene in Chinese patients with Reis-Bücklers corneal dystrophy, and to study the relationship between the gene mutation and the clinical appearance. METHODS: Ten patients and 2 unaffected family members from 2 unrelated families with corneal dystrophy were studied. Molecular genetic analysis was performed on DNA extracted from peripheral leucocytes, and exons 4 and 12 of the TGFBI gene were amplified by polymerase chain reaction for direct sequencing. RESULTS: Both pedigrees showed an autosomal dominant inheritance. The clinical appearance of the cornea consisted of fine granular, subepithelial opacities which spread and become confluent with time, and resembled geographic type of Reis-Bücklers corneal dystrophy. Direct sequencing of all affected members revealed a G-to-T transition at codon 124 (CGC to CTC), producing R124L mutation of TGFBI gene. CONCLUSIONS: R124L mutation of the TGFBI gene is found in two Chinese families with Reis-Bücklers corneal dystrophy. The phenotype of Reis-Bücklers corneal dystrophy in both families belongs to the geographic type. Molecular genetic approach may be useful for the proper diagnosis of this type of corneal dystrophy.

Adolescent↗
PubMed2003

[Detection and occurrence of BRCA 1 gene mutation in patients with carcinoma of the breast and ovary].

OBJECTIVE: The article presents a review of basic information on incidence and detection of BRCA 1 and BRCA 2 genes mutations. Results of investigation in a group of women with ovarian and breast cancer are presented. DESIGN: Retrospective clinical-laboratory study and review. SETTING: Department of Gynaecology and Obstetrics, 1st Medical Faculty of Charles University, Prague, Apolinárská 18, Czech Republic. MATERIAL AND METHODS: Investigated group consisted of 16 persons--12 patients with ovarian or breast cancer and 4 healthy relatives of a woman--breast cancer patient and a carrier of BRCA 1 gene mutation. Protein truncation test (PTT) was performed in order to detect BRCA 1 gene mutation. This test detects mutations leading to premature termination of protein synthesis. Truncated proteins are easily discriminated from full size. RESULTS: Three BRCA 1 gene alterations were identified in the investigated group of women suffering from ovarian or breast cancer. One asymptomatic person--carrier of BRCA 1 gene mutation--was identified in this study. She was daughter of a woman, a carrier of BRCA 1 gene mutation, with early onset of breast cancer and positive family history. CONCLUSIONS: BRCA 1 and BRCA 2 gene mutations are of particular importance in the increasing risk of ovarian cancer and early onset of breast cancer as well as some other malignancies. Genetic testing and counselling including investigation of some other genetic and environmental factors, related to cancer risk, may be of clinical significance in patients with increased risk of certain malignancies.

Adult↗