[Prenatal detection of genetic diseases. Experience with 317 diagnoses].
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Amniocentesis↗
Biomedical subjects
A Daver
Publications and source records attributed to A Daver.
Loss of heterozygosity at the ATM locus in colorectal carcinoma.
Patients homozygous for mutation of the ATM gene exhibit constitutional genetic instability and have a high risk of cancer. A-T heterozygotes also have an increased tendency to develop adenocarcinomas. Colorectal cancer (CRC) is the second most common cancer in western populations, and tumors of the right colon are typically highly genetically unstable. The DNA mismatch repair genes mutated in most familial and some sporadic CRCs account for one route by which cells acquire additional oncogenic mutations during the progression of malignancy. Mismatch repair defects, however, do not seem to account for the majority of CRCs. Because of its role in maintaining genomic stability, and the high risk of cancer to homozygotes, ATM is a candidate gene for inactivation in the evolution of chromosomal instability in tumor cells. We have examined 114 CRC patients for loss of heterozygosity (LOH) using six microsatellite markers tightly linked to the ATM locus. Our data suggest that LOH of this region is not associated with cancer of the proximal colon. In the distal colon, LOH was found in 23-31% of cases, which is moderately elevated above the non-specific LOH reported in tumors of this tissue. No correlations were found with regard to clinicopathological variables aside from tumor location.
Adult↗
Allelic imbalance at NBS1 is frequent in both proximal and distal colorectal carcinoma.
Nijmegen breakage syndrome (NBS) is a hereditary disorder involving chromosomal instability, cancer risk and radiosensitivity. NBS carriers have an increased risk of cancer, though the significance of mutations in the NBS1 gene in sporadic cancer has not yet been investigated. Because the loss of NBS1 is associated with increased chromosomal re-arrangements, and tumors of the colon are particularly prone to chromosomal anomalies, we have begun to study the NBS1 locus in colorectal cancer (CRC). DNA was isolated from 99 microdissected colorectal tumors, and microsatellite markers flanking the NBS1 locus at 8q21.3 as well as elsewhere on 8q were analyzed. Normal lymphocyte DNA from each patient served to normalize the amplification of each allele, and a reduction of at least 35% in the intensity of one allele was taken as evidence of allelic imbalance (AI). In proximal and distal CRCs we found 25.9 and 36.2% with AI at 8q21.3, respectively. AI in proximal CRC tended not to extend to marker D8S555 at 8q24.1, whereas in distal CRC the region of AI frequently included all the informative markers. AI of 8q21.3 was not associated with any clinical variable. These results suggest that 8q21.3 contains a tumor suppressor gene involved in proximal CRC, possibly NBS1. The large regions of AI make it difficult to determine the importance of AI at the NBS1 locus in distal CRC.
Alleles↗
[Value of carcinoembryonic antigens in cancers of the cervix and uterus].
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Carcinoembryonic Antigen↗
[CEA and therapeutic strategy especially in breast cancers].
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Adult↗
[Standardization and quality control in the evaluation of proliferation parameters in T1T2, N0N1, M0 breast cancer : multicentric retrospective study I. DNA synthesis enzyme activities].
As part of a clinical research project co-ordinated in Grenoble, six French institutions (CRLCC Angers, CHU Grenoble, Hospices civils Lyon, AP Marseille, CRLCC St-Cloud, CHU Tours) grouped together in order to study the following proliferative parameters in primary breast cancer: DNA synthesis enzymes [thymidine kinase (TK), thymidylate synthase (TS)], signal transduction enzyme [protein tyrosine kinase (PTK)] and S-phase fraction (%S). TK, TS and PTK were measured in cytosols using radio-enzymatic biochemical methods. S-phase was estimated using flow cytometry. The first step consisted in standardization and technical validation of the measurements. The second step consisted in the clinical validation by using a retrospective series of 1,003 breast cancers T1T2, N0N1, M0. We report the results of the first step, together with the distributions of the variables and their relationship with classical clinical variables: 1) Using standardized methods and a cytosolic control, a good reproducibility of measurements was obtained, whether assays were performed in one (TS, PTK) or in several laboratories (TK). 2) Significantly different distributions of TK and TS were observed between the different centres mainly due to different conditions of storage of tumours and cytosols. 3) A highly significant correlation was observed between TK, TS and PTK. Highest TK, TS and PTK levels were observed in tumours with high histological grade or receptor negative tumors. This study clearly illustrates the importance of quality assurance of multicentre studies.
Adult↗
Cytosolic p53 protein and serum p53 autoantibody evaluation in breast cancer. Comparison with prognostic factors.
Mutations of the TP53 gene induce the production of an abnormal protein (p53) with a prolonged half-life allowing its detection by monoclonal antibodies and leading to a development of serum p53 autoantibodies. We have quantified the protein p53 in 196 cytosols of primary breast cancer tissues, by an immunoluminometric method and searched for p53 autoantibodies in the sera of 101 patients, by an immunoenzymatic assay. The median value has been chosen as cut-off (0.26 ng/mg protein). 18.4% of tumors had a p53 level < 0.10 ng/mg protein, and 8.2% had a p53 level > or = 2.5 ng/mg protein (range: 0.43.37). We found a significant difference between p53 distribution (p = 0.003) and median level (p = 0.001) in ductal and lobular carcinomas. The p53 median levels were significantly different between the grade III versus the grade I tumors (p = 0.01) and versus the grade II tumors (p = 0.008). An inverse correlation was obtained between p53 levels and ER (p = 0.003) alone or with PR (p = 0.006). p53 autoantibodies were detected in 7.9% of cases (8/101). This p53 study shows correlations with some poor prognostic factors, but would require further evaluation to better define the patient groups with poor prognosis. The p53 detection autoantibodies is neither correlated with the p53 cytosolic assay nor with prognostic factors of breast cancer, and should therefore not be used for patient the selection of the patient groups with poor prognosis.
Adult↗
Specific H-Ras minisatellite alleles in breast cancer susceptibility.
Mutations in BRCA1 and BRCA2 genes account for the majority of familial aggregation of breast and ovarian cancers but other common genes in the population with low penetrance should be also involved in susceptibility to breast cancer. The H-ras minisatellite, located downstream of H-ras oncogene, is considered to be a likely candidate. Previous findings have estimated that as many as 1 in 11 cancers of the breast might be attributed to this region, but other studies observed inconsistent results. We propose to elucidate the potential role of H-ras locus in breast cancer, by looking at somatic alterations occurring in tumor DNAs such as the instability or the loss of heterozygosity (LOH) and by determining a potential correlation between constitutional specific H-ras alleles and clinical and/or pathological characteristics. DNA was extracted from 123 sporadic breast tumors and matched peripheral blood lymphocytes. 143 DNA samples from of peripheral blood lymphocytes from healthy donors served as a control population. The allelic diversity was determined by polymerase chain reaction analysis. Rare H-ras alleles were found to be present in about 9% of breast cancer patients while they were detected in only 1.4% of lymphocytes from healthy donors (P = 0.0044). Therefore, the risk of breast cancer is increased in patients with one or two rare alleles (odd ratio = 7.14 and 95% confidence interval = 1.94-22.27). Analyses of somatic alterations in tumor DNA have shown the lost of one allele, in general the longest, in 6.7% informative cases and an instability to H-ras locus in 6.5% tumors that appeared as a size increase of one of the two alleles. No correlation of rare H-ras alleles with clinicopathological parameters was found. Our results demonstrated an association of rare H-ras alleles with breast cancer and suggest that minisatellite H-ras may be considered as an informative marker for the breast cancer risk.
Adult↗
[Interpretation of the CA125 kinetics during first line chemotherapy of the ovarian cancer: methodological aspects and characteristic profiles].
Mathematical analysis of CA125 kinetics during first line chemotherapy allows calculation of various biologic parameters which are powerful indicators of the therapeutic efficiency. The purpose of this study is to present an original method of interpretation of CA125 kinetics based on both CA125 profile and its half-life value. The first part of this study reviews the practical modalities of CA125 kinetics analysis, the methods of calculation of the biologic parameters as well as the guidelines of interpretation. The second part of this work is dedicated to the presentation of CA125 profile characteristics in responders to chemotherapy, partially or totally nonresponders to chemotherapy, tumoral growth under treatment and tumor lysis syndrome.
Biomarkers, Tumor↗
Quantitative analysis of BRCA1, BRCA2 and Hmsh2 mRNA expression in colorectal Lieberkühnien adenocarcinomas and matched normal mucosa: relationship with cellular proliferation.
The human DNA mismatch repair gene hMSH2 is involved in the development of sporadic and hereditary nonpolyposis colorectal cancer. An increased risk of colorectal cancer has also been suggested in BRCA1 and BRCA2 mutation carriers. To address the relationship between the expression level of these genes and colorectal tumorigenesis, we studied BRCA1, BRCA2 and hMSH2 mRNA expression by real-time quantitative RT-PCR in 72 colorectal Lieberkühnien adenocarcinomas and matched normal mucosa. We investigated the relationship between mRNA levels and various clinicopathological parameters. The mean expression of BRCA1 3' and BRCA2 3' (mRNA pool), BRCA1 ex11 (with exon 11), BRCA2 ex12 (with exon 12) and hMSH2 mRNAs were increased in tumor samples. BRCA1 and BRCA2 mRNAs expressions were altered according to colon tumor site: BRCA1 3' and BRCA2 3' mRNAs levels were highest, respectively, in the right colon and left colon. No difference in hMSH2 mRNA levels was detected in relation to clinicopathological parameters. The mean SPF value was significantly higher in tumor than in non-tumor colonic tissue, and a high SPF value was correlated with high BRCA2 mRNA levels. BRCA2 3' mRNA levels tended to decrease as the Dukes' stage increased. In conclusion, the mechanisms of colorectal carcinogenesis seem to differ according to the right or left position of the tumor.
Adenocarcinoma↗
[Assay of serum elastase 1 in adenocarcinoma of the pancreas: diagnostic value, compared and combined study with serum CEA and CA 19-9].
Serum elastase 1, CEA and, CA 19-9 titers were determined by radioimmunoassay in 113 patients with benign non pancreatic digestive disease, 88 patients with non pancreatic carcinoma, 25 patients with chronic pancreatitis and 40 patients with pancreatic carcinoma (of whom 34 were classified according to Fortner's staging classification), respectively: a) to evaluate the diagnostic value of elastase in pancreatic carcinoma, b) to compare and to study the value of its association with CEA and CA 19-9 for earlier detection of this type of cancer. The specificity of serum elastase (greater than 500 ng/dl) was greater than that of CA 19-9 (greater than 37 U/ml), (93.3 p. 100 vs 64.6 p. 100, p less than 0.01), but its sensitivity was significantly lower than that of CA 19-9 (27.5 p. 100 vs 82.5 p. 100; p less than 0.001). The sensitivity of CA 19-9 (greater than 37 U/ml) and/or elastase (greater than 500 ng/dl) was 85.2 p. 100 (greater, but not significantly, than CA 19-9 alone) and 91.6 p. 100 in Fortner stage I or II tumors (greater, but not significantly, than Fortner stage III tumors which were at 83.6 p. 100). The specificity of the combined test was 62 p. 100, lower (but not significantly) than CA 19-9 alone. As serum CEA (greater than 5 ng/ml) alone and in association with CA 19-9 was disappointing, it might be replaced by the elastase assay. The combined CA 19-9-elastase assay coupled with morphologic investigations could represent an attractive approach for earlier detection of this cancer.
Adenocarcinoma↗
Immunostaining of colorectal cancer with monoclonal anti-CEA antibodies compared to serum and tumor CEA content.
Carcinoembryonic antigen was measured in serum and in extracts from 37 colorectal tumors and we found a poor correlation between circulating and tumor CEA. Monoclonal antiCEA antibodies were used in indirect immunoperoxidase staining of the corresponding formalin fixed tissue sections. We found that serum CEA measurement had a sensitivity of only 41.9% as compared to 90.3% for the immunohistochemical staining. The positive and negative predictive values for immunostaining were respectively 96.6% and 72.7%. Immunohistochemical staining of tissue sections with monoclonal anti CEA coupled to other biochemical or immunological assays could be a useful adjunct for the diagnosis of premalignant or slightly modified tissues.
Adult↗
Flow cytometric studies of colorectal tumors using fine needle aspiration.
The results are reported of cytofluorometric DNA analyses of colorectal tumors using cells obtained by mechanical disruption and fine needle aspiration. The latter method does not lower the level of debris or cell aggregates. We found a significantly higher proportion of aneuploid cells by needle aspiration. There was a good correlation between the data obtained by both methods, but for large heterogeneous tumors multiple site aspirations are needed to obtain representative specimens. Fine needle aspiration was found particularly useful for small tumors and polyps.
Biopsy, Needle↗
Association between H-ras minisatellite and colorectal cancer risk.
BACKGROUND: The H-ras locus has been suggested to play an important role in susceptibility to cancer. However, the results remain controversial. METHODS: In order to elucidate the potential role of the H-ras locus in colorectal carcinogenesis, 142 colorectal tumors with matched normal samples were studied for genomic instability and loss of heterozygosity (LOH), and 143 healthy samples of white blood cell DNA were examined by PCR, for H-ras allelic polymorphism. RESULTS: Nine percent of colorectal cancer patients constitutionally presented at least one rare allele versus 1.4% of healthy individuals (P = 0.0034). The risk of developing colorectal cancer increased significantly with the presence of rare H-ras alleles (odds ratio = 7.10 and 95% confidence interval = 1.92-26.35). The genotype associating one common allele and one rare allele was overrepresented in cancer patients (P < 0.01). No associations were observed between the rare alleles and tumor site or with the aggressiveness of cancer. Low frequencies of LOH (5%) and genetic instability (0.7%) at the H-ras locus were found in our colorectal cancer set. CONCLUSIONS: Consequently, the presence of uncommon alleles at the H-ras locus appeared to be an informative genetic marker.
Adenocarcinoma↗