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Biomedical subjects

C Cornelisse

Publications and source records attributed to C Cornelisse.

13 recordsLinked to original sources
PubMed2001

A targeted mouse Brca1 mutation removing the last BRCT repeat results in apoptosis and embryonic lethality at the headfold stage.

A mouse model with a targeted mutation in the 3' end of the endogenous Brca1 gene, Brca1(1700T), was generated to compare the phenotypic consequences of truncated Brca1 proteins with other mutant Brca1 models reported in the literature to date. Mice heterozygous for the Brca1(1700T) mutation do not show any predisposition to tumorigenesis. Treatment of these mice with ionizing radiation or breeding with Apc, Msh-2 or Tp53 mutant mouse models did not show any change in the tumor phenotype. Like other Brca1 mouse models, the Brca1(1700T) mutation is embryonic lethal in homozygous state. However, homozygous Brca1(1700T) embryos reach the headfold stage but are delayed in their development and fail to turn. Thus, in contrast to Brca1(null) models, the mutant embryos do not undergo growth arrest leading to a developmental block at 6.5 dpc, but continue to proliferate and differentiate until 9.5 dpc. Homozygous embryos die between 9.5-10.5 dpc due to massive apoptosis throughout the embryo. These results indicate that a C-terminal truncating Brca1 mutation removing the last BRCT repeat has a different effect on normal cell function than does the complete absence of Brca1.

Animals↗
PubMed2000

Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer.

TP53 has been implicated in regulation of the cell cycle, DNA repair, and apoptosis. We studied, in primary breast tumors through direct cDNA sequencing of exons 2-11, whether TP53 gene mutations can predict response in patients with advanced disease to either first-line tamoxifen therapy (202 patients, of whom 55% responded) or up-front (poly)chemotherapy (41 patients, of whom 46% responded). TP53 mutations were detected in 90 of 243 (37%) tumors, and one-fourth of these mutations resulted in a premature termination of the protein. The mutations were observed in 32% (65 of 202) of the primary tumors of tamoxifen-treated patients and in 61% (25 of 41) of the primary tumors of the chemotherapy patients. TP53 mutation was significantly associated with a poor response to tamoxifen [31% versus 66%; odds ratio (OR), 0.22; 95% confidence interval (CI), 0.12-0.42; P < 0.0001]. Patients with TP53 gene mutations in codons that directly contact DNA or with mutations in the zinc-binding domain loop L3 showed the lowest response to tamoxifen (18% and 15% response rates, respectively). TP53 mutations were related, although not significantly, to a poor response to up-front chemotherapy (36% versus 63%; OR, 0.34; 95% CI, 0.09-1.24). In multivariate analysis for response including the classical parameters age and menopausal status, disease-free interval, dominant site of relapse, and levels of estrogen receptor and progesterone receptor, TP53 mutation was a significant predictor of poor response in the tamoxifen-treated group (OR, 0.29; 95% CI, 0.13-0.63; P = 0.0014). TP53-mutated and estrogen receptor-negative (<10 fmol/mg protein) tumors appeared to be the most resistant phenotype. Interestingly, the response of patients with TP53 mutations to chemotherapy after tamoxifen was not worse than that of patients without these mutations (50% versus 42%; OR, 1.35, nonsignificant). The median progression-free survival after systemic treatment was shorter for patients with a TP53 mutation than for patients with wild-type TP53 (6.6 and 0.6 months less for tamoxifen and up-front chemotherapy, respectively). In conclusion, TP53 gene mutation of the primary tumor is helpful in predicting the response of patients with metastatic breast disease to tamoxifen therapy. The type of mutation and its biological function should be considered in the analyses of the predictive value of TP53.

Aged↗
PubMed1998

Different calculation methods for flow cytometric S-phase fraction: prognostic implications in breast cancer? The Swedish Society of Cancer Study Group.

S-phase fraction (SPF), estimated in the flow cytometric DNA histogram, is a prognostic factor in breast cancer. There are, however, some inherent difficulties in the estimation of SPF, such as the influence of debris, aggregates, and normal cells. Most of the available SPF calculation principles try to consider these difficulties, but so far no consensus has been reached with regard to which principle is to be recommended. The aim of the present study was to investigate the prognostic impact of SPF when estimated with different calculation methods in frozen breast cancer samples from 350 patients. Two nonparametric (Rman, Rmin/both rectangle) and three parametric (ACAS/DNA-base, ModFit, and MultiCycle) calculation methods, with and without correction for debris and aggregates, were used. The mean values for SPF varied from 4.3% (ACAS/DNA-base with correction for debris and aggregates) to 9.4% (MultiCycle without any correction for background). The pairwise correlation between methods varied considerably (R = 0.72-0.98). After categorization of SPF values into low SPF (lower two tertiles) and high SPF (upper tertile), all methods yielded statistically significant Pvalues for recurrence-free survival (median follow-up time 67 months), both univariately (0.0004-< 0.0001) and multivariately (0.048-0.0004), after adjusting for nodal status, tumor size, and estrogen receptor status. SPF with background correction did not yield lower P values than SPF without. Regardless of which method was used, SPF showed similar correlations with lymph node involvement, tumor size, and estrogen receptor content. In conclusion, as the mean value of SPF for different calculation methods varies, each laboratory must be restricted to use only one method. Background correction does not seem to improve the prognostic impact of SPF in DNA histograms. Based on the experiences obtained in the present study, S-phase calculation methods without background correction may therefore be the most suitable for routine evaluation of DNA histograms of fresh frozen breast cancer material (ModFit, MultiCycle, and Rman [the latter only for experienced operators]). The nonparametric Rmin, with an automatic setting of the region used for SPF calculation, may be an alternative, but suffers from the disadvantage of not being commercially available yet.

Breast Neoplasms↗
PubMed1996

E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain.

We have analysed a series of 49 human breast cancers for mutations in the entire coding region plus flanking intron sequences of the E-cadherin gene. The tumours included 41 infiltrating lobular carcinomas, two infiltrating ducto-lobular carcinomas and six infiltrative ductal carcinomas. In the lobular carcinomas 23 different somatic mutations were detected, of which seven were insertions, 11 deletions, two nonsense mutations and three splice site mutations. The other tumours showed no detectable E-cadherin mutations. All the frameshift and nonsense mutations are expected to generate a secreted E-cadherin fragment instead of a transmembrane protein with cell adhesion activity. The majority of the mutations (21 of 23) were found in combination with loss of heterozygosity of the wild type E-cadherin locus (16q22.1), a hallmark of classical tumour suppressor genes. The mutations were scattered over the whole coding region and no hot spots could be identified. All mutations described here were previously unreported. In conclusion, we have identified up to now E-cadherin mutations in 27 of 48 (56%) infiltrating lobular breast carcinomas and in 0 of 50 breast cancers of other histopathological subtypes. These data provide strong evidence that frequent E-cadherin mutations are involved in the particular etiology of sporadic lobular breast cancers.

Binding Sites↗
PubMed1995

E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers.

Compelling experimental evidence exists for a potent invasion suppressor role of the cell-cell adhesion molecule E-cadherin. In addition, a tumour suppressor effect has been suggested for E-cadherin. In human cancers, partial or complete loss of E-cadherin expression correlates with malignancy. To investigate the molecular basis for this altered expression we developed a comprehensive PCR/SSCP mutation screen for the human E-cadherin gene. For 49 breast cancer patients the occurrence of tumour-specific mutations in the E-cadherin gene was examined. No relevant DNA changes were encountered in any of 42 infiltrative ductal or medullary breast carcinoma samples. In contrast, four out of seven infiltrative lobular breast carcinomas harboured protein truncation mutations (three nonsense and one frameshift) in the extracellular part of the E-cadherin protein. Each of the four lobular carcinomas with E-cadherin mutations showed tumour-specific loss of heterozygosity of chromosomal region 16q22.1 containing the E-cadherin locus. In compliance with this, no E-cadherin expression was detectable by immunohistochemistry in these four tumours. These findings offer a molecular explanation for the typical scattered tumour cell growth in infiltrative lobular breast cancer.

Base Sequence↗
PubMed1991

Isolation of two distinct epithelial cell lines from a single feline mammary carcinoma with different tumorigenic potential in nude mice and expressing different levels of epidermal growth factor receptors.

From a single spontaneous feline mammary carcinoma, two subpopulations of epithelial tumor cells have been isolated. The variant cells were established as cell lines designated K248C and K248P. DNA ploidy analysis showed that the two cell lines represented cell populations already present in the original tumor. Chromosome analysis confirmed the feline origin of K248C and K248P and demonstrated that in addition to unique marker chromosomes characteristic for each cell line, both cell lines had several marker chromosomes in common. These data suggest that the two cell populations arose from a hypothetical single ancestor which diverged during tumor progression. The K248C and K248P cell lines differed from one another with respect to their tumorigenicity in athymic mice and epidermal growth factor (EGF) receptor content. The K248C cells were highly tumorigenic as indicated by a short latency period and high take rate. The K248P cells were poorly tumorigenic. Southern blot analysis revealed that the K248C cells contained an amplified EGF receptor gene that was accompanied by elevated levels of EGF receptor RNA and protein. The K248C cells were growth inhibited in vitro at EGF concentrations that stimulated growth of K248P cells. The amplification of the EGF receptor gene could be detected only in DNA derived from K248C cells at high passage numbers and not in DNA derived from the original tumor and K248C cells at low passage numbers. These data suggest that amplification of the EGF receptor gene occurred during establishment of the K248C cell line.

Animals↗
PubMed1987

On the radiochemical quality control of [123I] sodium iodide for thyroid scanning.

Use of [123I]sodium iodide of too high specific activity in preparations for the diagnosis of disorders of the thyroid can lead to erroneous values for protein bound iodine and 24 h iodine uptake in the thyroid. Commonly used radiochemical quality control methods such as thin layer chromatography and the procedure described in the 21st edition of the U.S. Pharmacopoeia failed to reveal impurities in such preparations. A simple and quick check method is described, for indicating preparations unsuitable for diagnosis of thyroid disorders.

Humans↗
PubMed1987

Amplification of the neu (c-erbB-2) oncogene in human mammmary tumors is relatively frequent and is often accompanied by amplification of the linked c-erbA oncogene.

We investigated alterations in the structure and expression of oncogenes in mammary tumors and mammary tumor-derived cell lines. In 16 of 95 samples, we detected amplification of the human neu oncogene, also known as c-erB-2, accompanied by overexpression in the tumors from which intact RNA could be isolated. In 10 of these DNAs, the linked oncogene c-erbA was also amplified, whereas another gene on human chromosome 17, p53, was present in normal copy numbers. Overexpression of c-erbA could not be detected in the tumors analyzed. The relatively high frequency of neu amplification points to a functional role in human breast cancer. Coamplification of the c-erbA oncogene could contribute to this disease as well but is most likely fortuitous.

Age Factors↗
PubMed1986

Investigation of the zinc status of surgical patients--II. Influence of vascular reconstruction on the zinc status.

Patients admitted for major vascular reconstruction operations received an i.v. dose of 65Zn. From the increased whole-body retention of 65Zn and the findings on other parameters it was concluded that the was concluded that the post-operative zinc metabolism of these patients differed from that of the control subjects. Unexpectedly, this difference persisted for several months. These patients can probably serve as controls in studies of patients who have undergone surgery of the intestinal tract. Increase of whole-body retention of 65Zn may be a sensitive indicator for subclinical zinc deficiency, but application in practice is hampered by the long duration of the period required for the measurement. From the present results it seems likely that measurement of the retention of 65Zn in the forearm as a function of time yields the same information but in a considerably shorter time.

Aged↗
PubMed1985

Morphological, cytochemical, functional, and proliferative characteristics of four murine macrophage-like cell lines.

The aim of the present study was to obtain objective data on the morphology and quantitative information about other characteristics of murine macrophage-like cell lines J774.1, PU5-1.8, WEHI-3, and P388-D1, and to compare the findings with those in resident and exudate macrophages collected directly from mice. Fetal fibroblasts were included to serve as controls. Evaluation of the morphological data showed that the cell lines J774.1 and WEHI-3 are almost identical in most respects, that the cells of P388-D1 differ widely from both of the former lines, and that the morphometric parameters of cell line PU5-1.8 occupy an intermediate position. The cells of the P388-D1 line show the most similarity to resident and exudate macrophages, and cell lines J774.1 and WEHI-3 the least. Fetal fibroblasts had divergent values for all morphometric parameters. Good correspondence was found when the quantitative data obtained by morphometric analysis of the cells in question were compared with the morphological pictures. No gross differences as to cytochemical characteristics were found between the cells of the four cell lines, except for 5'-nucleotidase activity. The occurrence of IgG receptors and the ingestion of EIgG were also similar, but the percentage of cells with C3b receptors was much lower in two of the cell lines (WEHI-3 and P388-D1) and the level of EIgMC ingestion was very much higher in one (J774.1) compared with both the other cell lines and the resident and exudate macrophages. The ingestion of opsonized bacteria and latex varied widely within and between the cell lines. Quantitative data on the binding of monoclonal antibodies by the cells of the macrophage cell lines and the resident and exudate macrophages showed a wide variation. The doubling time of the cell lines is on average 1 day; distinct differences were found between these lines with respect to the lag-time of proliferation after replating. Cluster analysis and statistical analysis of morphological and other characteristics gave insight into the degree of resemblance between the cells of the four cell lines on the one hand and the resident and exudate macrophages on the other.

Animals↗
PubMed1984

Investigation of the zinc status of surgical patients.

Zn kinetics were studied in two surgical patients and compared with the findings in three controls. One patient had malabsorption following resection of part of the small intestine, the other was suffering from malabsorption due to radiation enteropathy incurred more than 10 years earlier. Whole-body retention of i.v. administered 65Zn, measured with a simple linear scanner, showed a sharp initial drop in the first patient, followed by an increased retention. This was explained by large initial intestinal losses of Zn leading to a state of Zn deficiency. In the second patient, who had developed Zn deficiency over a period of years, the whole-body retention was increased from the beginning. Compared with other parameters, whole-body retention seems to be a good indicator for the Zn status of patients, although of limited clinical use because the measurements take too much time.

Adult↗