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P Devilee

Publications and source records attributed to P Devilee.

At least 73 records · Page 4Linked to original sources
PubMed1996

Confinement of PGL, an imprinted gene causing hereditary paragangliomas, to a 2-cM interval on 11q22-q23 and exclusion of DRD2 and NCAM as candidate genes.

Paragangliomas of the head and neck region, also known as glomus tumours, are mostly benign tumours of neuro-ectodermal origin. We mapped the familial form by linkage analysis in 6 families to chromosome region 11q22-q23, between the markers STMY and CD3D which currently span a 16-cM interval. Here, we performed detailed haplotype analysis of this region in a single Dutch multibranch 7-generation family. A region of 2 cM between the markers D11S938/D11S4122 and D11S1885 was shared between all patients of whom disease haplotypes could be reconstructed. In support of this localization, a recombination observed in a small French family with 2 affected nieces places the PGL gene proximal to marker D11S908, genetically coincident with D11S1885.

Chromosome Mapping↗
PubMed1995

Identification of an EWS-pseudogene using translocation detection by RT-PCR in Ewing's sarcoma.

The presence of a t(11;22)(q24;q12) translocation is one of the characteristic features of the Ewing family of tumors. The detection of the fusion gene product by RT-PCR using primers at both sides of the breakpoints has been advocated as a diagnostic tool. By applying this technique appropriate internal controls are required. We found that the use of normal non-rearranged EWS mRNA as an internal control for RNA quality may lead to conflicting data. We obtained PCR products of the expected size for the normal EWS mRNA in both RNA and DNA samples, suggesting, the existence of one or more EWS pseudogenes. A 109 bp sequence at the 5' end of this PCR-product contained a correctly spliced exon junction and was 97% homologous to the EWS cDNA sequence. Similarly two such junctions were found in a 346 bp sequence of the 3' end, which was 89% homologous. Hence EWS should not be used as an internal control for the RNA quality in a RT-PCR based test for the presence of the translocation.

Base Sequence↗
PubMed1995

[Initial Dutch results with a presymptomatic DNA tests in familial breast/ovarian carcinoma. Rotterdamse Werkgroep voor Erfelijke Tumoren].

Recent discoveries in the field of molecular-genetic research make it possible to detect an increased genetic risk of tumours, because several genes are linked to hereditary forms of breast cancer. The breast cancer gene BRCA1, located on chromosome 17q, is quantitatively the most important gene so far. A BRCA1 gene mutation is estimated to occur in 1-3 per 1000 women in the general population, i.e. in about 10,000 women among the 4 million Dutch women aged 25-55 years. In this study experiences are described concerning oncologic, clinical-genetic and psychologic aspects in the first Dutch family in which a BRCA1-gene defect was detected with the corresponding hereditary breast/ovarian cancer syndrome. Of the relatives 88% participated in the genetic family study and 76% wished to be informed on the individual DNA-test results. From the first-degree relatives of the breast cancer patients 54% appeared to be gene mutation carrier. The detection of a gene mutation in a woman could make her decide to undergo preventive mastectomy and (or) ovariectomy, besides regular breast examination and mammography. Surgeons and radiotherapists, the group of doctors who treat primary breast cancer, have to anticipate more radical operations with regard to breasts in this selected group of (future) patients. Detection of the gene may also have consequences for family planning. Identification of carriers of the gene mutation can lead to a selection of women with increased risk of breast cancer. Primary or secondary preventive measures, early diagnostic management and regular examination may lead to a decrease in death from breast cancer.

Adult↗
PubMed1995

Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13.

Loss of heterozygosity (LOH) on chromosome 13 occurs on 25-30% of breast tumours. This may reflect the inactivation of the retinoblastoma susceptibility gene RB1. However, recently another candidate tumour-suppressor gene has been identified on chromosome 13 by linkage analysis, the breast cancer susceptibility gene BRCA2. To investigate the involvement of BRCA2 in sporadic breast cancer 200 breast tumours were tested for LOH on chromosome band 13q12-q14, using 11 highly polymorphic microsatellite markers. LOH was found in 65 tumours, which all showed simultaneously loss of BRCA2 and RB1. Of 12 breast tumour cell lines tested with polymorphic microsatellite markers, seven showed a contiguous region of homozygosity on 13q12-q14, suggesting LOH in the tumour from which the cell line had been derived. One cell line showed homozygosity in the BRCA2 region and heterozygosity at RB1. This is the only indication that BRCA2 is a distinct target for LOH on chromosome 13 in addition to RB1.

Alleles↗
PubMed1995

Mapping of the breast basic conserved gene (D16S444E) to human chromosome band 16q24.3.

The breast basic conserved gene (D16S444E) is a candidate tumor suppressor gene previously mapped to human chromosome 16. We determined the map position of D16S444E more precisely using a somatic mouse x human hybrid panel and fluorescence in situ hybridization on metaphase spreads and interphase nuclei. We show that the D16S444E gene is localized on band 16q24.3 and is located between APRT and D16S44.

Animals↗
PubMed1995

An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Breast Cancer Linkage Consortium.

The breast-ovary cancer-family syndrome is a dominant predisposition to cancer of the breast and ovaries which has been mapped to chromosome region 17q12-q21. The majority, but not all, of breast-ovary cancer families show linkage to this susceptibility locus, designated BRCA1. We report here the results of a linkage analysis of 145 families with both breast and ovarian cancer. These families contain either a total of three or more cases of early-onset (before age 60 years) breast cancer or ovarian cancer. All families contained at least one case of ovarian cancer. Overall, an estimated 76% of the 145 families are linked to the BRCA1 locus. None of the 13 families with cases of male breast cancer appear to be linked, but it is estimated that 92% (95% confidence interval 76%-100%) of families with no male breast cancer and with two or more ovarian cancers are linked to BRCA1. These data suggest that the breast-ovarian cancer-family syndrome is genetically heterogeneous. However, the large majority of families with early-onset breast cancer and with two or more cases of ovarian cancer are likely to be due to BRCA1 mutations.

Adult↗
PubMed1994

Somatic genetic changes in human breast cancer.

Quantitative imbalance in chromosomal material relative to the normal diploid situation is the most conspicuous genetic change in breast tumors, affecting virtually all chromosomes in varying frequencies. This imbalance is reflected by deviant DNA stemlines observed in DNA flow cytometry analysis, by numerical chromosome abnormalities in karyotype analysis and by loss of heterozygosity in DNA polymorphism studies. Gene amplification might be caused by the same genetic mechanisms that cause these chromosomal abnormalities [134]. The number of known genes for which there is now good evidence for their role in the development of breast cancer is still limited, and basically restricted to TP53 and ERBB2. Clearly, the estrogen receptor, not discussed here, can be conjectured to be of importance in breast cancer development, yet the significance of the reported sequence variants [157] for hormone-independent growth is presently undetermined [158]. For many others, such as MYC, CCND1, EMS1, EGF, RB1, NME, DCC and prohibitin, the evidence is still largely circumstantial, or obtained only by in vitro studies on breast cancer cell lines. In many cases of chromosomal imbalance and certainly those affecting whole chromosomes or chromosome arms, it is unclear what their effect on tumor growth will be, because multiple potential candidate genes are located in the affected region. In addition, it is obvious that multiple chromosomes are affected simultaneously in a single tumor, but that the total set of chromosome changes varies in different tumors. This intra- and intertumor heterogeneity of chromosome involvement suggests that an unknown number of the observed abnormalities are not important for tumor development, but merely result from genetic instability. On the other hand, there is accumulating evidence, particularly from flow cytometry and allelotype studies reviewed here, to suggest that the genetic evolution associated with tumor development and progression does reach a stage of equilibrium despite the presence of extensive tumor heterogeneity. The number of genetic events found per tumor raises the question whether each event of heterozygosity loss represents the second step in the inactivation of a tumor suppressor gene. Also, LOH observed with polymorphic markers can sometimes be interpreted as allelic copy number gain instead of loss. Possibly, some of these allelic imbalances contribute to the tumorigenic process simply because they create a dosage effect in certain gene products [2]. This supposes that the sole presence of allelic imbalance at certain chromosomes is sufficient to provide selective growth advantage in certain cases.(ABSTRACT TRUNCATED AT 400 WORDS)

Breast Neoplasms↗
PubMed1994

Evidence for a gene on 17p13.3, distal to TP53, as a target for allele loss in breast tumors without p53 mutations.

In breast cancer, loss of heterozygosity (LOH) on 17p is a frequent event and a likely target is the p53 gene on 17p13.1. However, several LOH mapping studies have indicated that, in some breast tumors, LOH affects only the most distal 17p markers, suggestive of a second tumor suppressor locus in 17p13.3. In order to distinguish which gene has most probably served as the target for LOH on 17p, we have screened 141 breast tumors for somatic mutations in the p53 gene in conjunction with detailed LOH mapping on the short arm of chromosome 17. A total of 32 mutations were detected in 31 tumors, 15 of which have never been reported in breast cancer before. The majority are point mutations leading to an amino acid change in the protein. In addition, we have stained a subset of 87 tumors for the p53 protein by immunohistochemistry. In 21 of these tumors (24%), nuclear staining was detected in over 25% of the tumor cells with the anti-p53 antibody DO7. A positive correlation was found between p53-positive staining and p53 mutation (P < 0.001). A strong association was observed between p53 mutation and LOH at the TP53 locus but not between p53 expression and LOH on 17p. In breast tumors without a detectable p53 mutation but with LOH on 17p, the 17p13.3 region is always involved and, in some cases, even exclusively involved. These results suggest that a second tumor suppressor gene, located distal to TP53, is targeted by LOH on 17p in some breast tumors and that a substantial number of breast tumors stabilize p53 through mechanisms other than mutation.

Alleles↗
PubMed1994

At least two different regions are involved in allelic imbalance on chromosome arm 16q in breast cancer.

Loss of heterozygosity (LOH) or allelic imbalance, the latter term referring to both loss and gain of an allele, on the long arm of chromosome 16 has been repeatedly found in cancers of, e.g., the breast and prostate. This indicates the presence of one or more tumor suppressor genes on 16q. To locate the gene(s) more precisely, a detailed allelic imbalance map of 20 polymorphic markers on this chromosome arm was made for 79 sporadic breast carcinomas. LOH of one or more markers was found in 63% of the tumors. Some had allelic imbalance on a region of 16q which failed to overlap with the LOH in other tumors. We therefore assigned two separate "smallest regions of overlap" to 16q and suggest that this chromosome arm contains at least two different tumor suppressor genes.

Alleles↗
PubMed1994

Allelotype of head and neck paragangliomas: allelic imbalance is confined to the long arm of chromosome 11, the site of the predisposing locus PGL.

Paragangliomas of the head and neck region are usually slow growing, benign tumors. A considerable fraction has a positive family history, and the predisposing locus, PGL, has recently been assigned to 11q22-q23. The inheritance pattern of the disease suggests that PGL undergoes maternal genomic imprinting. We have investigated 26 tumor samples from 22 patients with head and neck paragangliomas for the occurrence of loss of heterozygosity (LOH) on all non-acrocentric autosome arms. LOH was found only on chromosome 11, with a marked clustering on the distal half of the q-arm. However, in many cases the resulting allelic imbalance relative to normal DNA was weak, suggesting that only part of the tumor showed this abnormality. In all eight cases where we were able to determine the parental origin, the allele undergoing loss was maternally derived. Clonality analysis with a polymorphic marker for the X-chromosome indicated that two of three informative female cases were polyclonal, although a number of tumors carry aneuploid stemlines in DNA flow cytometry. We conclude that either tumor heterogeneity or polyclonality may explain the partial allele loss events seen in certain cases.

Alleles↗
PubMed1994

Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q.

Breast cancer in men is about a hundredfold less common than in women and this has hindered research into its genetic basis. We have examined 22 families with at least one case of male breast cancer for linkage to the hereditary breast and ovarian cancer locus, BRCA1, on chromosome 17q. We found strong evidence against linkage to BRCA1 (lod score-16.63) and the best estimate of the proportion of linked families was 0% (95% CI 0-18%). Our results indicate that there is a gene(s) other than BRCA1 which predisposes to early-onset breast cancer in women and which confers a higher risk of male breast cancer. Identification of additional pedigrees that include cases of male breast cancer may therefore facilitate the mapping and isolation of this gene.

Breast Neoplasms↗
PubMed1994

Recent developments in the molecular genetic understanding of breast cancer.

The molecular genetic characterization of breast cancer has implicated or identified the involvement of at least 10 distinct gene alterations in the genesis or progression of this disease. The genes involved fall into three distinct classes, possibly reflecting their particular function in the tumorigenic process. First, there is a class of genes that is being amplified to various levels in clinically manifest breast cancer, most conspicuously c-neu, c-myc, and cyclin D1. Second, an as-yet unknown number of genes are targets for loss of heterozygosity or allelic imbalance events on a number of different chromosomes. Presumably, this reflects the presence of tumor suppressor genes located on chromosomes 3p, 6q, 16q, 17, and possibly a few additional chromosomes. Finally, at least three genes are implicated to confer heritable predisposition to breast cancer. These include the p53 oncogene on 17p, an as yet unknown gene on 17q, and at least one locus outside these regions. While a number of presently unknown genes will soon be identified and cloned, it is becoming evident from genetic mapping studies that the complexity of gene involvement in breast cancer has not yet seen its very limits. A comprehensive multidisciplinary molecular profiling of a large series of tumors of various histological subtypes may aid in understanding how the different genes may cooperate to cause breast cancer.

Breast Neoplasms↗