[Periodical screening of families with a hereditary predisposition for breast carcinoma].
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
P Devilee
Publications and source records attributed to P Devilee.
Evidence for limited molecular genetic heterogeneity as defined by allelotyping and clonal analysis in nine metastatic breast carcinomas.
To investigate genetic intratumor heterogeneity, 42 samples of nine primary breast carcinomas and 29 related lymph node metastases were examined for DNA ploidy status, allelotype, and X chromosome inactivation pattern. Two primary breast carcinomas showed DNA index heterogeneity and five contained a single DNA aneuploid tumor stemline, whereas the two remaining primary tumors were solely DNA diploid. Most primary DNA tumor stemlines recurred in lymph node metastases (9 of 11). The allelotype, constructed with 31 different probes mapping to 23 different chromosome arms showed allelic imbalances on nearly all chromosome arms investigated. All tumors contained multiple allelic imbalances (range, 3-12). An allelic imbalance present in a primary tumor was consistently present in all DNA samples of that primary tumor and also in all DNA samples of related lymph node metastases, irrespective of DNA index heterogeneity. X chromosome inactivation pattern analysis with probe M27 beta (DXS255) confirmed the presence of clonal tumor cell populations in these tumors at the time of diagnosis. Densitometry of autoradiograms, which by eye showed retention of heterozygosity, revealed a narrow clustering of allelic imbalance factors between 1.0 and 1.4. In contrast, autoradiograms visually showing an allelic imbalance exhibited a marked interprobe, intertumor and intratumor variation in allelic imbalance factors. No relation between densitometry results and DNA ploidy status was found. Thus, at the time of diagnosis, an advanced primary breast carcinoma consists of a clonal tumor cell population with an established complement of allelic imbalances in all parts of the primary tumor and in the related lymph node metastases. Secondary to the establishment of allelic imbalances, intratumor heterogeneity for the copy number of involved alleles may develop, which in turn probably precedes metastasis.
Adult↗
PCR-based microsatellite polymorphisms in the detection of loss of heterozygosity in fresh and archival tumour tissue.
PCR-based microsatellite polymorphisms have proved their power in genetic linkage analysis and other identification methods, due to their high information content and even distribution over the chromosomes. In the present study we applied microsatellite polymorphisms to detect loss of heterozygosity in fresh (snap-frozen) and in archival ovarian tumour tissue. Clear allele losses were found in fresh and paraffin embedded tumour samples. Conventional Southern analysis of flanking markers on the same tumour DNA samples confirmed the observed losses detected by microsatellite polymorphisms. Titration experiments suggest that loss of heterozygosity remains detectable in tumour samples despite 60% contamination with normal DNA. This technique provides a fast and reproducible alternative to conventional Southern blotting in the detection of loss of heterozygosity, with the crucial additional advantages of minimal sample requirements, making archival material available for genetic investigation.
Adenocarcinoma↗
Linkage to markers for the chromosome region 17q12-q21 in 13 Dutch breast cancer kindreds.
We have performed linkage analysis with five markers for the chromosome region 17q12-q21 in 13 Dutch breast cancer kindreds in order to find support for the claim by Hall et al. that a gene in this region, termed "BRCA1," is associated with predisposition to early-onset familial breast cancer. This work is part of a collaborative study, the results of which are published elsewhere in this issue. Best evidence for linkage was observed with the marker CMM86 (D17S74) in pedigrees with an average age at onset of < or = 47 years (LOD score = 1.77 at 1% recombination). In one breast-ovarian cancer family with a high probability of being linked to 17q, we observed one putative recombinant between D17S250 and D17S579, which suggests that BRCA1 is proximal to D17S579.
Adult↗
Allele loss patterns on chromosome 17q in 109 breast carcinomas indicate at least two distinct target regions.
Loss of heterozygosity (LOH) of markers for chromosome 17 is the most frequent genetic change observed in breast cancer to date. To assess whether the location of several candidate target genes is compatible with patterns of allele losses in the individual tumors, we examined the LOH status of chromosome 17 in 109 primary breast tumors with 15 polymorphic DNA markers (three for 17p and 12 for 17q). Allelic imbalance (AI) at 17q was observed in 44 of the 97 informative cases. A significant correlation was found between AI at the long arm and AI at the short arm of chromosome 17. The patterns of AI on 17q in the tumors differed and were highly complex in some cases. A number of tumors showed AI distal to the growth hormone locus, whereas others showed AI exclusively proximal of this marker. These results indicate that there are at least two different regions of allele loss on 17q.
Alleles↗
Amplification of genes within the chromosome 11q13 region is indicative of poor prognosis in patients with operable breast cancer.
Amplification of the chromosome 11q13 region, which harbors the BCL1 region and the PRAD1, EMS1, HSTF1, and INT2 genes, was found in 36 (16%) of a series of 226 breast carcinomas. In the 153 patients with stage I-IIIa disease who had received no therapy prior to surgery and who were treated with curative intent, 11q13 amplification was associated with the presence of lymph node metastases (P less than 0.002). The presence of an 11q13 amplification was associated with a significantly shorter relapse-free survival (P less than 0.002) and a higher breast cancer-specific mortality (P less than 0.003). Stepwise multivariate analysis showed that, in addition to lymph node status, 11q13 amplification was the best predictor for short survival. Stratified log-rank analysis indicated that, within the group of lymph node-positive breast cancer patients, 11q13 amplification identifies a subgroup at high risk.
Breast Neoplasms↗
Fractional allelic imbalance in human breast cancer increases with tetraploidization and chromosome loss.
We have previously reported a complete allelotype study of 86 primary breast carcinomas, in which each non-acrocentric chromosome arm was studied with at least one polymorphic DNA-marker for the presence of allelic imbalance (AI, allelic loss or allelic gain) in the tumor. Here we report the statistical analysis of this data set, investigating the relationships between AI, DNA aneuploidy and several clinico-pathological parameters of tumor progression. AI on 13 different chromosome arms, including 3p, 11p, and 17p, correlated significantly with the total number of AI events at other sites, suggesting that they are progression-related events. AI at 1q and 16q did not show such a correlation and may thus represent earlier events. Mean fractional allelic imbalance (FAI) was significantly higher in flow cytometrically aneuploid tumors than in diploid tumors (0.27 vs. 0.17, p = 0.007), and was highest in hypotetraploid tumors (0.37). This suggests that tetraploidization followed by chromosome segregation may underlie the development of AI at multiple sites. No correlation was found between mean FAI and clinico-pathological variables such as lymph-node involvement, stage, age, estrogen-receptor content and development of distant metastases, although there was a noticeable trend towards impaired survival for those patients with a higher-than-median FAI value.
Alleles↗
Alpha satellite DNAs on chromosomes 10 and 12 are both members of the dimeric suprachromosomal subfamily, but display little identity at the nucleotide sequence level.
We have investigated the organization and complexity of alpha satellite DNA on chromosomes 10 and 12 by restriction endonuclease mapping, in situ hybridization (ISH), and DNA-sequencing methods. Alpha satellite DNA on both chromosomes displays a basic dimeric organization, revealed as a 6- and an 8-mer higher-order repeat (HOR) unit on chromosome 10 and as an 8-mer HOR on chromosome 12. While these HORs show complete chromosome specificity under high-stringency ISH conditions, they recognize an identical set of chromosomes under lower stringencies. At the nucleotide sequence level, both chromosome 10 HORs are 50% identical to the HOR on chromosome 12 and to all other alpha satellite DNA sequences from the in situ cross-hybridizing chromosomes, with the exception of chromosome 6. An 80% identity between chromosome 6- and chromosome 10-derived alphoid sequences was observed. These data suggest that the alphoid DNA on chromosomes 6 and 10 may represent a distinct subclass of the dimeric subfamily. These sequences are proposed to be present, along with the more typical dimeric alpha satellite sequences, on a number of different human chromosomes.
Base Sequence↗
HindIII polymorphism in the DCC gene.
Explore the source record for details and available documents.
Alleles↗
Differences in patterns of allelic loss between two common types of adult cancer, breast and colon carcinoma, and Wilms' tumor of childhood.
Several chromosomal regions exhibit loss of heterozygosity (LOH) in different types of human tumor, and on this basis are presumed to carry-suppressor genes. We studied 7 of such chromosome regions, including 3p, 5q, 11p, 13q, 17p, 18q and 22q, using a selected set of DNA markers in 44 Wilms' tumors, 64 breast and 83 colon carcinomas. In Wilms' tumor only the short arm of chromosome 11 was preferentially involved (38% of the informative cases), whereas in breast and colorectal carcinomas all investigated chromosome regions showed allelic loss at frequencies ranging from 19-61% and 12-55%, respectively. We tried to explain this difference in terms of developmental stages and tissue homeostasis of the organs involved. We postulate that more widespread occurrence of allele loss in colorectal and breast carcinomas compared to Wilms' tumor is associated with a difference in the differentiation status of the tissues at the time of tumor initiation.
Adult↗
Frequent somatic imbalance of marker alleles for chromosome 1 in human primary breast carcinoma.
Loss of heterozygosity at particular chromosomal loci in the tumor cell, as evidenced by restriction fragment length polymorphism analysis, has been taken as a hallmark of the presence of tumor suppressor genes. Recent studies of breast carcinoma have suggested that such genes might be located on the short as well as on the long arm of chromosome 1. We report here that comparison of constitutional and tumor genotypes of 84 breast tumors at 7 polymorphic chromosome 1 loci indicates a frequent imbalance of alleles on both 1p (12 of 61 informative patients) and 1q (37 of 71 informative patients). In about one-half of these cases, however, this imbalance was consistent with a gain in copy number of one allele in tumor DNA relative to normal DNA, rather than loss of the other. In 10 tumors we performed chromosome 1 enumeration in the interphase nucleus using in situ hybridization with a probe detecting the heterochromatin region at 1q12. These experiments confirmed the supernumerary presence of region 1q12 in those tumors showing an allelic copy number gain of 1q. We suggest that there are several genes on chromosome 1 serving as targets for these changes, some of them associated with breast cancer development through their deletion and others through an increase in copy number.
Alleles↗
Improved interpretation of complex chromosomal rearrangements by combined GTG banding and in situ suppression hybridization using chromosome-specific libraries and cosmid probes.
Chromosome aberrations of a hypodiploid ovarian carcinoma cell line (modal chromosome number 38) having a complex karyotype were analyzed using biotinylated DNA library probes that specifically hybridize to chromosomes 3, 6, 7, 8, 11, 13, and 16 from telomere (pter) to telomere (qter). A series of cosmid probes localized to the short arm of chromosome 16 were used to further investigate one of the two aberrant chromosomes 16 present in this cell line. The competitive in situ suppression (CISS) hybridization of DNA-libraries was mostly performed subsequent to GTG-banding of the same metaphase cell in order to interpret the hybridization signals optimally. This combined approach made it possible to detect the origin of chromosomal material that could not be identified using GTG-banding. Furthermore, the in situ hybridization techniques appeared to be helpful in the characterization of complex translocations and for accurate breakpoint determination.
Adenocarcinoma↗
Allelotype of human breast carcinoma: a second major site for loss of heterozygosity is on chromosome 6q.
Loss of heterozygosity (LOH), which is detected with polymorphic DNA markers by comparing constitutional and tumor genotypes, has been observed at a number of different chromosome arms in primary breast tumors. These include 1p, 1q, 3p, 11p, 13q, 17p and 18q. We present here the results of a screening of all non-acrocentric chromosome arms, including those of the X chromosome, with at least one polymorphic marker per arm, in a total of 86 breast carcinomas. This dataset, termed an allelotype, indicates that in addition to the chromosome regions listed above, allelic loss may be observed in more than 30% of informative cases on 6q, 8q, 9q, 15q, and 16q. Multiple LOH involving at least two different chromosomes in a single tumor was observed in approximately 75% of the investigated tumors, and revealed complex chromosome involvement. Six different combinations of concurrent LOH at two different chromosome arms were found to be significantly correlated (r greater than 0.45; P less than 0.01). Tumors showing LOH at 3p or 17p were preferentially aneuploid, while LOH at 6q and 17q was inversely correlated with the number of positive lymph nodes and age respectively.
Alleles↗
Somatic genetic changes on chromosome 18 in breast carcinomas: is the DCC gene involved?
Recently, a gene has been isolated from the long arm of chromosome 18 which was shown to be frequently deleted in colorectal carcinomas and hence designated the DCC gene (Fearon et al., 1990). To explore the possible involvement of this gene in breast cancer, we have used 5 polymorphic DNA markers (one for 18p, and four for 18q) to examine the status of chromosome 18 in 49 primary breast carcinomas by comparing the genotypes of lymphocyte and tumour DNA samples. Imbalance of alleles, resulting in allelic loss of duplication, was observed in 17 cases (38% of informative cases). In 13 of these, this imbalance included the locus D18S8 located within the DCC gene region. In the remaining 4 cases this locus was not involved, with the affected chromosome region mapping proximally of D18S8 in 3 cases, and distally in 1 case. These results indicate that chromosome 18 is rearranged in breast cancer more frequently than is expected on the basis of cytogenetic data alone, and warrant a closer inspection of the DCC gene in this tumour.
Alleles↗
Loss of heterozygosity in Wilms' tumors, studied for six putative tumor suppressor regions, is limited to chromosome 11.
Studies on the loss of heterozygosity (LOH) in human malignancies have shown that a number of different chromosomal regions associated with putative tumor suppressor genes may be involved in any one given tumor. We have carried out a similar study on Wilms' tumor using a range of DNA markers for a number of tumor suppressor regions. We tested a total of 44 Wilms' tumors including material from bilateral cases and from patients with Beckwith-Wiedemann syndrome, Drash syndrome, Perlman syndrome, and hemihypertrophy. In 11 of 36 informative tumors we found LOH for markers for the short arm of chromosome 11; only one of these tumors had additional LOH for regions 5q and 17p. No LOH was found for regions 3p, 13q, and 22q. Thus our findings support a major role for chromosome 11p in Wilms' tumor development and apparent noninvolvement of other tumor suppressor genes. No correlation was found between allelic losses and the International Society of Paediatric Oncology tumor stage or histology.
Child↗
Direct nonradioactive in situ hybridization of somatic cell hybrid DNA to human lymphocyte chromosomes.
Biotinylated DNA from various human-rodent hybrids was hybridized to human lymphocyte spreads after preannealing of the repeated sequences with sonicated total human DNA. Fluorescent labeling was achieved by successive treatments with fluorescein-labeled avidin and biotinylated antiavidin antibody. The use of labeled total DNA from hybrids with known chromosome composition permits the fluorescent staining-("painting") of specific chromosomes, or parts thereof, in human lymphocyte metaphases. Alternatively, the human chromosome content of cell hybrids with unknown chromosome composition is directly assessed from the labeling pattern of human lymphocyte spreads using the total hybrid DNA as probe.
Animals↗
Loss of heterozygosity on 17p in human breast carcinomas: defining the smallest common region of deletion.
The marker D17S5, mapping to the short arm of chromosome 17, was recently reported by us and others to undergo frequent heterozygous deletion in human primary breast carcinomas, implicating the presence of a tumor suppressor gene in this region. To narrow down the location of this gene more precisely, we have performed a deletion-mapping study in an extended series of 78 breast carcinomas, using nine polymorphic markers for the short arm and two polymorphic markers for the long arm of chromosome 17. Partial allele losses on 17p were observed in nine cases, which, taken together, suggest that the target gene for the deletions maps to the region extending between the markers D17S5 (17p13.3) and D17S67 (17p12).
Breast Neoplasms↗
Rapid subchromosomal localization of cosmids by nonradioactive in situ hybridization.
A rapid method for localizing large numbers of complete cosmids by nonradioactive in situ hybridization is described. The cosmids are nick translated in the presence of biotin-16-dUTP, incubated with an excess of sonicated human DNA, and used as a probe for in situ hybridization. Sites of hybridization are detected by successive treatments with FITC-labeled avidin and biotinylated anti-avidin antibody. Fifty-two cosmids were localized on chromosome 16 in 5 d relative to translocation breakpoints contained in two cell lines. Rapid identification of chromosome 16 was achieved by cohybridization with a chromosome 16-specific centromeric repeat probe.
Cell Line, Transformed↗