Numerical chromosome alterations in colorectal carcinomas detected by fluorescence in situ hybridization. Relationship to 17p and 18q allelic losses

This study concerns DNA ploidy, numerical changes of chromosomes 7, 8, 10, 17 and 18, and allelic losses at chromosomes 17p13.3 (flanking the p53 gene) and 18q21 (location of the DCC gene) in 31 freshly resected colorectal tumours. Cytological smears were used to determine DNA ploidy by image analysis, and chromosome numbers by fluorescence in situ hybridization (FISH) using chromosome-specific pericentromeric alpha-satellite DNA probes. Allelic losses were assessed by Southern blotting and by the polymerase chain reaction loss of heterozygosity method. Approximately 50% of the tumours were aneuploid. There was heterogeneity with respect to chromosome numbers, but gains and losses of chromosomes, or both, were detected in all carcinomas examined, including 10 that were nonaneuploid by image analysis. Trisomy 7 was found in 74% of the tumours, and monosomy of chromosome 18 in 32%. Allelic loss at chromosome 17p13.3 was evident in 13 of 26 informative cases, and only one case exhibited monosomy 17. In comparison monosomy 18 was found in 10 cases; 7 of them corresponded to approximately half of the cases with allelic loss within the DCC gene, and the other three were noninformative. These findings indicate that the loss of one chromosome 18 is an important mechanism producing allelic deletion of the DCC gene in colorectal carcinomas. Our data also suggest that monosomy 18 is a useful indicator for studying colorectal cancer progression on a cell by cell basis.     

Frequent gains on chromosome arms 1q and/or 8q in human endometrial cancer

Comparative genomic hybridization (CGH) was employed to survey genomic regions with increased and decreased copy number of the DNA sequence in 15 endometrial cancers [10 cases with microsatellite instability positive (MI+) and 5 cases with MI-]. Twelve of these 15 tumors (80%) showed abnormalities in copy number at one or more of the chromosomal regions. There were no regions with frequent chromosomal losses. Conversely, 11 of 15 cases (73%) showed gains on chromosome arms 1q (8/15; 53%) and/or 8q (6/15; 40%). Concordant gains of both chromosome arms 1q and 8q were observed in all three endometrial cancers of histological grade 3. These results suggest that these two chromosomal regions may contain genes whose increased expression contributes to development and/or progression of endometrial carcinogenesis. Two cases were further analyzed by fluorescence in situ hybridization (FISH) using three probes on chromosome 1 and two probes on chromosome 8 to more accurately determine increases in copy number. We found gains of chromosome 1q to 2.9-3.6 copies per cell and on 8q to 4.4 copies per cell.     

Loss of heterozygosity at chromosome 6q in preinvasive and early invasive breast carcinomas

We have used polymerase chain reaction (PCR) analysis to study the incidence of allelic imbalance at four polymorphic microsatellite markers on chromosome 6q25.1-27, three dinucleotide repeats and one trinucleotide repeat, for microdissected tumour foci from a group of 75 'early' breast carcinomas. The tumours comprised 16 preinvasive cases of ductal carcinoma in situ (DCIS) and 59 mammographically detected early invasive carcinomas. Loss of heterozygosity (LOH) was detected at all four loci and in all types and grade of disease. The frequency of LOH ranged from 23% to 50% depending on the marker studied. The highest frequency of LOH was observed at the D6S186 locus for the cases of DCIS and at the oestrogen receptor locus for the invasive carcinomas. These data suggest that the inactivation of tumour-suppressor genes within this region on chromosome 6q is important for the development of these early lesions.     

Isolation of a pancreas-specific gene located on human chromosome 14q31: expression analysis in human pancreatic ductal carcinomas

We have isolated a novel cDNA (SEL1L) that shows sequence similarities to SEL-1, a gene identified as an extragenic suppressor of the lin-12 hypomorphic mutant from Caenorhabditis elegans (7, 8). SEL1L exhibits a tissue-specific pattern of expression: a single poly(A)+ RNA species of 7.5 kb is abundantly expressed only in the pancreas of healthy individuals, whereas low to undetectable levels are observed in other adult and in some fetal tissues. Somatic hybrid panel and fluorescence in situ hybridization positioned this gene in the q31 band of human chromosome 14. The tissue-specific expression of this gene induced us to study its role in human pancreatic carcinomas. Our analysis revealed that 17% of adenocarcinomas of the pancreas did not express SEL1L to a detectable level; however, no gross genomic alterations were apparent in the few hundred kilobases of the relevant region.     

Infrequent mutation of the H-cadherin gene on chromosome 16q24 in human breast cancers

To investigate the molecular basis of altered expression of the H-cadherin gene, we used polymerase chain reaction-single strand conformation polymorphism and DNA sequencing to examine the H-cadherin gene in 48 primary breast cancers in which loss of the long arm of chromosome 16 had been detected. We identified no mutations other than somatic 5-bp deletion within the coding region in a single tumor. The very low frequency of mutation found in these experiments suggests that H-cadherin is usually not a primary target for carcinogenesis in human breast cancers, and that reduction of its expression is likely to be a consequence of some other genetic event(s).     

Allelic imbalance study of 16q in human primary breast carcinomas using microsatellite markers

The high incidence of allelic imbalance on the long arm of chromosome 16 in breast cancer suggests its involvement in the development and progression of the tumor. Several loss of heterozygosity (LOH) studies have led to the assignment of commonly deleted regions on 16q where tumor suppressor genes may be located. The most recurrent LOH regions have been 16q22.1 and 16q22.4-qter. The aim of this study was to gain further insight into the occurrence of one or multiple "smallest regions of overlap" on 16q in a new series of breast carcinomas. Hence, a detailed allelic imbalance map was constructed for 46 sporadic breast carcinomas, using 11 polymorphic microsatellite markers located on chromosome 16. Allelic imbalance of one or more markers on 16q was shown by 30 of the 46 tumors (65%). Among these 30 carcinomas, LOH on the long arm of chromosome 16 was detected at all informative loci in 19 (41%); 13 of them showed allelic imbalance on the long but not on the short arm, with the occurrence of variable "breakpoints" in the pericentromeric region. The partial allelic imbalance in 11 tumors involved either the 16q22.1-qter LOH region or interstitial LOH regions. A commonly deleted region was found between D16S421 and D16S289 on 16q22.1 in 29 of the 30 tumors. The present data argue in favor of an important involvement of a tumor suppressor gene mapping to 16q22.1 in the genesis or progression of breast cancer.     

High frequency of allelic imbalance at chromosome region 16q22-23 in human breast cancer: correlation with high PgR and low S phase

PURPOSE: The validity and reproducibility of an instrumented dynamic examination method to measure sacroiliac (SI) joint stiffness was tested in vitro. METHODS: Four embalmed human female pelvises were excitated by a pelvic vibrator. A color Doppler imaging (CDI) scanner was used to image the amplitude of vibrations at different sites of the pelvis. Vibrations were applied to the anterior superior iliac spines unilaterally and were received by CDI all over the ipsilateral SI region. Three different stability conditions were created in the SI joints: no intervention, screwed and ligaments cut. Test results were quantified by taking the minimum threshold levels of the bones. The relative difference of vibration intensity between ipsilateral ilium and sacrum at each stability condition is accepted as the stiffness level for the SI joint. RESULTS: Statistics showed high reproducibility and significant differences between the stability conditions. Dynamic testing based on the use of vibrations provides visible and quantifiable intra- and inter-individual differences between SI joint stiffnesses. CONCLUSIONS: This new method is objective and reproducible. Future in vivo application is promising since there are no technical and safety restrictions.     

The human homologue of the retroviral oncogene qin maps to chromosome 14q13

Chromosomal mapping of the human QIN gene (renamed FKH2 by the Human Genome Organization Nomenclature Committee) was initially accomplished by correlation of the presence of the QIN locus with specific chromosome regions in a rodent-human hybrid panel. This analysis revealed that the human QIN gene maps to chromosome region 14q11.2-->14q32, between the TCR and IGH loci. Further analysis by fluorescence in situ hybridization techniques with a human QIN genomic clone refined the human QIN gene localization to 14q13.     

Identification of a 100-kb region of common allelic loss on chromosome bands 10q25-q26 in human endometrial cancer

A 10-year-old boy with Henoch-Sch?nlein purpura complicated by encephalopathy, transient cortical blindness, and a secondary generalized seizure is reported. Reversible changes in the posterior white and gray matter were seen on magnetic resonance imaging. Our patient illustrates uncommon neurologic manifestations of Henoch-Sch?nlein purpura. The nature and location of the lesions and the normalization of the patient's magnetic resonance imaging is consistent with a posterior predominant parieto-occipital encephalopathy and suggests that cerebral edema from blood-brain barrier breakdown may play a central role in the pathophysiology of the central nervous system symptomatology in some patients.     

Mutation at chromosome 11q23 in human non-familial breast cancer: a microdissection microsatellite analysis

We tested the hypothesis that time series analysis can provide accurate predictions of future poison center telephone call volume by a prospective stochastic time series modeling of calls to a university-based regional poison center. All callers evaluated and managed during two sequential years had the time and date of the call recorded in a computer database. Time series variables were formed for poison center calls per hour. Prediction models were developed from the 1992 data and included four types: raw observations, moving average, means with moving average smoothing, and autoregressive integrated moving average. Forecasts from each model were tested against observations from the first 26 weeks of 1993. Each model's adequacy was tested on residuals by autocorrelation functions, integrated periodograms, linear regression, and differences among the variances. A total of 44,584 calls were received in 1992 and 24,781 in the first half of 1993. Large periodic variations in call volume with time of day were found (p < 0.001). The model based on arithmetic means of each hour of the week with three-point moving average smoothing yielded the most accurate forecasts and explained 58.5% of the variation observed in the 1993 test series (p < 0.001). Time series analysis can provide powerful, accurate short range forecasts of future poison center telephone call volume. Simpler, less expensive models performed best in this study.     

Prognostic significance of allelic losses in primary melanoma

Loss of genetic material, including loss of loci on chromosome arms 6q, 9p, and 10q, occurs frequently in cutaneous melanoma but infrequently in benign melanocytic nevi or other melanocytic lesions, suggesting that these genetic alterations are important in the development and progression of melanoma. To examine whether allelic loss is of prognostic importance in melanoma, disease-free survival was related to loss of heterozygosity on 6q, 9p and 10q in 83 individuals with sporadic primary cutaneous melanoma. Loss of chromosome arms 6q and 10q were each significantly associated with a poorer clinical outcome (P=0.013 and P=0.001 respectively). In a subgroup of 41 subjects whose primary tumours were allelotyped, the fractional allelic loss (FAL) at 39 autosomal arms also significantly correlated with disease-free survival (P=0.013), with an increase in FAL associated with a poorer outcome; this association remained significant when controlled for tumour thickness (P=0.035). In addition, a greater proportion of cells were immunopositive for Ki67 antigen, p53 and p21WAF1 protein in the primary melanomas than in the benign melanocytic nevi, however, only p53 over-expression was significantly associated with improved survival (P=0.041).     

Four regions of allelic imbalance on 17q12-qter associated with high-grade breast tumors

Rearrangements or loss of chromosome 17 are frequent events in breast tumors. Chromosome 17 contains at least four genes implicated in breast cancer (TP53, ERBB2 (Her2/neu), BRCA1, and NM23), as well as other putative tumor suppressor genes and oncogenes implicated in loss of heterozygosity or allelic imbalance studies. Allelic imbalance represents the addition or loss of genetic material in tumor samples, providing circumstantial evidence for the location of cancer related genes. We have analyzed a panel of 85 breast tumor/normal tissue pairs with 21 PCR-based short tandem repeat (STR) markers located at 17q12-qter to more precisely define regions of allelic imbalance and to determine their relation to clinical parameters. Our analysis revealed at least four common regions of allelic imbalance: proximal to BRCA1, including D17S800 (17q12); distal to NM23 around D17S787 (17q22); near the growth hormone (GH) locus, at D17S948 (17q23-24); and between markers D17S937 and D17S802 (17q25). These data also reveal that loss (or gain) of 17q genetic material correlates with poorly differentiated (grade III) tumors (P = < 0.001), high S phase fraction (P = 0.034), and positive TP53 immunohistochemical staining (P = 0.011). However steroid receptor status, ERBB2 (Her2/neu) staining, and aneuploidy do not correlate with allelic imbalance at 17q.     

Structure and transcriptional regulation of the human mammaglobin gene, a breast cancer associated member of the uteroglobin gene family localized to chromosome 11q13

This research describes the development of the Marital Self-Disclosure Questionnaire (MSDQ), a brief, self-report measure of the quantity and quality of marital self-disclosure. Consisting of 40 true-false items, the MSDQ provides a global index of marital self-disclosure as well as assesses four facets of self-disclosure between spouses: Relationship, Sex, Money, and Imbalance. Results indicate that the MSDQ scales are reliable, and preliminary data suggest that the MSDQ may have validity for distinguishing among groups hypothesized to differ in terms of marital distress and self-disclosure. Further evaluation of the MSDQ for its clinical and research utility appears to be warranted.     

Linkage analysis of bronchial hyperreactivity and atopy with chromosome 11q13

There are two key clinical features of asthma: allergy and bronchial hyperreactivity (BHR). Some pedigree studies of atopy have indicated linkage with the high affinity IgE receptor (Fc epsilon RI-beta) gene on chromosome 11q13, but others failed to confirm this linkage. We examined the genetic linkage of three polymorphic microsatellite markers to atopy and BHR in 120 affected sibling pairs recruited from the general community. We found no linkage to atopy at any of the three 11q13 loci studied. Our findings also do not favour linkage between BHR and loci approximately 8-9 cM either side of the Fc epsilon RI-beta gene.     

Frequent allelic loss at 7p14-15 associated with aggressive histologic types of breast cancer

Cats were initially trained to make operant conditioned food responses to light by an "active selection of reinforcement" method. Provision of low-quality (a mixture of meat and bread) or high-quality (meat) reinforcement depended on the animal pressing a pedal in response to switching on a light with a short (1 sec) or long (10 sec) delay. Some animals responded to long delays--group I, animals with "self control," while others responded with short delays--group II, "impulsive" animals. Implanted semimicroelectrodes were used in chronic experiments to record multineuron activity in the basolateral amygdala. Cross-correlation analysis was used to study interneuron interactions in the spike discharges of individual neurons, extracted from multineuron activity. The numbers of interneuron interactions were significantly higher in "impulsive" cats of group II in all behavioral situations than in animals with "self control," and were dominated in "impulsive" animals by the shortest connections, with latencies of 0-30 msec. The largest numbers of connections in both groups were seen on omission of the conditioned pedal-pressing movement response, i.e., when the reinforcement selection task was more difficult. These data indicate that the basolateral amygdala should be regarded as a structure determining the individual typological characteristics of the animals' behavior.