Genetic predisposition to cancer.
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Breast Neoplasms↗
Biomedical subjects
M H Skolnick
Publications and source records attributed to M H Skolnick.
Inheritance of proliferative breast disease in breast cancer kindreds.
Previous studies have emphasized that genetic susceptibility to breast cancer is rare and is expressed primarily as premenopausal breast cancer, bilateral breast cancer, or both. Proliferative breast disease (PBD) is a significant risk factor for the development of breast cancer and appears to be a precursor lesion. PBD and breast cancer were studied in 103 women from 20 kindreds that were selected for the presence of two first degree relatives with breast cancer and in 31 control women. Physical examination, screening mammography, and four-quadrant fine-needle breast aspirates were performed. Cytologic analysis of breast aspirates revealed PBD in 35% of clinically normal female first degree relatives of breast cancer cases and in 13% of controls. Genetic analysis suggests that genetic susceptibility causes both PBD and breast cancer in these kindreds. This study supports the hypothesis that this susceptibility is responsible for a considerable portion of breast cancer, including unilateral and postmenopausal breast cancer.
Adult↗
Identification of mutations in the COL4A5 collagen gene in Alport syndrome.
X-linked Alport syndrome is a hereditary glomerulonephritis in which progressive loss of kidney function is often accompanied by progressive loss of hearing. Ultrastructural defects in glomerular basement membranes (GBM) of Alport syndrome patients implicate an altered structural protein as the cause of nephritis. The product of COL4A5, the alpha 5(IV) collagen chain, is a specific component of GBM within the kidney, and the gene maps to the same X chromosomal region as does Alport syndrome. Three structural aberrations were found in COL4A5, in intragenic deletion, a Pst I site variant, and an uncharacterized abnormality, which appear to cause nephritis and deafness, with allele-specific severity, in three Alport syndrome kindreds in Utah.
Blotting, Southern↗
Detection of proliferative breast disease by four-quadrant, fine-needle aspiration.
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Biopsy, Needle↗
A gene mapping expert system.
Expert systems are now commonly developed to solve practical problems. Nevertheless, genetics has just begun to benefit from this new technology, since genetic expert systems are extremely rare and often purely experimental. A prototype for risk calculation in pedigrees was developed at the University of Utah, using a commercial frames/rules developmental shell (Intelligence Compiler), which runs on an IBM PC. When small data sets were used, the implementation functioned well, but it could not handle larger data sets. Performance became a major issue, with two possible solutions. The first possibility would have been to port the system to a more powerful machine, and the second would have been to use several different shells or languages, each efficiently representing a specific type of knowledge. Neither of these solutions was applicable in this case. From this experience, we learned that performance, portability, and modifiability were three major requirements for genetic expert systems. To achieve these goals, we implemented the gene mapping expert system GMES: (GMES is unrelated to the gene mapping system, GMS in Lisp combined with a frame/object shell (FROBS). We were able to efficiently represent, control, and optimize a gene mapping experiment, achieving portability by building GMES on top of a C-based version of Common Lisp. Lisp combined with the FROBS expert system shell permitted a declarative representation of each of the components of the experiment, resulting in a transplant specification of the problem within a maintainable system.
Algorithms↗
Augmented analgesic effects of L-tryptophan combined with low current transcranial electrostimulation.
The analgesic effects of low current transcranial electrostimulation are both naloxone and pCPA-reversible, suggesting that they may be mediated in part by endogenous opioid and serotonergic activity. The present experiments indicate that pretreatment with the serotonin precursor L-tryptophan results in an increased analgesic effect of electrostimulation as measured by the 50 degrees C wet tail flick test in the rat. Rats receiving both L-tryptophan and electrostimulation displayed significantly more analgesia than rats receiving electrostimulation and injection vehicle alone, rats receiving drug and sham stimulation or rats receiving vehicle and sham stimulation.
Analgesia↗
A genetic map of human chromosome 17p.
A genetic linkage map was constructed with 18 loci from the short arm and pericentric region of chromosome 17 typed on the CEPH reference families. The genetic map includes three markers extracted from the CEPH public database. Nine loci could be ordered using a threshold of odds of at least 1000:1 against alternative orders during the map construction process. With a reduced tolerance of 100:1, a total of 13 loci could be placed on the map spanning a distance of approximately 60 cM in females and 46 cM in males. There were statistically significant differences between the male and the female genetic maps. The order inferred from the genetic data was consistent with the physical localizations of these probes obtained from somatic cell hybrids and tumor deletion studies. This map should be useful for genetic fine mapping of 17p loci.
Alleles↗
Isolation, characterization, and physical localization of 33 human X-chromosome RFLP markers.
In a search for highly polymorphic X-specific loci, the X-chromosome DOE Ch35 phage library (LAOXNL01) was screened with three oligonucleotides representative of minisatellite consensus sequences. A total of 170 clones containing human inserts were isolated by hybridization to the oligonucleotide sequences; each was tested for polymorphism on five random female DNAs with six restriction enzymes. Among the 53 clones demonstrating a polymorphic pattern, 47 were of distinct origin. Twelve of the polymorphisms (23%) were determined to be autosomal. Polymorphisms for the remaining 35 clones were characterized, These polymorphisms represent 33 new X-chromosome RFLP loci, since two pairs of clones detected partially overlapping patterns. A pattern of similar length variation with multiple enzymes ("VNTR-type") was demonstrated in 6 (50%) of the 12 non-X-polymorphic clones. However, only 3 (9%) of the 33 X polymorphic loci showed VNTR-like patterns, suggesting a decreased amount of VNTR polymorphism on the X chromosome. The 33 polymorphic X loci were physically localized with a set of rodent x human somatic cell hybrid DNAs representing nine different X-chromosome breakpoints.
Base Sequence↗
Report of the committee on the genetic constitution of chromosome 20.
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Chromosome Mapping↗
Evidence against the reported linkage of the cutaneous melanoma-dysplastic nevus syndrome locus to chromosome Ip36.
The reported linkage between cutaneous melanoma and the dysplastic nevus syndrome (CM/DNS) to markers located on the distal portion of the short arm of chromosome 1 was examined in three Utah kindreds ascertained for multiple cases of melanoma. Family members in these kindreds were genotyped for the two markers reported to be most closely linked in the Bale study, PND and D1S47. Both melanoma alone and a combined melanoma/DNS phenotype were analyzed; no evidence for linkage was found. By multipoint linkage analysis the CM/DNS locus was excluded from an area of 55 cM containing the PND-D1S47 region. Diagnostic or genetic heterogeneity are alternate explanations for the discrepancy between our observations and those of Bale et al.
Chromosome Mapping↗
Histopathologic characteristics of dysplastic nevi. Limited association of conventional histologic criteria with melanoma risk group.
Studies of dysplastic melanocytic nevi (DMN) have suggested that lesions from patients with a personal or family history of malignant melanoma are histologically more atypical than are those from control populations without such histories. To evaluate this possibility, we examined histologic sections of DMN that had been removed from patients in three groups. Group A consisted of 17 subjects with a past history of melanoma; group B comprised 79 subjects with DMN and a family history of melanoma in first-degree relatives; group C consisted of 64 subjects who were unrelated spouses of members of groups A and B. For each group, sections of DMN were initially selected on the basis of architectural atypia as defined by the National Institutes of Health Consensus Conference. All biopsy material was then further evaluated for four histologic features suggested to be discriminatory for DMN associated with increased melanoma risk; the features are degree of junctional activity, irregularity of melanocytic nests, presence of dusty melanin, and size of melanocytic nuclei. A subjective rating was given for each on a 0 to 3 scale of increasing severity. Three pathologists individually rated the specimens without knowledge of the patient group. The means of the individual observer cumulative scores of the four histologic criteria for each biopsy specimen and the average of these means from the three observers exhibited a trend to increasing values from groups C to A, but none of the differences reached statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Characteristics of familial colon cancer in a large population data base.
Early age onset and proximal colonic location are two specific characteristics of colon cancer which have been used clinically to assess the risk that an individual case is of familial rather than sporadic origin. This practice derives from the observation that these characteristics are typical of the rare, nonpolyposis inherited colorectal cancer syndromes. This study examines these two characteristics in cases of common colon cancer to determine whether they actually distinguish individuals at increased risk for familial colorectal cancer. Familial clusters of colon cancer in the Utah Population Data Base were examined. Common colon cancers were found to cluster excessively in families; however, the measure of familial clustering for distal colonic cases was increased to the same degree as proximal colonic cases. Early age onset was likewise not a distinguishing factor of familial cases. These results suggest that factors other than those that predispose to the rare syndromes are important in determining familial risk for common colon cancers, and that the absence of these two clinical features should not suggest the absence of familial risk of colorectal cancer.
Adult↗
Restriction fragment polymorphisms of the HLA-DR, HLA-DQ, and insulin gene regions in IDDM: the GAW5 data.
The primary aim of the insulin-dependent diabetes mellitus (IDDM) component of Genetic Analysis Workshop 5 (GAW5) was to collect and analyze new data on DNA polymorphisms closely linked to the HLA-D region and the insulin gene. The probes and restriction enzymes described here were used by all ten participating labs, and the data from Southern blotting were interpreted and reported according to conventions developed for the Workshop. These DNA data on members of 94 families with two or more IDDM sibs constitute the largest such sample available. The data were used in most of the analyses presented at the Workshop meeting, and are available on request.
Chromosome Mapping↗
Applying expert system techniques to human genetics.
Although expert systems have been developed in a variety of medical areas, there has been very little application of expert system techniques to the field of human genetics. The purpose of the research project described in this paper was (1) to experiment with different types of knowledge representation for data and knowledge structures in human genetics and (2) to explore the applicability of different inference mechanisms for various genetic problems. We present an object-oriented and a fact-based model for the representation of genealogical information and describe two prototype systems.
Algorithms↗
HLA-linked hemochromatosis alleles in sporadic porphyria cutanea tarda.
We tested the hypothesis that the hepatic siderosis that characterizes sporadic porphyria cutanea tarda is due to the presence of HLA-linked hemochromatosis alleles. We studied 21 probands with sporadic porphyria cutanea tarda and 135 of their relatives by determining HLA haplotypes and measuring transferrin saturation and serum ferritin concentration. Liver biopsies were performed in all probands and in relatives when appropriate. Seventeen pedigrees were available and were studied by both likelihood analysis and by a gene counting method. We estimated that 10 of the 17 probands with available living relatives possessed at least one hemochromatosis allele. Thirteen of the 21 probands (62%) possessed at least one HLA-A3 alloantigen. Eighteen of 69 relatives who shared an HLA haplotype with a proband (26%) had an elevation of transferrin saturation or serum ferritin concentration. Only one first-degree relative not sharing an HLA haplotype with a proband had an elevated transferrin saturation or serum ferritin concentration. These findings indicate that HLA-linked hemochromatosis alleles are far more common in patients with sporadic porphyria cutanea tarda than in individuals in the general population and may be responsible for the hepatic siderosis associated with most cases of sporadic porphyria cutanea tarda.
Adult↗
Augmented analgesic effects of enkephalinase inhibitors combined with transcranial electrostimulation.
The analgesic effects of very low current transcranial electrostimulation are naloxone-reversible and thus presumably mediated by endogenous opioid activity. The present experiments indicate that blocking enkephalinase activity by i.c.v. thiorphan or i.p. acetorphan results in an increased analgesic effect of electrostimulation as measured by the 50 degrees C wet tail flick test. In the case of each drug, rats receiving both drug and electrostimulation displayed significantly more analgesia than rats receiving electrostimulation and injection vehicle alone, rats receiving drug and sham stimulation or rats receiving vehicle and sham stimulation.
Analgesia↗
The dysplastic melanocytic nevus: a prevalent lesion that correlates poorly with clinical phenotype.
We estimated the prevalence of persons with histologic dysplasia in at least one of two nevi examined by biopsy to be 53% in Utah's caucasians. This apparently high prevalence indicates that such lesions may represent a normal variant of a melanocytic nevus, perhaps those in the process of active proliferation. Regardless of the apparent ubiquity of these lesions, examination of biopsy specimens led to a grading scheme of histologic dysplasia that may reflect chronologic stages in the neoplastic development of melanocytic nevi. Comparison of these histologic findings with the clinical examination yielded the unexpected result that dysplasia and lesion size are independent of each other. Lesions 3 mm in diameter or smaller were as likely to be dysplastic as those much larger. There was, however, a statistically significant relationship between histologic dysplasia of a nevus examined by biopsy and the person's total number of melanocytic lesions. This finding indicates that the pathology grading scheme may be useful. The high prevalence of dysplastic nevi dilutes the clinical significance of a dysplastic nevus as an isolated finding and thereby lessens the importance of pathologic findings in the diagnosis of dysplastic nervus syndrome.
Adolescent↗
Low current electrostimulation produces naloxone-reversible analgesia in rats.
A new form of transcranial electrostimulation (TE) has been shown to induce analgesia in rats, as measured by the wet tail flick test. Charge-balanced rectangular current pulses of very low amplitude were delivered bilaterally into low impedance regions of the rat pinnae. The resultant analgesia was studied as a function of systematic variations in stimulus frequency, amplitude and duration. The optimal current for inducing analgesia was found to be 10 microA, well below the startle threshold, and several orders of magnitude below effective stimulus current levels required for other treatment modalities. The optimal stimulation duration was 30 min, during which time a slow onset of analgesia was noted. Significant analgesia persisted for at least 200 min after stimulation ended, and no evidence was found of tolerance developing in the course of 5 daily stimulation sessions. Consistent with findings for other forms of electrostimulation, the analgesic effect of TE was abolished by subcutaneous injection of 3 mg/kg naloxone, suggesting that the mechanism of TE analgesia has an endogenous opioid component.
Animals↗