Biomedical subjects

K C Halling

Publications and source records attributed to K C Halling.

25 records · Page 2Linked to original sources

PubMed1996

Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer.

To date, at least four genes involved in DNA mismatch repair, hMSH2, hMLH1, hPMS1 and hPMS2, have been demonstrated to be altered in the germline of patients with hereditary nonpolyposis colorectal cancer (HNPCC). Additionally, defective mismatch repair is thought to account for the observation of microsatellite instability (MIN) in tumors from these patients. The genetic defect responsible for the MIN+ phenotype in sporadic colorectal cancer, however, has yet to be clearly delineated. In order to better understand the role of somatic and germline alterations within hMSH2 and hMLH1 in the process of colorectal tumorigenesis, we examined the entire coding regions of both of these genes in seven patients with MIN+ sporadic colorectal cancer, 19 patients with familial colorectal cancer, and 20 patients meeting the strict Amsterdam criteria for HNPCC. Thirteen germline, two somatic, and four neutral alterations were identified. The two somatic mutations occurred in patients having familial cancer, while the germline mutations were distributed among one sporadic (14%), three familial (16%), and nine HNPCC (45%) cases. All patients with identified mutations in the mismatch repair genes, whose tumors were available for analysis, demonstrated MIN. On the other hand, we could not identify mutations in the subset of clinically defined HNPCC patients with MIN negative tumors nor in the majority (6/7) of MIN+ sporadic tumors.

Adaptor Proteins, Signal Transducing↗

PubMed1995

Microsatellite instability in keratoacanthoma.

BACKGROUND: Tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) and from a subset of patients with the related Muir-Torre syndrome (MTS) exhibit a novel type of genomic instability known as microsatellite instability (MIN). In general, this form of genomic instability results from mutations that inactivate DNA mismatch repair genes. The detection of MIN in a keratoacanthoma (KA) from a patient with MTS suggested that defective mismatch repair may play a role in the pathogenesis of these neoplasms. METHODS: Randomly selected paraffin embedded KA from 53 patients and paraffin embedded tumors from an additional 12 patients diagnosed with KA and colorectal carcinoma were examined for MIN at six loci. In addition, several KA were examined for mutations within the hMSH2 gene. RESULTS: Six of the 53 randomly selected KAs had MIN at two or more loci. One of these six patients had HNPCC, whereas another had MTS. Two patients with KAs lacking MIN had colon tumors that exhibited widespread MIN, and one of these patients had MTS. Three of the 12 additional patients diagnosed with a KA and a colorectal carcinoma had at least one tumor that had MIN at two or more loci, and one of these patients had HNPCC: A 2-base pair somatic deletion in exon 3 of the hMSH2 gene was identified in one of the MIN+ KAs. CONCLUSIONS: Defective mismatch repair appears to play a role in the process of tumorigenesis in some KAs. Microsatellite instability in a KA or the cooccurrence of a colorectal carcinoma and a KA in a patient suggests that the patient may have either HNPCC or its phenotypic variant MTS.

Aged↗

PubMed1995

Genomic instability in neoplasia.

Recent studies have demonstrated novel alterations of microsatellite DNA in tumor tissue. The alterations, termed microsatellite instability or replication error phenotype, have now been observed in tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC), the Muir-Torre syndrome (MTS) and in an increasing number of sporadic tumors. These observations, along with the use of genetic linkage analysis, have led to the identification of at least four genetic susceptibility loci for HNPCC, hMSH2, hMLH1, hPMS1 and hPMS2, each of which are involved in DNA mismatch repair. For those tumors demonstrating microsatellite instability, several different phenotypes may exist, the significance of which is currently unknown. Defective DNA mismatch repair may have important implications for the mechanism of tumorigenesis and the clinical behavior of tumors.

Colorectal Neoplasms↗

PubMed1994

Microsatellite instability in Muir-Torre syndrome.

Muir-Torre syndrome (MTS) is characterized by the presence of at least one sebaceous tumor and at least one visceral malignancy. Although a wide range of internal malignancies have been reported, the most frequently observed internal neoplasm is colorectal carcinoma. MTS and hereditary nonpolyposis colorectal carcinoma (HNPCC) share many clinical and pathological characteristics and thus may share similar genetic mechanisms of tumorigenesis. Recently, microsatellite instability (MIN) has been reported in tumor tissue from patients with HNPCC. In order to determine if tumors from MTS patients might also show MIN, we examined DNA extracted from paraffin-embedded tissues for the presence of MIN at (CA)n repeats on chromosomes 5q, 15q, 17p, and 18q. Data was obtained on 13 patients, 9 of which had at least one colorectal tumor. Of these, six demonstrated widespread MIN in all sebaceous and colorectal tumors examined, as well as in a transitional cell carcinoma of the renal pelvis, a prostatic adenocarcinoma and a keratoacanthoma. Overall, patients with MIN differed from patients without MIN in several respects, the most important of which include: (a) uniform presence and early onset of colorectal cancer (average age, 40 versus 70 years); (b) prolonged survival following diagnosis of visceral malignancy (median survival, 32 versus 11 years); and (c) a greater number of visceral and skin tumors. These data suggests that patients with MTS may be composed of at least two subgroups, each demonstrating different genetic, pathological and clinical features. Furthermore, the subgroup demonstrating MIN may share similar genetic mechanisms of tumorigenesis with patients having HNPCC, supporting the notion that these syndromes are allelic.

Adult↗

PubMed1994

Granuloma annulare in patients with malignant lymphoma: clinicopathologic study of thirteen new cases.

BACKGROUND: Reports of necrobiotic granulomas or granuloma annulare in patients with malignant lymphoma are rare. OBJECTIVE: Our intent was to determine any unique clinical or histopathologic features in patients with granuloma annulare and lymphoma. METHODS: We reviewed the medical records and biopsy material from 13 patients with granuloma annulare and lymphoma. RESULTS: Three patients had Hodgkin's disease and 10 had non-Hodgkin's lymphoma. The granuloma annulare lesions showed typical histopathologic features. However, the clinical pattern was frequently atypical, with painful lesions in unusual locations including the palms and soles. Three patients displayed granulomatous inflammation in noncutaneous sites, either within the malignant lymphoma or in uninvolved tissues, and all three had atypical clinical presentations of granuloma annulare. CONCLUSION: Granuloma annulare with atypical clinical presentations may be associated with an underlying hematopoietic malignancy and may be part of a generalized granulomatous reaction to malignant lymphoma.

Adult↗

PubMed1993

Human epithelial ovarian cancer allelotype.

To determine which chromosomes and chromosomal regions contain putative tumor suppressor genes important for human epithelial ovarian cancer, we performed loss of heterozygosity (LOH) studies on 37 primary epithelial ovarian tumors. Using 70 polymorphic markers, we examined all chromosome arms (excluding acrocentric arms) on all specimens. Our findings show a high frequency of LOH for the following chromosome arms: 5q (43%); 6p (62%); 6q (57%); 7p (36%); 8p (40%); 9q (54%); 13q (56%); 14q (47%); 15q (36%); 17p (81%); 17q (76%); 18q (43%); 21q (36%); and 22q (71%). When separated into low and high grade tumors, there were statistically significant differences of LOH for the following chromosome arms: 6p (29% versus 70%); 13q (0% versus 72%); 17p (33% versus 90%); and 17q (29% versus 87%). No statistically significant difference was found between different histological subtypes. The average fractional allelic loss for low grade tumors was 0.17 versus 0.40 for high grade and 0.35 for all tumors. In an effort to more specifically localize common regions of molecular genetic deletion, we examined the following chromosomes in greater detail: chromosome 13 (5 markers); chromosome 17 (8 markers); and chromosome 6 (8 polymorphic markers). No tumor showed deletion of only a portion of chromosome 13. When any informative marker for chromosome 13 showed loss, all markers showed loss. Similarly, the tumors of most patients demonstrated LOH of all informative markers that map to chromosome 17; however, regional deletion of 17p markers was observed in 3 tumors. Twelve tumors demonstrated regional deletions of portions of chromosome 6. These tumors suggest that at least 2 regions of chromosome 6 are important for ovarian epithelial carcinogenesis. One region appears to be on distal 6q and a second region is near the centromere of chromosome 6 proximal to the HLA locus.

Alleles↗

PubMed1985

Genomic cloning and characterization of a ricin gene from Ricinus communis.

A genomic clone that specifies a single polypeptide precursor for ricin, a toxic lectin of Ricinus communis (castor bean), was isolated, sequenced and Sl mapped. The gene encodes a 64 kDa precursor which contains, in the following order: a 24 or 35 amino acid signal peptide, the A chain, a 12 amino acid linker peptide, and the B chain. The 5'-end of the ricin mRNA maps approximately 35 bases upstream from the first methionine codon. Two putative TATA boxes and a possible CAAT box lie in the 5'-flanking region. Two possible polyadenylation signals were found in the 3' flanking region. No introns were found, which is typical of other lectin genes that have been sequenced. Southern blot analysis suggests that the castor bean genome contains approximately six ricin-like genes.

Amino Acid Sequence↗