Biomedical subjects
S Schlack
Publications and source records attributed to S Schlack.
Del(10)(q22.3q24.1) associated with juvenile polyposis.
Juvenile polyps are the most frequent gastrointestinal polyps with a malignant potential for which the genetic basis is unknown. Juvenile polyps, with a normal epithelium but hypertrophic lamina propria, are histologically quite distinct from adenomatous polyps which have dysplastic changes in epithelial nuclei. Furthermore, the adenomatous polyposis coli (APC) gene on Chr 5, mutated somatically in adenomatous polyps and mutated in the germline of patients with familial adenomatous polyposis, is not linked to hereditary juvenile polyposis. We provide the first report indicating that a tumor suppressor gene associated with juvenile polyposis may be located at 10q22.3q24.1. Cytogenetic studies of a patient with juvenile polyposis and multiple congenital abnormalities of the head, extremities, and abdomen revealed a de novo interstitial deletion of Chr 10 as the only defect, del(10)(10q22.3q24.1).
A juvenile polyposis tumor suppressor locus at 10q22 is deleted from nonepithelial cells in the lamina propria.
BACKGROUND & AIMS: Juvenile polyps are characterized by an abundant lamina propria that lacks smooth muscle and may contain cystically dilated glands, with epithelium that seems normal and is nondysplastic. Rarely, an autosomal dominant inheritance pattern occurs. The aim of this study was to test the hypothesis that the genetic defect in both sporadic juvenile polyps and hereditary juvenile polyposis involves loss of function for a tumor suppressor gene. METHODS: Allelic losses were detected by comparing normal DNA with tumor DNA from a series of 47 juvenile polyps from 16 patients using polymerase chain reaction amplification of microsatellite markers and fluorescent in situ hybridization (FISH). RESULTS: Somatic deletions at 10q22 were detected in 39 of 47 juvenile polyps (83%) from 16 unrelated patients with either hereditary or sporadic juvenile polyps, and the minimum overlap localized juvenile polyposis coli to the 3-cM interval D10S219-D10S1696. Fluorescent in situ hybridization shows that the cells affected by deletion mutation reside exclusively in the lamina propria, not in the epithelium. CONCLUSIONS: The location of a novel tumor suppressor gene on chromosome 10 that is affected by deletion mutation in the majority of juvenile polyps was mapped. Unlike adenomas and carcinomas of the colonic epithelium, juvenile polyps originate in the lamina propria.
Genetic instability associated with adenoma to carcinoma progression in hereditary nonpolyposis colon cancer.
BACKGROUND & AIMS: Genetic instability related to defective DNA mismatch repair genes may be involved in the pathogenesis of carcinoma in hereditary nonpolyposis colon cancer (HNPCC). However, nonneoplastic tissues from patients inheriting defects in human MSH2 or human MLH1 do not show significant genetic instability. The aim of this study was to determine whether acquisition of genetic instability at the adenoma stage promotes malignant transformation by studying adenoma-carcinoma progression in HNPCC. METHODS: Dinucleotide repeat loci were analyzed by polymerase chain reaction from microdissected adenoma and/or carcinoma stages from formalin-fixed paraffin-embedded HNPCC tumors. RESULTS: Although genetic instability was observed at some loci in almost all cases, the proportion of microsatellite loci altered was significantly less (P < 0.01) in completely benign adenomas (24%) than in benign areas of adenomas with malignancy (54%). Molecular fingerprints indicated intratumor heterogeneity, with evolution of related subclones of neoplastic cells. However, in all cases of tumor progression, at least one subclone from the adenoma stage was closely related to the carcinoma. CONCLUSIONS: Some genetic instability develops at the benign adenoma stage in most HNPCC tumors. Adenomas with a greater rate of genetic instability are more likely to progress to carcinoma. Topographic genotyping data provides evidence supporting the hypothesis of adenoma-carcinoma progression in HNPCC.
Genetic analysis of colon cancer susceptibility in mice.
Mouse models may aid in the identification of genes involved in colon cancer. Our mating scheme involved mouse strains selected for maximum differences in susceptibility to DMH-induced colon tumors. Tumors were found in 40 of 122 progeny from a backcross to the resistant strain. We examined progeny animals for segregation of 177 genetic markers distributed at intervals of 5-30 cM on all mouse chromosomes. Multiple loci contribute to the phenotype, with significant linkage to a novel locus, Ccs1, between D12Mit5 and D12Mit6 on mouse Chr 12. Comparative maps suggest that the human homologue of Ccs1 is near FOS on human chromosome 14q.