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Thrashbingham CA , Salazar H , Freed JJ , Greenberg RE , Tartof KD
Genomic Alterations and Instabilities in Renal-Cell Carcinomas and Their Relationship to Tumor Pathology
Cancer Research. 1995 Dec 15;55(24) :6189-6195
PMID: ISI:A1995TK21100034   
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Abstract
A comprehensive genome scan for loss of heterozygosity (LOH) in 33 renal cell carcinomas indicates that mutations of tumor suppressor genes on several different chromosomes are required for malignant transformation in this disease, In the case of nonpapillary renal carcinomas chromosomes 3p, 6q, 8p, 9pq, and 14q exhibit elevated levels of LOH. Although 3p is the most frequently lost chromosome arm, in no case is 3p observed as the sole allelic loss because it always occurs in conjunction with the loss of either 6q, 8p, or 14q, This result indicates that the mutation of a tumor suppressor gene on 3p, most likely von Hippel-Lindau disease (VHL), may be necessary but is not sufficient for the development of nonpapillary renal cell carcinoma. In papillary renal tumors, LOH is observed most often for chromosomes 6pq, 9p, 11q, 14q, and 21q. This suggests that tumor suppressor genes located on chromosomes 6q, 9pq, and 14q may be involved in the development and/or progression of both nonpapillary and papillary renal cell carcinomas, However, LOH in papillary tumors appears to be especially elevated for 11q and 21q and reduced for 3p and 8p indicating that there are also tumor suppressor genes specific to each form of the disease. There is no correlation between stage of disease and the extent of LOH, loss of a particular chromosome, or the number of chromosomes that show allele inbalance, Early and late stage tumors may exhibit either extensive LOB or no apparent allele loss; similarly, allelic imbalances are observed in both early and late stage renal cell carcinomas. This suggests that a gene (or genes) regulating mitotic chromosome stability may be mutated in some renal tumors. Preliminary evidence points to an association between genome instability and LOH of 14q. Finally, a distinct type of microsatellite instability has been detected in 21% of renal cell carcinomas and occurs at a frequency of 4.4 x 10(-4)/ locus, The most common mutation is a 2-bp insertion in a CA repeat, This alteration is not restricted to a particular histopathology or clinical stage, and it is not associated with allelic loss of a specific chromosome, The frequency of this event is similar to that which occurs spontaneously in germline microsatellite loci and is probably not the result of a defect in a mismatch repair gene, It is possible that this type of microsatellite instability is general and may occur in most, if not all, carcinomas.
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Times Cited: 48 Article TK211 CANCER RES