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LOH Patterns (loh + pattern)
Selected AbstractsClear-cell adenofibroma can be a clonal precursor for clear-cell adenocarcinoma of the ovary: a possible alternative ovarian clear-cell carcinogenic pathway,THE JOURNAL OF PATHOLOGY, Issue 1 2008S Yamamoto Abstract Several studies have reported that ovarian clear-cell adenocarcinoma can be derived from endometriosis. Although the clear-cell adenofibroma (CCAF), a major form of benign and borderline ovarian clear-cell tumour, has been suggested as another precursor for clear-cell adenocarcinoma (CCA), there is no supportive genetic evidence for this presumption. To examine the genetic linkage between CCAF and CCA of the ovary, we conducted allelotype analysis for both CCAF and adjacent CCA components in 14 cases of CCA associated with benign CCAF and/or borderline CCAF. DNA isolated from laser-microdissected tissue was subjected to polymerase chain reaction and analysis for loss of heterozygosity (LOH), using 17 polymorphic markers located on 11 chromosomal arms: 1p, 5q, 8p, 9p, 9q, 10q, 11q, 13q, 18q, 19p and 22q. For all informative loci, the frequency of LOH in adenocarcinoma was 49% (54/110 loci), and was significantly higher than those in the components of benign CCAF (22%, 20/92 loci) and borderline CCAF (30%, 25/83 loci) (,2 test; p < 0.05, respectively). The concordance rate in allelic patterns at all informative loci was 74% between benign CCAF and adenocarcinoma components, 81% between borderline CCAF and adenocarcinoma components, and 95% between benign CCAF and borderline CCAF components. Furthermore, between CCAF and adenocarcinoma components, an identical LOH pattern, involving the same alleles, was found in 13 (93%) of 14 cases at one or more chromosomal loci, and estimation of probability indicated that these events were very unlikely to have occurred by chance. Among the markers examined, LOHs on 5q, 10q and 22q were frequent in both CCAF and adenocarcinoma components, whereas LOHs on 1p and 13q were rare in CCAF components but frequent in adenocarcinoma components. These findings suggest that CCAF can be a clonal precursor for ovarian clear-cell adenocarcinoma. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] 3,-azido-3,-deoxythymidine induces deletions in L5178Y mouse lymphoma cells,,ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3-4 2007Jianyong Wang Abstract 3,-Azido-3,-deoxythymidine (AZT), a nucleoside analogue used for the treatment of acquired immunodeficiency syndrome (AIDS), induced a significant dose-related increase in the thymidine kinase (Tk) mutant frequency (MF) in L5178Y/Tk+/, 3.7.2C mouse lymphoma cells. Treatment with 1 mg/ml (3,742 ,M) AZT for 24 hr resulted in a MF of 407 × 10,6 compared to a control MF of 84 × 10,6. The MFs of the large and small colony mutants resulting from AZT exposure were 142 × 10,6 and 265 × 10,6, respectively. One hundred and fifty mutants from the 1 mg/ml (3,742 ,M) AZT-treated culture and sixty-nine mutants from independent untreated cultures were isolated and analyzed. LOH analysis using a heteromorphic microsatellite locus located in the Tk gene was performed to determine the presence or absence of the Tk+ allele. Eight other microsatellite markers spanning the entire mouse chromosome 11 also were examined for heterozygosity to determine the extent of LOH. In addition, Tk gene dosage analysis was conducted using Real-Time PCR in those mutants showing LOH at the Tk locus. The presence of only one Tk allele based on Real-Time PCR indicated that the mutant resulted from deletion while the presence of two alleles was consistent with a recombination event. More mutants from the AZT-treated culture showed Tk LOH than did independent mutants from the untreated cultures (91% vs. 64%) and the induced mutants also showed distinct chromosome 11 LOH patterns. The mutation spectrum of mutants from AZT-treated cells was also significantly different from that of spontaneous mutants. More deletions and fewer intragenic mutations were observed in the mutants from the AZT-treated culture than independent mutants from the untreated control. Our data indicate that AZT primarily induced LOH mutations in L5178Y mouse lymphoma cells and a large number of LOH mutations resulted from deletions. Environ. Mol. Mutagen., 2007. Published 2007 Wiley-Liss, Inc. [source] Loss of heterozygosity on chromosome 6 in HPV-16 positive cervical carcinomas carrying the DRB1*1501-DQB1*0602 haplotypeGENES, CHROMOSOMES AND CANCER, Issue 4 2004Hugo Arias-Pulido High-risk human papillomaviruses (HPVs), specifically HPV-16 and -18, have been associated with the development of carcinoma in situ (CIS) and of invasive cervical cancer (CC). However, only a small fraction of HPV-infected women will show signs of disease progression, suggesting that other factors in the carcinogenic pathway are needed. We previously demonstrated that human leukocyte antigen (HLA) DRB1*1501-DQB1*0602 (high risk) was associated with the development of CIS and CC tumors in HPV-16-positive patients. To characterize the molecular changes that could be relevant to tumor progression, we compared the extent of loss of heterozygosity (LOH) on chromosome 6 in HPV-16-positive CIS patients who were carriers of high-risk and neutral HLA haplotypes. CIS and CC cases demonstrated similar LOH patterns. A wide range of LOH frequencies was found at 6p (10,53%) and 6q (5,28%) in CIS cases, suggesting that LOH is an early event in the carcinogenic process. A comparative analysis of LOH frequencies in the high-risk versus the neutral HLA haplotypes showed a statistically significant difference in the extent of LOH at 6p24,p25 (58.6% versus 25.8%; P = 0.018) and at 6p21.3 (79.3% versus 35.5%; P = 0.001), a region that contains the HLA complex. LOH at this region could affect genes encoding HLA class I,II molecules, as well as factors responsible for the assembly, transport, and stable expression of HLA molecules. These losses may be a reflection of both an abnormal immune response and a general genome-wide instability resulting from virus persistence. © 2004 Wiley-Liss, Inc. [source] Genomic analysis of Barrett's esophagus after ablative therapy: Persistence of genetic alterations at tumor suppressor lociINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006Mariska Hage Abstract Barrett's esophagus (BE) is a major predisposing factor for the development of esophageal adenocarcinoma. Current strategies for treatment of BE, both dysplastic and nondysplastic, include photodynamic therapy (PDT) and argon plasma coagulation (APC). However, the effect of ablative therapy at the genetic level is unclear. We performed loss of heterozygosity (LOH) analysis of BE in baseline and follow-up biopsy specimens from 21 patients with BE (17 male, 4 female) treated with PDT and/or APC. At baseline, 14 patients had intestinal metaplasia without dysplasia (MET), 4 low-grade dysplasia (LGD) and 3 high-grade dysplasia (HGD). LOH was assessed using a panel of 9 polymorphic markers for evaluation of the P53 gene on 17p, P16 on 9p, DCC and SMAD4 on 18q and the APC gene on 5q. The tissue specimens obtained at baseline (t = 0) were analysed, as well as the first (t = 1; mean interval: 4 months) and last (t = 2; mean interval: 8 months) available biopsy with residual or recurrent BE after ablation. At t = 0, allelic loss was detected of 5q in 27%, 9p in 56%, 17p in 31% and 18q in 6% of informative cases. At t = 1 (18 patients with persistent MET and 3 with LGD) and at t = 2 (8 MET, 2 LGD), the LOH patterns were not statistically different from t = 0. Further, multiple genetic lineages before and after therapy were detected in 15 cases illustrating the multiclonal nature of BE. We conclude that recurrent and/or persistent BE after ablative therapy still contains genetic alterations associated with malignant progression to cancer. Therefore, the goal of treatment should be the complete elimination of Barrett's mucosa. © 2005 Wiley-Liss, Inc. [source] Comparison of HPV infection, p53 mutation and allelic losses in post-transplant and non-posttransplant oral squamous cell carcinomasJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 3 2002L. Zhang Abstract Background:, Oral squamous cell carcinoma (SCC) is increasingly found in transplant recipients, although little is known of the natural history of the disease or the mechanism underlying this increase. Methods:, In this article we describe the history of development of 5 oral post-transplant SCCs (PSCCs) and compare their genetic profiles to 34 non-posttransplant SCCs (NPSCCs). Results:, Of the five patients with PSCCs, 3 had bone marrow transplants and two, kidney. All three PSCCs from bone marrow recipients were preceded locally by graft-vs.-host disease (GVHD). Two of the GVHD were biopsied and demonstrated dysplasia. Similar frequencies of loss of heterozygosity (LOH) occurred in PSCCs and NPSCCs at 3p, 9p, 17p and 8p, with lower frequencies in PSCCs at 4q (39% vs. 0%), 11q (53% vs. 20%) and 13q (45% vs. 20%), although the latter were not significantly different. Only 1 PSCC had a p53 mutation, compared to historical values of 40,60% for NPSCC. Interestingly, human papillomavirus (HPV) DNA was detected in 3 (60%) PSCCs, in comparison to only 4 (12%) of the 34 NPSCCs (P = 0.0346). Conclusions:, Dysplasia in oral GVHD may be a strong indicator of cancer risk and should not be regarded as reactive changes to lichenoid mucosites. The low level of p53 mutation and increased HPV infection support the involvement of HPV in the development of PSCC, while the similarity in LOH patterns suggests that other aspects of carcinogenesis may be comparable in these two types of SCCs. [source] Clonal origin of multifocal hepatocellular carcinomaCANCER, Issue 17 2010Kurt B. Hodges MD Abstract BACKGROUND: Hepatocellular carcinoma is the most common primary tumor of the liver. Patients frequently have multiple histologically similar, but anatomically separate tumors. The clonal origin of multiple hepatocellular carcinomas is uncertain. METHODS: The authors analyzed 31 tumors from 12 different patients (11 women, 1 man), who had multiple hepatocellular carcinomas involving 1 or both lobes. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue using laser capture microdissection. DNA was analyzed for loss of heterozygosity (LOH), X chromosome inactivation status, and TP53 gene mutations. RESULTS: Ten (83%) of the 12 patients showed LOH in at least 1 of the analyzed microsatellite markers. Concordant LOH patterns between separate hepatocellular carcinomas in individual patients were seen in 8 (80%) of 10 cases, whereas discordant patterns were seen in 2 (20%) of 10 cases. Five (50%) of 10 informative female patients showed identical nonrandom X chromosome inactivation patterns in multiple tumors; 1 case showed discordant nonrandom X chromosome inactivation pattern. TP53 mutations were identified in 8 (67%) of 12 patients. Tumors in 7 (88%) of these 8 patients showed different point mutations. Three patients (Cases 4, 5, and 10) had tumors with additional TP53 point mutations, indicating additional genetic abnormalities in these tumors. CONCLUSIONS: The data suggested that the significant proportion of patients with multifocal hepatocellular carcinomas have tumors of common clonal origin. Cancer 2010. © 2010 American Cancer Society. [source] | ||||||||||