Molecular profile of nasopharyngeal carcinoma: analysing tumour suppressor gene promoter hypermethylation by multiplex ligation-dependent probe amplification

AimsTo assess differences in methylation profiles, and thus pathogenesis, between Epstein-Barr virus (EBV)-positive and negative nasopharyngeal carcinomas (NPCs). Also, promoter hypermethylation is a common phenomenon in early carcinogenesis to inactivate tumour suppressor genes. Since epigenetic changes are reversible, the therapeutic application of methylation inhibitors could provide treatment options.MethodsWe evaluated promoter hypermethylation profiles of 22 common tumour suppressor genes in 108 NPCs using methylation-specific multiplex ligation-dependent probe amplification. Correlation between methylation, clinicopathological features (including EBV) and survival was examined. Cluster analysis was also performed.ResultsHypermethylation of RASSF1A and ESR1 was significantly more frequent in EBV-positive NPC, while hypermethylation of DAPK1 was more frequent in EBV-negative NPC. In logistic regression, age, with EBV-positive NPC occurring at earlier age, and RASSF1, with RASSF1 hypermethylation being more frequent in EBV-positive NPC, remained significant. In EBV-positive NPC, hypermethylation of RASSF1A predicted worse overall survival (OS) (HR 3.058,95% CI 1.027 to 9.107). In EBV-negative NPC, hypermethylated adenomatous polyposis coli (APC) was a predictor of poor disease-free survival (DFS) (HR 6.868, 95% CI 2.142 to 22.022).ConclusionThere are important epigenetic differences between EBV-negative and EBV-positive NPCs, with EBV-negative NPC having a more similar hypermethylation profile to other head and neck squamous cell carcinomas than EBV-positive NPC. Hypermethylation of RASSF1A might contribute to worse OS in EBV-positive NPC, and may be an important event in the pathogenesis of EBV-infected NPC. Hypermethylation of APC might contribute to worse DFS in EBV-negative NPC.

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Use of Monozygotic Twins in Search for Breast Cancer Susceptibility Loci

Twin Research ◽

10.1375/twin.4.4.251 ◽

2001 ◽

Vol 4 (4) ◽

pp. 251-259 ◽

Cited By ~ 4

Author(s):

Asta Försti ◽

Qianren Jin ◽

Lena Sundqvist ◽

Magnus Söderberg ◽

Kari Hemminki

Keyword(s):

Breast Cancer ◽

Cancer Susceptibility ◽

Monozygotic Twins ◽

Monozygotic Twin ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Tumour Suppressor ◽

Tumour Suppressor Genes ◽

Suppressor Genes ◽

Twin Model

AbstractWe have used Swedish monozygotic twins concordant for breast cancer to study genetic changes associated with the development of breast cancer. Because loss of heterozygosity (LOH) at a specific genomic region may reflect the presence of a tumour suppressor gene, loss of the same allele in both of the twins concordant for breast cancer may pinpoint a tumour suppressor gene that confers a strong predisposition to breast cancer. DNA samples extracted from the matched tumour and normal tissues of nine twin pairs were analysed for allelic imbalance using a set of microsatellite markers on chromosomes 1, 13, 16 and 17, containing loci with known tumour suppressor genes. The two main regions, where more twin pairs than expected had lost the same allele, were located at 16qtel, including markers D16S393, D16S305 and D16S413, and at 17p13, distal to the p53 locus. Our results show that the monozygotic twin model can be used to suggest candidate regions of potential tumour suppressor genes, even with a limited number of twin pairs.

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Non-accidental structural chromosome aberrations in established monkey B-lymphocyte cell lines

Biologija ◽

10.6001/biologija.v65i4.4119 ◽

2020 ◽

Vol 65 (4) ◽

Author(s):

Daredzhan Araviashvili ◽

Olga Chzhu ◽

Igor Marinich ◽

Irina Danilova

Keyword(s):

Cell Lines ◽

Chromosomal Aberrations ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Tumour Suppressor ◽

Chromosome 8 ◽

Tumour Suppressor Genes ◽

Suppressor Genes ◽

Cultivation In Vitro ◽

Lymphocyte Cell

Established primate lymphocyte cell lines obtained from tumour samples and from EBV-positive monkeys served us as the model system for studying the role of genetic factors and chromosomal abnormalities in malignization. The investigation of chromosome regions and genes involved in chromosomal aberrations leading to malignization in these lines was the aim of our work. Cytogenetic analysis was performed at different stages of cultivation in vitro. To determine the oncogenes and tumour suppressor genes located on aberrant chromosomes, data on mapping rhesus macaque genes, and high similarity of human and monkey karyotypes were used. We found that, in the line obtained from lymphomatous baboon tissue, the inactivation of tumour suppressor gene RB1 on chromosome 17 after chromosomal rearrangement is one of the most probable causes of in vivo malignization. Chromosomal aberrations at the region of oncogene c-Ki-ras and tumour suppressor gene TP53 change the proliferative status and differentiation in established cell lines obtained from healthy but EBV-seropositive primates. The other cause of malignization in these lines is an increase in expression of the oncogene c-myc caused by trisomy of chromosome 8 where c-myc is located. Structural aberrations in established primate cell lines affecting several chromosomal loci were identified as: (1) causing the proto-oncogene activation – the central event in the tumour clone occurrence, and (2) deactivating tumour suppressor genes. The change in the chromosome number leads to increase in oncogenic products and to damage of regulatory functions associated with cell proliferation.

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The molecular biology of Wilms' tumour

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399401003027 ◽

2001 ◽

Vol 3 (13) ◽

pp. 1-16 ◽

Cited By ~ 14

Author(s):

Keith W. Brown ◽

Karim T.A. Malik

Keyword(s):

Kidney Development ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Tumour Suppressor ◽

Kidney Neoplasm ◽

Tumour Suppressor Genes ◽

Loss Of Function ◽

Wilms Tumour ◽

Suppressor Genes ◽

Renal Stem Cells

Wilms' tumour (WT; nephroblastoma), a kidney neoplasm, is one of the most frequently occurring solid tumours of childhood. It arises from the developing kidney by genetic and epigenetic changes that lead to the abnormal proliferation of renal stem cells (metanephric blastema). WT serves as a paradigm for understanding the relationship between loss of developmental control and gain of tumourigenic potential. In particular, loss of function of tumour suppressor genes has been implicated in the development of WT, and the Wilms' tumour suppressor gene WT1 (at chromosome 11p13) was the second tumour suppressor gene to be cloned, after the retinoblastoma gene RB-1. WT1 plays an essential role in kidney development, but is mutated in only approximately 20% of WTs, which suggests that further lesions and genetic loci are involved in Wilms' tumourigenesis. Other chromosomal regions associated with WT include 7p, 11p15, 16q and 17q. Although many of these loci probably contain tumour suppressor genes, imprinted genes (genes showing expression of only one parental allele) and oncogenes have also been implicated in WT. Some loci have been shown to be associated with particular clinical outcomes, suggesting that they might be used to determine prognosis, and especially to identify poor prognostic subgroups that can be targeted for aggressive and/or novel therapies.

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