HMGA2 expression pattern and TERT mutations in tumors of the vulva

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Abstract

Malignant tumors of the vulva account for only 5% of cancers of the female genital tract in the USA. The most frequent cancers of the vulva are squamous cell carcinoma (SCC) and malignant melanoma (MM). Little is known about the genetic aberrations carried by these tumors. We report a detailed study of 25 vulva tumors [22 SCC, 2 MM, 1 atypical squamous cell hyperplasia (AH)] analyzed for expression of the high-mobility group AT-hook family member genes HMGA2 and HMGA1, for mutations in the IDH1, IDH2 and TERT genes, and for methylation of the MGMT promoter. The RT-PCR and immunohistochemistry analyses showed that HMGA2 was expressed in the great majority of analyzed samples (20 out of 24; SCC as well as MM) but not in the normal controls. HMGA1, on the other hand, was expressed in both tumors and normal tissues. Five of the 24 tumors (all SCC) showed the C228T mutation in the TERT promoter. Our results showed that HMGA2 and TERT may be of importance in the genesis and/or the progression of tumors of the vulva.

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Most cited references 18

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Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia.

M. Esteller, S Hamilton, P Burger … (1999)

The DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) removes alkyl adducts from the O6 position of guanine. MGMT expression is decreased in some tumor tissues, and lack of activity has been observed in some cell lines. Loss of expression is rarely due to deletion, mutation, or rearrangement of the MGMT gene, but methylation of discrete regions of the CpG island of MGMT has been associated with the silencing of the gene in cell lines. We used methylation-specific PCR to study the promoter methylation of the MGMT gene. All normal tissues and expressing cancer cell lines were unmethylated, whereas nonexpressing cancer cell lines were methylated. Among the more than 500 primary human tumors examined, MGMT hypermethylation was present in a subset of specific types of cancer. In gliomas and colorectal carcinomas, aberrant methylation was detected in 40% of the tumors, whereas in non-small cell lung carcinomas, lymphomas, and head and neck carcinomas, this alteration was found in 25% of the tumors. MGMT methylation was found rarely or not at all in other tumor types. We also analyzed MGMT expression by immunohistochemistry in relation to the methylation status in 31 primary tumors. The presence of aberrant hypermethylation was associated with loss of MGMT protein, in contrast to retention of protein in the majority of tumors without aberrant hypermethylation. Our results suggest that epigenetic inactivation of MGMT plays an important role in primary human neoplasia.

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Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours.

E F Schoenmakers, S Wanschura, R Mols … (1995)

We recently showed that the 1.7 megabase multiple aberration region (MAR) on human chromosome 12q15 harbours recurrent breakpoints frequently found in a variety of benign solid tumours. We now report a candidate gene within MAR suspected to be of pathogenetical relevance. Using positional cloning, we have identified the high mobility group protein gene HMGI-C within a 175 kilobase segment of MAR and characterized its genomic organization. By FISH analysis, we show the majority of the breakpoints of eight different benign solid tumour types fall within this gene. By Southern blot and 3'-RACE analysis, we demonstrate consistent rearrangements in HMGI-C and/or expression of altered HMGI-C transcripts. These results suggest a link between a member of the HMG gene family and benign solid tumour development.

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High level expression of the HMGI (Y) gene during embryonic development.

G Chiappetta, V Avantaggiato, R Visconti … (1996)

The HMGI protein family includes three proteins, named HMG-I, HMG-Y and HMGI-C. The first two proteins are coded for by the same gene, HMGI (Y), through an alternative splicing mechanism. Their expression is elevated in neoplastic tissues and cells and this overexpression has a causal role in the process of cellular neoplastic transformation. We demonstrate that the HMGI (Y) gene is expressed at very low levels in normal adult tissues, whereas in embryonic tissues it is expressed at high levels comparable to those detected in neoplastic tissues. Specifically, a very high expression of the HMGI (Y) gene was detected in all embryonic tissues at 8.5 dpc. Then in the following days, even though the gene is expressed essentially in all tissues, an abundant gene expression was restricted to some tissues. These results indicate an important role of the HMGI (Y) gene in development.

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Author and article information

Journal

Journal ID (nlm-ta): Oncol Rep

Journal ID (iso-abbrev): Oncol. Rep

Title: Oncology Reports

Publisher: D.A. Spandidos

ISSN (Print): 1021-335X

ISSN (Electronic): 1791-2431

Publication date (Print): June 2015

Publication date (Electronic): 30 March 2015

Publication date PMC-release: 30 March 2015

Volume: 33

Issue: 6

Pages: 2675-2680

Affiliations

[1 ]Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

[2 ]Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway

[3 ]Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

[4 ]Faculty of Medicine, University of Oslo, Oslo, Norway

[5 ]Department of Gynecology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

Author notes

Correspondence to: Professor Francesca Micci, Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway, E-mail: francesca.micci@ 123456labmed.uio.no

Article

Publisher ID: or-33-06-2675

DOI: 10.3892/or.2015.3882

PMC ID: 4431449

PubMed ID: 25823555

SO-VID: 2c75ba46-81cf-4a3e-aae7-46c8ec785543

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This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

HMGA2 expression pattern and TERT mutations in tumors of the vulva

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Most cited references 18

Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia.

Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours.

High level expression of the HMGI (Y) gene during embryonic development.

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