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Molecular alterations in squamous cell carcinomas of the skin: emphasis on genes on chromosome 9q
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Skin cancer is the most common type of cancer in the western world. The incidence of melanoma and non-melanoma skin cancer is continuously increasing and, in Sweden, 2300 new cases per year are diagnosed of squamous cell carcinoma (SCC) alone. In this thesis, we have investigated genes and proteins from signal transduction pathways important for tumor development. Special emphasis has been put on chromosomal region 9q22-q31 where frequent loss of heterozygosity has been observed in non-melanoma skin cancers.

Mutation analysis of the PTCH1 and XPA genes, connected to the familial cancer syndromes nevoid basal cell carcinoma syndrome and xeroderma pigmentosum, respectively, was performed. Based on lack of mutation or altered mRNA expression, we conclude that these two genes are not likely to be involved in development of sporadic SCCs. Next, we studied the correlation of the two phenotypes, anchorage independence and tumorigenicity, to the loss of chromosome 9 material in a panel of somatic cell hybrids. By microsatellite analysis, we show that the anchorage independence gene is located distal to the marker D9S155. The mapping of the gene for tumor suppression revealed three commonly deleted regions on chromosome regions 9p23-p22, 9p21-p12 and 9q31-q33. Another two candidates from the 9q22-q31 region, CORO2A and TßR-I, were investigated both at the gene and the protein level. We did not detect any alterations in the TßR-I gene or protein, but CORO2A protein was over-expressed in 4 of 40 (10%) tumors, indicating an involvement in sec carcinogenesis in a subset of tumors. In one healthy individual from the control population, we found a heterozygous germline mutation in CORO2A creating a stop codon, which results in a truncated protein. Thus, one functional allele might be sufficient to sustain a normal cellular function. When investigating occurrence of aberrant protein expression in the interconnected Wnt and Notch pathways, Notch1 was found to be expressed in only 5 of 40 (14%) of the normal epidermal cells, while strong staining was displayed in all the tumors. No altered expression of the most central protein of the Wnt pathway, ß-catenin, was observed, but the up-stream Dvl-1 protein was found to be up-regulated in 8 of 38 (21%) tumors. Dvl-1 was also detected in the nucleus in the majority of normal and tumor cases and a potential nuclear localization signal was identified in the Dvl-1 A isoform.

None of the genes from the chromosomal region 9q22-q31 displayed alterations consistent with those of a tumor suppressor gene. Most likely, this gene remains to be identified.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2004. , 78 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 850
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-23974Local ID: 3525ISBN: 91-7373-823-9 (print)OAI: oai:DiVA.org:liu-23974DiVA: diva2:244290
Public defence
2004-05-19, Elsa Brändström-salen, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-11-02Bibliographically approved
List of papers
1. Mutation analysis of the human homologue of drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin
Open this publication in new window or tab >>Mutation analysis of the human homologue of drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin
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1998 (English)In: Molecular Carcinogenesis, ISSN 0899-1987, E-ISSN 1098-2744, Vol. 21, no 2, 87-92 p.Article in journal (Refereed) Published
Abstract [en]

The human homologue of Drosophila patched (PTCH), located at chromosome 9q22.3, was recently identified as a candidate tumor suppressor gene for familial and sporadic basal cell carcinomas. Squamous cell carcinomas (SCCs) of the skin display allelic loss in this chromosomal region, which, in addition to the PTCH gene, contains the DNA repair gene xeroderma pigmentosum complementation group A (XPA). Patients with xeroderma pigmentosum are predisposed to non-melanoma skin tumors because of deficient excision repair of ultraviolet-induced DNA damage. Mutation analysis by single-strand conformation analysis and direct DNA sequencing of all 23 exons of the PTCH gene and all six exons of the XPA gene in 14 SCCs did not reveal structural alterations in any of these genes. Additionally, analysis of PTCH expression by in situ hybridization in SCCs revealed no evidence of upregulation of PTCH mRNA, confirming the lack of mutations in this gene. These findings suggest that another, yet to be identified gene or genes on chromosome 9q are involved in SCC tumorigenesis. 

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85078 (URN)10.1002/(SICI)1098-2744(199802)21:2<87::AID-MC2>3.0.CO;2-L (DOI)
Available from: 2012-11-02 Created: 2012-11-02 Last updated: 2017-12-07
2. Regional mapping of suppressor loci for anchorage independence and tumorigenicity on human chromosome 9
Open this publication in new window or tab >>Regional mapping of suppressor loci for anchorage independence and tumorigenicity on human chromosome 9
2001 (English)In: Cancer Genetics and Cytogenetics, ISSN 2210-7762, E-ISSN 2210-7770, Vol. 130, no 2, 118-126 p.Article in journal (Refereed) Published
Abstract [en]

By microcell-mediated chromosome transfer to the malignant Syrian hamster cell line BHK-191-5C, we previously identified two suppressor functions on human chromosome 9 (HSA9), one for anchorage independence and another for tumorigenicity. However, the precise chromosomal locations of these suppressor functions were not determined. The present study was undertaken to define the regional location of these suppressor loci using a panel of microcell hybrids containing structurally altered HSA9 with different deleted regions in the BHK-191-5C background. DNA derived from the cell hybrids was analyzed by PCR for verification of the presence of HSA9 genetic material by amplifying 62 microsatellite markers and 13 genes, covering the entire length of HSA9. Our deletion mapping data on anchorage independent and tumorigenic hybrids suggest that the suppressor function for anchorage independence is located in the region between 9q32 to 9qter. The suppressor for tumorigenicity may be located in one of three deleted regions on HSA9, the first one between the markers D9S162 and D9S1870, the second one between the markers D9S1868 and TIGRA002I21, and the third one between the markers D9S59 and D9S155.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25000 (URN)10.1016/S0165-4608(01)00471-X (DOI)9420 (Local ID)9420 (Archive number)9420 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
3. Over-expression of coronin 2a and lack of alterations in transforming growth factor ß receptor I in squamous cell carsinomas of the skin
Open this publication in new window or tab >>Over-expression of coronin 2a and lack of alterations in transforming growth factor ß receptor I in squamous cell carsinomas of the skin
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Allelic losses in several regions of chromosome 9q have been connected to the development of squamous cell carcinoma (SCC) of the skin. We have studied two candidate genes in the 9q22 region using mutational analysis of genomic DNA as well as immunohistochemistry for assessment of changes in protein expression. The coronin 2A (CORO2A) protein shows strong resemblance to actin-binding proteins, implying a role in cytokinesis or cell motility. It has also been found to be part of the nuclear receptor co-repressor complex involved in transcriptional regulation. We elucidated the exon-intron structure by sequence alignment of the mRNA to a "high-throughput genomic sequence" entry in GenBank. By using single strand conformation analysis and DNA sequencing we found eight silent mutations in tumor DNA, one of which was found in a subset of a normal control population. Surprisingly, immunostaining revealed over-expression in 4/40 tumors. This cannot explain the high frequency of allelic loss in cutaneous secs, but is yet indicating a possible involvement of CORO2A in cutaneous SCC development. The gene for transforming growth factor ß receptor 1 (TßR-I) has previously been positioned to the 9q22 region. TßR-I is part of a protein complex necessary for binding of the TGFß ligand initiating a signaling cascade, which affects downstream targets important for cell cycle regulation. We could not identify any alterations at either protein or DNA level and therefore exclude TßR-I as candidate for cutaneous sec development.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85099 (URN)
Available from: 2012-11-02 Created: 2012-11-02 Last updated: 2012-11-02
4. Abnormal expression of proteins in Notch and Wnt pathways in human squamous cell carcinoma of the skin
Open this publication in new window or tab >>Abnormal expression of proteins in Notch and Wnt pathways in human squamous cell carcinoma of the skin
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background Members of the Notch pathway are involved in various differentiation processes. Signalling via the Wnt/ß-catenin-pathway controls transcription of genes involved in proliferation events. These two pathways are interconnected through the cytoplasmic protein Dishevelled (Dvl-1).

Objectives To evaluate the expression patterns of Notch1, Dvl-1 and ß-catenin proteins in human squamous cell carcinomas of the skin.

Methods 40 formalin-fixed paraffin-embedded SCCs were included in this study. Expression was detected with immunohistochemistry using avidin-biotin and DAB visualization.

Results The majority of the normal epidermal cells lacked expression of Notch1, while the dysplastic and invasive tumour cells showed strong staining. Expression of Dvl-1 was observed in normal human epidermis, with a more intense staining indysplastic cells in 8 of 38 (21%) cases. Besides the expected cytoplasmic staining, 27 of 38 (71%) secs displayed nuclear staining and a potential nuclear localisation signal was identified. ß-catenin showed membranous and weak cytoplasmic staining in normal as well as tumour cells.

Conclusions We have found enhanced expression of Notch1 in the majority of SCCs, indicating a disturbed differentiation process. We have also for the first time showed over-expression of Dvl-1 in dysplastic epidermal cells as well as normal staining of the nucleus. A classical nuclear localization signal is also identified in the Dvl-1 isoform A, whereas two other isoforms lack this recognition sequence.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85100 (URN)
Available from: 2012-11-02 Created: 2012-11-02 Last updated: 2012-11-02

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