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Mutation analysis of the human homologue of drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden.
Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden and Department of Dermatology, Karolinska Hospital, Stockholm, Sweden.
Department of Pathology, Huddinge University Hospital, Huddinge, Sweden.
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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. 

Place, publisher, year, edition, pages
1998. Vol. 21, no 2, 87-92 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-85078DOI: 10.1002/(SICI)1098-2744(199802)21:2<87::AID-MC2>3.0.CO;2-LOAI: diva2:564564
Available from: 2012-11-02 Created: 2012-11-02 Last updated: 2012-11-02
In thesis
1. Molecular alterations in squamous cell carcinomas of the skin: emphasis on genes on chromosome 9q
Open this publication in new window or tab >>Molecular alterations in squamous cell carcinomas of the skin: emphasis on genes on chromosome 9q
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.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 850
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-23974 (URN)3525 (Local ID)91-7373-823-9 (ISBN)3525 (Archive number)3525 (OAI)
Public defence
2004-05-19, Elsa Brändström-salen, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-11-02Bibliographically approved

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Eklund, Lena K.Söderkvist, Peter
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