Gene expression analyses on skin lesions from patients with familial adenomatous polyposis

Stegmann, Danielle Alexandra. Gene expression analyses on skin lesions from patients with familial adenomatous polyposis. 2014, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_10856

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Familial adenomatous polyposis coli (FAP) is an autosomal dominant colorectal cancer predisposition syndrome caused by germline mutations in the APC gene. It is characterized by an increased risk for the development of both several internal cancers and benign skin tumors such as fibromas, lipomas, and epidermal cysts occurring with different frequencies early in life. The molecular mechanisms underlying these skin lesions are still poorly understood.
In this study we aimed to clarify the underlying molecular mechanisms in the development of FAP-associated skin lesions. Such mechanisms were hypothesized to either follow the APC second hit model or to include other genes, possibly such independent of Wnt signaling.
To this end we analyzed 9 fibromas, 3 lipomas, and 3 epidermal cysts from 14 FAP patients of 7 families with pathogenic APC germline mutations for somatic alterations by direct sequencing of the mutation cluster region (MCR), exon-overlapping cDNA analysis, and locus-specific marker analysis. Somatic changes were found in two skin lesions, one lipoma and one epidermal cyst. Both lesions displayed loss of heterozygosity (LOH) at APC marker locus D5S346. The epidermal cyst in addition carried a somatic mutation (c.4778delA) in the MCR of APC. These results suggest that somatic APC alterations may influence the development of FAP-associated lipomas and epidermal cysts.
For the investigation of APC-independent processes we analyzed in total 5 fibromas, 6 lipomas and 3 epidermal cysts compared to healthy skin of 13 FAP patients by whole genome expression analysis and confirmed targets of highest expression changes by qPCR. We show that genes mostly changed in fibromas and lipomas of FAP patients mainly function in cell proliferation processes. Therefore we suggest that FAP-associated cutaneous neoplasia might develop by the influence of activated proto-oncogenes and deactivated tumor suppressors similar to other tumors. We suppose that an invasive growth is prevented by increased expression of tumor suppressors in those benign neoplasms. In comparison to the general population expression results of FAP lipomas have also been compared to similar lesions of non-FAP individuals. Non-FAP lipomas tend to be mainly influenced by genes involved in lipid metabolism.
In conclusion, we assume that FAP-associated skin lesions are mostly not caused by APC second hits. In contrast, we rather suppose Wnt independent mechanisms. In addition, we suggest that lipomas develop differentially in FAP patients and in the general population.
Advisors:Krähenbühl, Stephan
Committee Members:Burger, Bettina and Lindberg Gasser, Raija L.P.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmakologie (Krähenbühl)
UniBasel Contributors:Krähenbühl, Stephan and Burger, Bettina and Lindberg Gasser, Raija L.P.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:10856
Thesis status:Complete
Number of Pages:146 S.
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edoc DOI:
Last Modified:22 Apr 2018 04:31
Deposited On:30 Jul 2014 13:46

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