Mutational analyses of the tumor suppressor gene Patched1 : role in non-melanoma skin cancer and nevoid basal cell carcinoma
Author: Lindström, Erika
Date: 2008-05-23
Location: Föreläsningssal 9Q Månen, Alfred Nobels allé 8, Huddinge
Time: 10.00
Department: Biovetenskaper och näringslära / Biosciences and Nutrition
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thesis.pdf (797.1Kb)
Abstract
Skin cancer is the most common cancer in Western countries, with a
rapidly increasing incidence. The majority of these tumors are
non-melanoma skin cancer (NMSC). The most common NMSC is basal cell
carcinoma (BCC) followed by squamous cell carcinoma (SCC). In the US more
than 1.3 million NMSCs are diagnosed each year, while in Sweden
approximately 43000 cases were diagnosed in 2006. BCCs are slow growing
tumors that are locally invasive but rarely metastasize. In contrast,
SCCs are rapidly growing, invasive and have a metastatic potential.
Exposure to UV radiation is the most important risk factor for developing
BCCs and SCCs, followed by fair skin. NMSC occurs mostly as sporadic
cases, but is also associated with certain genetic diseases, including
the Nevoid basal cell carcinoma syndrome (NBCCS). NBCCS is characterized
by multiple BCCs, developmental defects and predisposition to other types
of tumors. Additionally, Multiple-self healing squamous epithelioma
(MSSE) is a genetic disease with tumors similar to SCCs, as its hallmark.
Both the NBCCS and MSSE responsible gene(s) are mapped to 9q22.3. The
following studies were performed in order to investigate the role of
genetic components in the development of these diseases and in NMSCs.
In Paper I, the NBCCS gene was further mapped to the 9q22.3 region and confirmed to be involved in familial and sporadic BCCs. Moreover, we obtained evidence that (a) the NBCCS gene is indeed a tumor suppressor gene (TSG) and (b) another TSG in the same chromosomal region is likely to have a role in the development of the squamous type of skin cancer.
In Paper II, the NBCCS gene, PTCH1, was verified to be the gene underlying NBCCS in Swedish patients, as inactivating PTCH1 mutations in the blood from these patients were identified. We also obtained evidence that the PTCH1 gene is an important TSG involved in the development of both sporadic and familial BCCs.
In Paper III, we investigated whether genetic alterations in the PTCH1 and XPA genes are critical for the development of the squamous type of skin cancer. However, no mutations but only a high degree of polymorphism of the PTCH1 gene could be detected. Therefore, both PTCH1 and XPA were excluded as of major importance for the development of this type of skin cancer. It is likely that other gene(s), distal to PTCH1, are involved in SCCs development.
The PTCH1 gene is mutated in different cancer types, but mainly in BCCs and other tumors associated with NBCCS. To better understand the role of PTCH1 in human disease, a locus-specific database, the PTCH Mutation Database, was set up in order to collect all relevant mutations. In Paper IV, the distribution pattern of PTCH1 mutations and single nucleotide polymorphisms that were compiled from the database were investigated. Unique distribution and mutation-type patterns that characterize the NBCCS disease, sporadic BCCs, BCCs from Xeroderma pigmentosum patients and sporadic medulloblastomas were identified. Additionally, domains and regions in the PTCH1 protein that are critical in the development of sporadic tumors and NBCCS were revealed.
Conclusion: PTCH1 mutations result in deregulated Hedgehog signaling and are of major importance in the pathogenesis of NBCCS and BCCs but not SCCs.
In Paper I, the NBCCS gene was further mapped to the 9q22.3 region and confirmed to be involved in familial and sporadic BCCs. Moreover, we obtained evidence that (a) the NBCCS gene is indeed a tumor suppressor gene (TSG) and (b) another TSG in the same chromosomal region is likely to have a role in the development of the squamous type of skin cancer.
In Paper II, the NBCCS gene, PTCH1, was verified to be the gene underlying NBCCS in Swedish patients, as inactivating PTCH1 mutations in the blood from these patients were identified. We also obtained evidence that the PTCH1 gene is an important TSG involved in the development of both sporadic and familial BCCs.
In Paper III, we investigated whether genetic alterations in the PTCH1 and XPA genes are critical for the development of the squamous type of skin cancer. However, no mutations but only a high degree of polymorphism of the PTCH1 gene could be detected. Therefore, both PTCH1 and XPA were excluded as of major importance for the development of this type of skin cancer. It is likely that other gene(s), distal to PTCH1, are involved in SCCs development.
The PTCH1 gene is mutated in different cancer types, but mainly in BCCs and other tumors associated with NBCCS. To better understand the role of PTCH1 in human disease, a locus-specific database, the PTCH Mutation Database, was set up in order to collect all relevant mutations. In Paper IV, the distribution pattern of PTCH1 mutations and single nucleotide polymorphisms that were compiled from the database were investigated. Unique distribution and mutation-type patterns that characterize the NBCCS disease, sporadic BCCs, BCCs from Xeroderma pigmentosum patients and sporadic medulloblastomas were identified. Additionally, domains and regions in the PTCH1 protein that are critical in the development of sporadic tumors and NBCCS were revealed.
Conclusion: PTCH1 mutations result in deregulated Hedgehog signaling and are of major importance in the pathogenesis of NBCCS and BCCs but not SCCs.
List of papers:
I. Holmberg E, Rozell BL, Toftgård R (1996). "Differential allele loss on chromosome 9q22.3 in human non-melanoma skin cancer." Br J Cancer 74(2): 246-50
Pubmed
II. Unden AB, Holmberg E, Lundh-Rozell B, Stähle-Bäckdahl M, Zaphiropoulos PG, Toftgård R, Vorechovsky I (1996). "Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation." Cancer Res 56(20): 4562-5
Pubmed
III. Eklund LK, Lindström E, Undén AB, Lundh-Rozell B, Ståhle-Bäckdahl M, Zaphiropoulos PG, Toftgård R, Söderkvist P (1998). "Mutation analysis of the human homologue of Drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin." Mol Carcinog 21(2): 87-92
Pubmed
IV. Lindström E, Shimokawa T, Toftgård R, Zaphiropoulos PG (2006). "PTCH mutations: distribution and analyses." Hum Mutat 27(3): 215-9
Pubmed
I. Holmberg E, Rozell BL, Toftgård R (1996). "Differential allele loss on chromosome 9q22.3 in human non-melanoma skin cancer." Br J Cancer 74(2): 246-50
Pubmed
II. Unden AB, Holmberg E, Lundh-Rozell B, Stähle-Bäckdahl M, Zaphiropoulos PG, Toftgård R, Vorechovsky I (1996). "Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation." Cancer Res 56(20): 4562-5
Pubmed
III. Eklund LK, Lindström E, Undén AB, Lundh-Rozell B, Ståhle-Bäckdahl M, Zaphiropoulos PG, Toftgård R, Söderkvist P (1998). "Mutation analysis of the human homologue of Drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin." Mol Carcinog 21(2): 87-92
Pubmed
IV. Lindström E, Shimokawa T, Toftgård R, Zaphiropoulos PG (2006). "PTCH mutations: distribution and analyses." Hum Mutat 27(3): 215-9
Pubmed
Issue date: 2008-05-02
Rights:
Publication year: 2008
ISBN: 978-91-7357-590-4
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