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NRAS and BRAF mutations in melanoma turnours in re ation to clinical characteristics: a study based on mutation screening by pyrosequencing
KTH, School of Biotechnology (BIO), Gene Technology.
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2006 (English)In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 16, no 6, 471-478 p.Article in journal (Refereed) Published
Abstract [en]

We have previously demonstrated the use of pyrosequencing to investigate NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog] mutations in melanoma biopsies. Here, we expanded the analysis to include BRAF (V-raf murine sarcoma viral oncogene homolog 1311), another member of the Ras-Raf-mitogen-activated protein kinase (MAPK) signalling pathway, and analysed a total of 294 melanoma tumours from 219 patients. Mutations in BRAF exons 11 and 15 were identified in 156 (53%) tumours and NRAS exon 2 mutations in 86 (29%) tumours. Overall, mutations in NRAS or BRAF were found in 242 of 294 tumours; (82%) and were found to be mutually exclusive in all but two cases (0.7%). Multiple metastases were analysed in 57 of the cases and mutations were identical in all except three, indicating that BRAF and NRAS mutations occur before metastasis. Association with preexisting nevi was significantly higher in BRAF mutated tumours (P=0.014). In addition, tumours with BRAF mutations showed a significantly more frequent moderate to pronounced infiltration of lymphocytes (P=0.013). NRAS mutations were associated with a significantly higher Clark level of invasion (P=0.022) than BRAF mutations. Age at diagnosis was significantly higher in tumours with NRAS mutations than in those with BRAF mutations (P=0.019). NRAS and BRAF mutations, however, did not influence the overall survival from time of diagnosis (P=0.7). In conclusion, the separate genotypes were associated with differences in several key clinical and pathological parameters, indicating differences in the biology of melanoma tumours with different proto-oncogene mutations.

Place, publisher, year, edition, pages
2006. Vol. 16, no 6, 471-478 p.
Keyword [en]
BRAF, melanoma, NRAS, pyrosequencing, n-ras mutations, malignant melanocytic lesions, human cutaneous melanoma, tumor progression, point mutations, cell-lines, cancer, skin, nevi, activation
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-16231DOI: 10.1097/01.cmr.0000232300.22032.86ISI: 000243159000001Scopus ID: 2-s2.0-33845592531OAI: oai:DiVA.org:kth-16231DiVA: diva2:334273
Note
QC 20100525Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Molecular Signatures of Cancer
Open this publication in new window or tab >>Molecular Signatures of Cancer
2006 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Cancer is an important public health concern in the western world, responsible for around 25% of all deaths. Although improvements have been made in the diagnosis of cancer, treatment of disseminated disease is inefficient, highlighting the need for new and improved methods of diagnosis and therapy. Tumours arise when the balance between proliferation and differentiation is perturbed and result from genetic and epigenetic alterations.

Due to the heterogeneity of cancer, analysis of the disease is difficult and a wide range of methods is required. In this thesis, a number of techniques are demonstrated for the analysis of genetic, epigenetic and transcriptional alterations involved in cancer, with the purpose of identifying a number of molecular signatures. Pyrosequencing proved to be a valuable tool for the analysis of both point mutations and CpG methylation. Using this method, we showed that oncogenes BRAF and NRAS, members of the Ras-Raf-MAPK pathway, were mutated in 82% of melanoma tumours and were mutually exclusive. Furthermore, tumours with BRAF mutations were more often associated with infiltrating lymphocytes, suggesting a possible target for immunotherapy. In addition, methylation of the promoter region of the DNA repair gene MGMT was studied to find a possible correlation to clinical response to chemotherapy. Results showed a higher frequency of promoter methylation in non-responders as compared to responders, providing a possible predictive role and a potential basis for individually tailored chemotherapy. Microarray technology was used for transcriptional analysis of epithelial cells, with the purpose of characterization of molecular pathways of anti-tumourigenic agents and to identify possible target genes. Normal keratinocytes and colon cancer cells were treated with the antioxidant N-acetyl L-cysteine (NAC) in a time series and gene expression profiling revealed that inhibition of proliferation and stimulation of differentiation was induced upon treatment. ID-1, a secreted protein, was proposed as a possible early mediator of NAC action. In a similar study, colon cancer cells were treated with the naturally occurring bile acid ursodeoxycholic acid (UDCA) in a time series and analysed by microarray and FACS analysis. Results suggest a chemopreventive role of UDCA by G1 arrest and inhibition of cell proliferation, possibly through the secreted protein GDF15.

These investigations give further evidence as to the diversity of cancer and its underlying mechanisms. Through the application of several molecular methods, we have found a number of potential targets for cancer therapy. Follow up studies are already in progress and may hopefully lead to novel methods of treatment.

Place, publisher, year, edition, pages
Stockholm: KTH, 2006. 59 p.
Keyword
: BRAF, NRAS, MGMT, methylation, pyrosequencing, microarray technology, gene expression analysis
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-3954 (URN)91-7178-348-2 (ISBN)
Public defence
2006-05-24, Sal FD5, AlbaNova, Roslagstullsbacken 21, Stockholm, 13:00
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Supervisors
Note
QC 20110121Available from: 2006-05-11 Created: 2006-05-11 Last updated: 2011-01-21Bibliographically approved

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