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Clinical aspects of molecular profiles in metastatic malignant melanoma

Ekedahl, Henrik LU (2017)
Abstract
Malignant melanoma is a heterogeneous, malignant neoplastic disease, most often originating in the skin. Melanoma is characterized by a high mutational load and has a vastly variable prognosis, depending on disease stage. Genetic aberrations in the mitogen-activating protein kinase (MAPK) pathway are important in melanoma, of which mutations in BRAF and NRAS are the most common. Additionally, recurrent mutations in the promoter of TERT, the catalytic subunit of telomerase, have been associated with a poor prognosis in primary melanoma. The introduction of the first T-cell activating antibody, ipilimumab, and the first selective inhibitor of mutant BRAF, vemurafenib, marked the beginning of a new paradigm in the... (More)
Malignant melanoma is a heterogeneous, malignant neoplastic disease, most often originating in the skin. Melanoma is characterized by a high mutational load and has a vastly variable prognosis, depending on disease stage. Genetic aberrations in the mitogen-activating protein kinase (MAPK) pathway are important in melanoma, of which mutations in BRAF and NRAS are the most common. Additionally, recurrent mutations in the promoter of TERT, the catalytic subunit of telomerase, have been associated with a poor prognosis in primary melanoma. The introduction of the first T-cell activating antibody, ipilimumab, and the first selective inhibitor of mutant BRAF, vemurafenib, marked the beginning of a new paradigm in the treatment of metastatic melanoma. The rapidly increasing number of treatment options warrants improved prognostic and predictive capability. The aim of this thesis was to examine clinical aspects, in particular prognostic and predictive values, of mutational and transcriptional profiles in metastatic melanoma.
Frozen tumor samples from the Lund Melanoma Study Group molecular melanoma cohort were subjected to mutation analysis of BRAF, NRAS (paper I), and the TERT promoter (paper III), as well as global gene expression
analysis and deep targeted sequencing (paper II). Patients with BRAF-mutant tumors not treated with BRAF inhibitor showed an inferior overall survival from stage IV disease compared with patients treated with BRAF inhibitor (hazard ratio (HR) 2.35, confidence interval (CI) 1.10-5.01). There was a trend towards better prognosis for patients with wildtype tumors compared with BRAFV600E-mutants (HR 0.64, CI 0.39-1.04). TERT promoter mutations were not associated with prognosis in non-acral cutaneous metastatic melanoma. Two hundred
fourteen melanoma samples, mostly metastases, were classified into four gene expression phenotypes, reflecting distinct biological features: ‘proliferative’, ‘pigmentation’, ‘high-immune response’, and ‘normal-like’. Mutational
patterns were similar across the phenotypes. Among patients with regional metastatic disease, the proliferative and the pigmentation phenotypes were associated with an increased risk of distant metastasis (HR 2.8, CI 1.43-
5.57, and HR 1.9, CI 1.05-3.28) compared with the high-immune response phenotype. In two external datasets, the proliferative phenotype was found to be enriched in tumors progressing on MAPK inhibition. In paper IV, the one-year clinical use of a next generation sequencing-based 26-genes mutation panel in advanced melanoma was characterized in relation to given treatment. The fraction of BRAF hotspot-mutant alleles was highly heterogeneous, and patients with tumors harboring a fraction in the highest and lowest deciles progressed early on MAPK inhibition. In conclusion, metastatic melanoma displays various mutational and transcriptional profiles, relevant for prognosis and treatment prediction. (Less)
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author
supervisor
opponent
  • associate professor Ny, Lars, University of Gothenburg, Sahlgrenska Academy.
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Melanom, Prognos, BRAF, TERT, Genuttryck, Next generation sequencing, Melanoma, Prognosis, BRAF, TERT, Gene Expression, Next generation sequencing
pages
83 pages
publisher
Lund University, Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32, Lund
defense date
2017-05-11 13:00
ISBN
978-91-7619-446-1
language
English
LU publication?
yes
id
9ac595c1-4e7d-40e1-8ddc-d5ff305f2eb5
date added to LUP
2017-04-19 20:44:45
date last changed
2017-05-24 12:36:19
@phdthesis{9ac595c1-4e7d-40e1-8ddc-d5ff305f2eb5,
  abstract     = {Malignant melanoma is a heterogeneous, malignant neoplastic disease, most often originating in the skin. Melanoma is characterized by a high mutational load and has a vastly variable prognosis, depending on disease stage. Genetic aberrations in the mitogen-activating protein kinase (MAPK) pathway are important in melanoma, of which mutations in<i> BRAF</i> and <i>NRAS</i> are the most common. Additionally, recurrent mutations in the promoter of <i>TERT</i>, the catalytic subunit of telomerase, have been associated with a poor prognosis in primary melanoma. The introduction of the first T-cell activating antibody, ipilimumab, and the first selective inhibitor of mutant BRAF, vemurafenib, marked the beginning of a new paradigm in the treatment of metastatic melanoma. The rapidly increasing number of treatment options warrants improved prognostic and predictive capability. The aim of this thesis was to examine clinical aspects, in particular prognostic and predictive values, of mutational and transcriptional profiles in metastatic melanoma.<br/>Frozen tumor samples from the Lund Melanoma Study Group molecular melanoma cohort were subjected to mutation analysis of <i>BRAF</i>, <i>NRAS</i> (paper I), and the <i>TERT</i> promoter (paper III), as well as global gene expression<br/>analysis and deep targeted sequencing (paper II). Patients with <i>BRAF</i>-mutant tumors not treated with BRAF inhibitor showed an inferior overall survival from stage IV disease compared with patients treated with BRAF inhibitor (hazard ratio (HR) 2.35, confidence interval (CI) 1.10-5.01). There was a trend towards better prognosis for patients with wildtype tumors compared with <i>BRAFV600E</i>-mutants (HR 0.64, CI 0.39-1.04). <i>TERT</i> promoter mutations were not associated with prognosis in non-acral cutaneous metastatic melanoma. Two hundred<br/>fourteen melanoma samples, mostly metastases, were classified into four gene expression phenotypes, reflecting distinct biological features: ‘proliferative’, ‘pigmentation’, ‘high-immune response’, and ‘normal-like’. Mutational<br/>patterns were similar across the phenotypes. Among patients with regional metastatic disease, the proliferative and the pigmentation phenotypes were associated with an increased risk of distant metastasis (HR 2.8, CI 1.43-<br/>5.57, and HR 1.9, CI 1.05-3.28) compared with the high-immune response phenotype. In two external datasets, the proliferative phenotype was found to be enriched in tumors progressing on MAPK inhibition. In paper IV, the one-year clinical use of a next generation sequencing-based 26-genes mutation panel in advanced melanoma was characterized in relation to given treatment. The fraction of<i> BRAF</i> hotspot-mutant alleles was highly heterogeneous, and patients with tumors harboring a fraction in the highest and lowest deciles progressed early on MAPK inhibition. In conclusion, metastatic melanoma displays various mutational and transcriptional profiles, relevant for prognosis and treatment prediction.},
  author       = {Ekedahl, Henrik},
  isbn         = {978-91-7619-446-1},
  keyword      = {Melanom,Prognos,BRAF,TERT,Genuttryck,Next generation sequencing,Melanoma,Prognosis,BRAF,TERT,Gene Expression,Next generation sequencing},
  language     = {eng},
  pages        = {83},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {Clinical aspects of molecular profiles in metastatic malignant melanoma},
  year         = {2017},
}