Title: Identification of genetic markers involved in development of metastases and second cancers in melanoma.


Project Coordinator:
Rajiv KUMAR (Germany) German Cancer Research Center, Heidelberg


Project Partners:
Nelleke GRUIS (The Netherlands) Leiden University Medical Center, Leiden
Anders MOLVEN (Norway) University of Bergen, Bergen
Dace PJANOVA (Latvia) Latvian Biomedical Research and Study Center, Riga
Maurizio CARDELLI (Italy) INRCA-IRCCS, Istituto Nazionale di Riposo e Cura per Anziani, Ancona


Project Abstract:
Malignant melanoma, one of the three major skin cancers, is associated with the worst outcome due to its propensity to metastasize and its resistance to therapy. It afflicts mainly Caucasian populations and due to its increasing prevalence, approximately, one in 60 persons will be diagnosed with melanoma during their lifetime. Within Europe, melanoma has become the most common cancer in young adults. About 20 percent of melanomas progress to regional and distant metastases. Additionally, development of secondary primary cancers in melanoma patients contributes to enhanced personal and financial burden. The involvement of genetic factors in combination with environmental factors and individual phenotypes are known to increase the risk of primary melanoma. However, the genetic factors that pre-dispose to development of metastases or second primary cancers in melanoma patients remain mostly unknown. Taking advantage of advanced techniques, we propose to identify genetic alterations having a prognostic value in development of metastases and second melanomas in asymptomatic patients that have undergone surgical treatment for primary cutaneous melanoma. We will use a unique collective collection of samples from over 2200 melanoma patients (including young adults and elderly patients) of whom more than 450 developed metastases or second melanomas, recruited at the partner centers. We propose to use a two-stage strategy to discover genetic markers prognostic of metastases and second melanomas. In the discovery phase we will use exome-sequencing and genome wide analysis of retroelements to screen tumor and normal DNA from a subgroup of melanoma patients with and without metastases and second melanomas. We will then validate identified markers in the entire pooled collection of tumors tissue samples with clinical data available within the resources of the consortium. This study will reveal genetic markers that can be useful in identifying patients who run a substantial risk of developing metastases or second melanomas. Early identification of such patients remains a valid medical issue. The development of a prognostic test based on genetic markers for clinical use is the ultimate goal of the proposal.

Publishable Summary:
Malignant melanoma, one of the three major skin cancers, is associated with the worst outcome due to its propensity to metastasize and resistance to therapy of advanced disease. About 20 percent of melanomas progress to local and distant metastases. Additionally, development of secondary primary melanomas contributes to enhanced personal burden. At present the treatment of metastatic melanoma due to onset of resistance remains an exercise in disease management. Therefore, identification of genetic markers of advanced disease that could help in identification of patients with primary melanoma at particularly high risk of developing metastases or secondary melanomas remains a crucial task and the aim of the present project. To fulfil the aims of the project, tumors from primary melanoma patients with and without metastases were screened for genetic alterations by exome sequencing and genome-wide analysis of retroelement insertions. In addition epigenetic alterations in primary melanomas were also investigated. Exome sequencing has been also been carried out on patients with multiple melanomas. The data from those analyses have been and are currently being validated in our unique collection of tumors from melanoma patients. The markers identified so far are being tested through functional studies for possible use in clinical practice. Besides detecting numerous novel mutations and identifying the functional pathways involved in melanoma, our data showed that the TERT promoter mutations defined patients with poor survival. In addition, we identified a combination of specific mutations that defines patients at risk for developing advanced disease and poor survival. Moreover, we also observed that the overall mutational burden has an effect on progression and survival in melanoma patients.

(Project funded under JTC 2013)