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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

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

Awarded: NOK 2.4 mill.

There are three main types of skin cancer, of which malignant melanoma is the most serious. Each year over 1,700 Norwegians are diagnosed with melanoma. During recent years new and very promising treatments have become available, but still around 20% of melanoma patients die from the disease. People with light skin color are particularly vulnerable, and melanoma has become the most commonly diagnosed form of cancer in young European adults. What makes melanoma so serious is that the tumors have a tendency to spread in the body (metastasize). In addition, some patients experience one or more additional melanomas later in life or they get another type of cancer. The reason is probably a combination of genetic and environmental factors, but little is known about why some persons develop metastases/new cancers and others do not. The aim of the project was to reduce this knowledge gap in order to be able to identify high-risk melanoma patients. The partners in the project have had access to samples from over 2,000 patients who have undergone surgical treatment for melanoma. Of these, 450 have developed metastases or new tumors. We have been using advanced genetic techniques to analyze mutations in tumor and blood samples from a selected group of patients who quickly experienced metastatic spread or new tumors. The results were compared with data from patients who have lived for a long time without new tumors arising. We are particularly interested in how genetic elements stemming from retroviruses might be involved in the most serious disease cases. Our initial findings will now be tested further by screening larger patient materials for the most interesting genetic alterations. The aim is to establish a gene-based test that may help to identify those melanoma patients that have the greatest risk of disease reoccurrence or acquiring new tumors.

(1) Kunnskapen om kva for tyding genetiske variantar har for spreiing av malignt melanom har auka. (2) Vi veit meir om kva for genetiske variantar det er som påverkar melanomutvikling i norske pasientar. (3) Gjennom det internasjonale samarbeidet i prosjektet har vi etablert eit nettverk med leiande europeiske melanomforskarar som vil komme til nytte i den vidare forskinga vår på denne kreftforma.

Malignant melanoma is associated with the worst outcome among skin cancers due to its propensity to metastasize and its resistance to therapy. It afflicts mainly Caucasian populations where about one in 60 persons will be diagnosed with melanoma during their lifetime. 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, 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 prognostic genetic markers. 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. The development of prognostic tests for clinical use, based on genetic markers, is the ultimate goal of the proposal.

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering