Determining if there are distinct molecular pathways involved in the development of nodular melanomas and evaluating the clinical, and pathologic features of these poorly understood melanoma

The aim of the project is to determine if nodular melanomas (the type of malignant skin cancer associated with the highest mortality in Victoria), have distinct molecular profiles. This will be carried out by examining both a number of candidate molecules in nodular melanomas plus examining a panel of novel genomic changes in these molecules using next generation sequencing. These finding will be integrated with ongoing efforts in the Victorian Melanoma Service to develop imaging technologies for early detection of melanoma.

Melanomas can be classified by histology into four histological subtypes: lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma and the previously little understood entity of nodular melanoma (NM).

Pure NM comprises only 8.5% of the incident melanoma in Victoria but more than 60% of melanomas that are defined as “thick” and are also responsible for almost 50% of the melanoma associated mortality (Devitt B, Liu W, Salemi R, et al. Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma. Pigment Cell Melanoma Research 2011;24:666-672. (I.F. 4.75)). NM does not fulfill the ABCD (Area, Border, Colour, Diameter) diagnostic criteria that apply to other melanomas and are frequently misdiagnosed. They are not associated with the risk factors identified for more common melanomas such as the presence of large numbers of melanocytic naevi and dysplastic naevi or a history of sunburns. They affect a different target population and are more common in the elderly and in men than other melanomas. They grow much more rapidly than other melanomas (0.5mm of thickness per month vs 0.1mm of thickness per month) and diagnostic delays carry a heavy penalty in mortality terms. Not only are the clinical features distinctive but recent studies have defined distinctive dermoscopic and confocal microscopic features.

Recent population data from the Victorian Cancer Registry has indicated that although melanoma mortality is falling in younger people, especially women, there has been a staggering 26% increase in mortality from melanoma in men age > 60 years over the last decade. As NM’s represent approximately 40% of melanomas in this population (Liu, Kelly and McArthur,) we suggest that the aggressive biology associated with NM may be the most significant explanation of this excess mortality. Taken together, these studies suggest that NM may have unique biological features indicating a need for separate prevention, early detection and treatment strategies. As an atypical and under recognized form of melanoma and the major contributor to mortality there is clearly an opportunity to reduce mortality through a better understanding of NM.

We therefore consider it a major priority in melanoma research to better understand the molecular features of NM

In work already carried out at the Peter MacCallum Cancer Centre and emerging work in the literature lead by a collaborator Boris Bastian it was fount that there are distinct molecular features of lentigo maligna melanoma with low rates of mutations in BRAF4,5 and NRAS 6 (Devitt et al) and higher rates of mutations in KIT7.

In contrast superficial spreading melanomas have a higher frequency of the opposite genotype with higher frequencies of BRAF and NRAS mutations and lower frequencies of KIT mutations.

Little published data is available on NM, however our preliminary analysis of 251 cases of melanoma containing 46 NM suggest a lower frequency of BRAF mutations but a higher frequency of NRAS mutations that occur at twice the frequency of superficial spreading melanoma (26 v 14%) and six times the frequency of lentigo maligna melanoma (26 v 4%).

Although preliminary, this data is suggesting that NM may have distinct molecular features. We therefore hypothesize that NM is characterized by aberrations in distinct molecular pathways that are associated with aggressive behaviour, provide insights into the molecular pathogenesis of melanoma, and open new opportunities for diagnosis and therapeutic intervention in our collaborative clinical trial program.

Understanding human melanoma progression through developing laboratory models.

A fundamental limitation in improving outcomes for cancer patients is the lack of experimental approaches that are available for studying human cancer cells in a way that mimics human malignant disease.

In this project, a modified “xenotransplantation” assay has been developed that permits with remarkably high efficiency the growth of tumors in mice from cancer cells donated by melanoma patients.

This assay is being used to identify key features of melanoma growth and to identify the genetic changes that control this growth and thus that could be targeted by new therapies.

The results obtained from these studies are being compared with data from the Melbourne Melanoma Project in order to determine whether the genetic and biological features of tumors grown through mouse xenotransplantation are also present in the corresponding patient’s tumour. If so, this will provide a strong rationale for using mouse xenotransplantation to enabe the more rapid development of new and better anti-melanoma therapies.