Clinical and molecular characteristics of aggressive melanoma
thesisposted on 27.02.2017, 02:26 by Mar, Victoria Jane
Despite awareness campaigns, there has been no reduction in melanoma incidence or mortality. Thick, poor prognosis melanomas can be the result of diagnostic delay, but are often due to rapid tumor growth. Nodular melanomas (NM) are known to grow more rapidly and do not conform to the diagnostic criteria applied to more common subtypes. NM possibly represents a more aggressive subtype, though tumor subtype has not been found to be a prognostic factor independent of tumor thickness. It is unclear whether primary tumor growth rate provides prognostic information additional to thickness and mitotic rate. Rapid advances in molecular sequencing techniques have led to significant discoveries in the genetic landscape of melanoma and subsequent therapies for advanced disease. Correlating clinical features of cutaneous melanomas with molecular data may help to identify the molecular aberrations that drive aggressive tumor behavior. The aims of this thesis were to identify clinical characteristics associated with aggressive melanomas and to investigate molecular aberrations that might be responsible for more aggressive tumor development. The first part of the thesis investigates melanoma diagnosis, incidence and mortality using data from the Victorian Cancer Registry. Melanoma growth rate and mutational status are assessed as prognostic factors in a cohort of patients from the Victorian Melanoma Service and Peter MacCallum Cancer Centre. The second part of the thesis involves molecular sequencing of a discovery set of 34 cutaneous melanomas and validation of relevant findings in a cohort of approximately 800 patients. Studies in Part 1 of this thesis show that rapidly growing melanomas have a poorer prognosis, independent of thickness, in early (stage I and II) disease. Nodular tumors are found to contribute disproportionately to mortality in Victoria, likely by virtue of their more rapid vertical growth. Molecular studies detailed in Part 2 of the thesis reveal two main groups of cutaneous melanoma: those with a low mutation burden which tend to be BRAF mutant, and those with a high mutation burden associated with chronic sun exposure, which tend to be BRAF/NRAS wild-type. Long-term follow-up of 196 patients with Stage I-III disease reveals patients with BRAF mutant tumors having poorer melanoma-specific survival after adjustment for known prognostic factors. In a larger cohort of 812 patients, BRAF mutant tumors were significantly thinner compared to BRAF wild-type, but were more likely to present with regional nodal disease at diagnosis. These results suggest that the presence of a dominant driver mutation is important for tumor progression. Supporting this, melanomas harboring the RAC1 P29S mutation were found to be thicker and more likely to involve regional lymph nodes at diagnosis compared to RAC1 wild-type cases. RAC1 mutations were also more common in the NM subtype. A strong association was found between RAC1 protein immunoreactivity and the presence of a BRAF mutation, which may explain why BRAF mutant tumors have a propensity to spread to regional nodes early despite being thinner tumors. RAC1 signaling pathways may be important therapeutic targets for both BRAF mutant and wild-type disease.