Molecular and Genetic Properties of Changing Naevi
Centre of Research Excellence (CRE)
Start / End Date: 2016 to 2019
Program III will study the rapid naevi changes in people with advanced melanoma undergoing targeted therapies and/or immunotherapy.
How rapidly are naevi changing in Stage III and IV melanoma patients undergoing targeted therapies and/or immunotherapies and which germline genotype and molecular naevi characteristics predict these changes?
Are involuting and/or growing naevi clinical markers of response to targeted therapies and/or immunotherapies?
What differences in the somatic genotype of naevi are characterizing changeable naevi?
What defines distinct epigenetic profiles attributable to changeable naevi and how does this relates to dermoscopic and histopathologic naevus types?
Objectives: Improve understanding of the naevi life cycle under current targeted therapies and immunotherapies with an emphasis on the conversion into atypical lesions and early melanomas.
State of the evidence: The CRE Investigators have previously described that naevi change frequently in children and adolescents, but even in adults naevus volatility is much greater than previously thought and largely independent of a person’s naevus count. However, the molecular and genetic profile of changing naevi in adults is unknown.
Program III will focus on changing naevi in advanced melanoma patients. Melanoma patients with loco-regional or distant metastases are now being successfully treated with targeted therapies and/or immunotherapies. In contrast to traditional chemotherapy, new therapies such as BRAF inhibitors offer prolonged progression-free survival and overall survival. Under such treatment, keratinocyte skin cancers and new melanomas become more frequent and phenotypic changes in naevi are very common and detectable within months.
CRE staff and students will study the molecular properties of these rapidly changing naevi following already established protocols.
Proposed research: To undertake a prospective clinical study with epidemiological analysis.
Research will be undertaken to define the molecular properties of changeable naevi. A minimum of 80 melanoma patients (Stage III and IV) will be recruited over one year with a two year follow-up. Patients enrolled for treatment with targeted therapies and/or immunotherapies at the Cancer Services (PAH Hospital) will be asked to join this study for imaging with 3-D total body photography and dermoscopy imaging of all naevi larger > 5mm. As well as the images, baseline demographic data and saliva, for isolation of germline DNA, will also be obtained. Upon follow-up, stable, growing and involuting naevi will be sampled using our standardized protocol described in the CRE Core Study, assuming that study participants will donate an average of 2 naevi for research purposes.
We plan to use direct or whole genome amplified DNA to perform whole exome sequencing to detect rare variants and somatic mutations; and SNP arrays to determine copy number variations. RNA will undergo RNA-seq to determine absolute expression values. We will also perform miRNA-seq. Data analysis will be conducted, with this highly informative data being directly compared to other large publically available datasets for melanoma including The Cancer Genome Atlas (TCGA).
The uniqueness of this research project is the correlation of stable and changeable naevi with genotypic profiling under targeted therapies and/or immunotherapies with techniques such as dermoscopy, 3-D whole body photography, and current molecular techniques resulting in molecular markers predictive of subtle changes in naevi morphology.
Expected outcomes: To acquire new knowledge about molecular and genetic characteristics of changeable and stable naevi based on individual genetic phenotypes.
Significance and innovation: Deciphering genetic and molecular characteristics of changeable and stable naevi will enable researchers to determine the naevi life cycle with implications for melanoma prevention and naevus surveillance programs.