The largest integrative analysis of cutaneous melanoma in 331 patients performed by The Cancer Genome Atlas researchers establishes a framework for melanoma genomic classification into 4 subtypes: BRAF, RAS, NF1, and triple-wild-type. The study identifies additional subtypes that may benefit from MAPK- and RTK-targeted therapies. In addition, multi-dimensional analyses identify immune signatures associated with improved survival.
The five-year study resulted from an international collaboration of over 300 researchers. This comprehensive genomic classification of melanomas creates a framework that could be used to further personalise therapeutic decision-making in both the targeted and immunotherapy arena, as well as to develop more impactful prognostic and predictive models. The results from the study are published in the June 18 issue of Cell.
Genomic classification of cutaneous melanoma: Graphical abstract
Reprinted from Cell;161(7):1681-1696, Copyright (2015), with permission from Elsevier.
The researchers described the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. They established a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes:
- mutant BRAF,
- mutant RAS,
- mutant NF1, and
- triple-wild-type.
The scientists found all four genomic subtypes share common downstream signalling pathways, but differ in how they activate these pathways.
Understanding the genomic underpinnings of melanoma may provide additional information on other existing therapies. For example, BRAF and MEK inhibitor combinations are now used to treat patients with BRAF mutant melanomas, and MEK inhibitor combinations are being explored for RAS mutant melanomas. Pre-clinical studies have already demonstrated that some NF1 melanoma cell lines respond to MEK inhibitors, but more work is needed to identify responders and non-responders within this new melanoma subtype, as well as to determine strategies to treat patients with triple-wild-type melanoma.
Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the triple-wild-type subtype.
There was no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival.
This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumour stroma immunobiology. The team hypothesizes that this information could prove useful in the emerging field of immunotherapy, which has shown success in treating late-stage melanoma patients.
This international collaboration from more than 20 tissue source sites and 50 institutions around the globe included pathologists who analyzed samples for immune infiltration, computational biologists who identified significant driving genetic alterations, and clinician scientists who aided in acquiring samples and interpreting data.
The study was funded by the US National Institute of Health grants.