From MMDM

Smruti J Vidwans¹, Keith T Flaherty², David E Fisher³, Jay M Tenenbaum¹, Michael D Travers^1** & Jeff Shrager^4,1.

Editor: George D Lundberg¹

Acknowledgements: We thank Prof. Boris Bastian and Prof. Stephen Hodi for overall guidance and for pointing us to key pathways and genetic tests and Dr. Gavin Gordon for his thoughtful comments and proof-reading of this document.

_{1 CollabRx Inc. Palo Alto CA 94301, USA 2 Department of Dermatology, Cutaneous Biology Research Center, and Melanoma Program, Massachusetts General Hospital, Boston, MA 021114, USA, 3 Massachusetts General Hospital Cancer Center, Boston, MA 02114, 4 Symbolic Systems Program (Consulting) & Stanford University CA 94301 USA,** Current address: SRI International, Artificial Intelligence Department, Menlo Park CA94025.}

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Subtypes are defined based on the status of key melanoma genes/ pathways & their combinations. Each subtype is defined by one key oncogene/tumor suppressor (such as BRAF for subtypes 1.1 to 1.4 and c-KIT for subtype 2.1) either by itself or in combination with others that play a supportive role (such as PTEN, AKT and CDK4 in the case of subtypes 1.2, 1.3 and 1.4).

The following two tables of subtypes are generally organized by order of importance of associated oncogene/tumor suppressor, prevalence and potential for therapeutic intervention. We believe that the oncogenes that define subtypes in table one are capable of serving as the dominant oncogene and putative point of intervention for therapy. Whereas, the oncogenes and tumor suppressor genes that define subtypes in the second table play a supportive role and typically co-exist with the mutations outlined in the first table.

Melanomas that do not fit into the 8 currently defined subtypes are parked in subtype 9 (TBD) pending further research. Additionally, melanomas that do fit into an established subtype but do not respond as predicted may necessitate splitting of that subtype. It is our expectation that the reference model will thus serve to focus translational research on issues that may directly impact patient care.

Primary Melanoma Molecular SubtypesSecondary Melanoma Molecular Subtypes

I. MAPK pathway
1.1, 1.2, 1.3, 1.4

II. c-KIT pathway
2.1

III. GNAQ/GNA11 pathway
3.1, 3.2

IV. NRAS pathway
4.1

V. MITF pathway
5.1

VI. AKT/PI3K pathway
6.1, 6.2, 6.3

VII. CDK pathway
7.1, 7.2, 7.3

VIII. P53/BCL pathway
8.1, 8.2

IX. New subtype