Oral Presentation 6th Australian Health and Medical Research Congress 2012

The genetics of metastatic melanoma- using our existing knowledge and high-throughput sequencing strategies to shed light on a rare form of melanoma (#247)

Ken Dutton-Regester 1
  1. Queensland Institute of Medical Research, Herston, QLD, Australia

Advances in sequencing technologies have enabled comprehensive investigations into the genetic mutations driving the growth of cancer, including metastatic melanoma. Recent studies have shown that melanomas arising from different areas of the body have distinct and characteristic “mutation profiles”. For example, melanomas arising sun-exposed cutaneous sites have high rates of mutation burden and frequently exhibit BRAF/ NRAS mutations; this is in contrast to melanomas arising from acral and mucosal linings of the body and the eye (uveal), which have a lower rate of mutation and typically harbour mutations in KIT and GNAQ/ GNA11 respectively. Using this knowledge, we can begin to address a number of important clinical questions, such as the mechanism of development in melanomas of unknown primary.

Melanoma of unknown primary (MUP) is a rare phenomenon whereby patients present with metastatic disease, but for which the primary site is not evident. Little is known about how MUP occur, however, theories explaining their occurrence include spontaneous regression of the primary tumor, origin of the melanoma from naevus cells in lymph nodes or internal organs, or the primary melanoma being unrecognized. To determine the likely site of origin of MUP, we performed a comprehensive genetic analysis of MUP using characteristic mutation profiles associated with various melanoma subtypes of known primary site.  This included exome sequencing of 11 early passage MUP cell lines, in addition to oncogenic mutation screening of an independent cohort of ~100 MUP FFPE tumours. Our results reveal that a large proportion of MUP have mutation profiles consistent with that of cutaneous sun exposed melanomas, supporting the theory that MUP arise from regressed or unrecognized primary cutaneous melanoma, or from nevus cells that have migrated to neighbouring lymph nodes. 

This talk will summarise recent findings from large scale next-generation sequencing studies characterising the melanoma genome, the latest therapuetic strategies for the treatment of this disease, and how these findings apply to our investigtation of MUP.