Oral Presentation ASPCR-ASDR Conference 2013

BRAF/NRAS wild-type melanomas have a high mutation load correlating with histological and molecular signatures of UV damage   (#44)

Victoria Mar 1 , Stephen Wong 1 , Jason Li 1 , Richard Scolyer 2 , Catriona McLean 3 , Anthony T Papenfuss 4 , Richard Tothill 1 , Hojabr Kakavand 2 , Graham J Mann 5 , John F Thompson 6 , Andreas Behren 7 , Jonathan Cebon 7 , Rory Wolfe 8 , John W Kelly 9 , Alexander Dobrovic 1 , Grant McArthur 1
  1. Peter MacCallum, East Melbourne, Vic, Australia
  2. Pathology, Melanoma Institute Australia, Sydney, Australia
  3. Anatomical Pathology, Alfred Hospital, Melbourne, Australia
  4. Bioinformatics, WEHI, Melbourne, Australia
  5. Oncology, Melanoma Institute Australia, Sydney, Australia
  6. Surgical Oncology, Melanoma Institute Australia, Sydney, Australia
  7. Molecular Oncology, Ludwig Institute, Melbourne, Australia
  8. Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
  9. Victorian Melanoma Service, Melbourne, Australia

Purpose: The mutation load in melanoma is high compared to other tumor types due to extensive UV damage. Translation of exome sequencing data into clinically relevant information is therefore challenging. Melanoma exome sequencing studies have predominantly concentrated on mutations identified in cell lines generated from melanoma metastases. This study sought to characterize mutations identified in primary cutaneous melanomas and correlate these with clinico-pathologic features.

 Experimental design: DNA was extracted from 34 fresh frozen primary cutaneous melanomas and matched peripheral blood. Tumor histopathology was reviewed by two dermatopathologists. Exome sequencing was performed and mutation rates were correlated with age, sex and tumor site and histopathologic variables. Differences in mutations between categories of solar elastosis, pigmentation and BRAF/NRAS mutational status were investigated.

 Results: The average mutation rate was 12 per megabase, similar to published results in metastases. Tumors arising in severely sun-damaged (SSD) skin (p=0.003) and BRAF/NRAS wild-type tumors (p=0.0001) had higher mutation loads. There was an inverse correlation between mutation rate and tumor thickness (Spearman r=-0.4, p=0.02). Tandem CC>TT/GG>AA mutations comprized 70% of all dinucleotide substitutions and were more common in tumors arising in SSD skin (p=0.0008) and in BRAF/NRAS wild-type tumors (p=0.0007). Targetable and potentially targetable mutations in wild-type tumors, including NF1, KIT and NOTCH1, were spread over various signaling pathways.

 Conclusion: Melanomas arising in SSD skin have higher mutation loads and contain a spectrum of molecular subtypes compared to BRAF and NRAS-mutant tumors. It is likely that a number of genomic insults are required for melanoma progression in this group. Potentially targetable mutations in wild type tumors are spread over different signaling pathways and this may have implications for therapeutic approaches in the future. Classification of melanoma into BRAF mutant, NRAS mutant and high mutation load groups may be helpful for identification of patients more likely to respond to combined drug therapies.