Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis

Abstract

Canine malignant melanoma, a significant cause of mortality in domestic dogs, is a powerful comparative model for human melanoma, but little is known about its genetic etiology. We mapped the genomic landscape of canine melanoma through multi-platform analysis of 37 tumors (31 mucosal, 3 acral, 2 cutaneous, and 1 uveal) and 17 matching constitutional samples including long- and short-insert whole genome sequencing, RNA sequencing, array comparative genomic hybridization, single nucleotide polymorphism array, and targeted Sanger sequencing analyses. We identified novel predominantly truncating mutations in the putative tumor suppressor gene PTPRJ in 19% of cases. No BRAF mutations were detected, but activating RAS mutations (24% of cases) occurred in conserved hotspots in all cutaneous and acral and 13% of mucosal subtypes. MDM2 amplifications (24%) and TP53 mutations (19%) were mutually exclusive. Additional low-frequency recurrent alterations were observed amidst low point mutation rates, an absence of ultraviolet light mutational signatures, and an abundance of copy number and structural alterations. Mutations that modulate cell proliferation and cell cycle control were common and highlight therapeutic axes such as MEK and MDM2 inhibition. This mutational landscape resembles that seen in BRAF wild-type and sun-shielded human melanoma subtypes. Overall, these data inform biological comparisons between canine and human melanoma while suggesting actionable targets in both species.

Longitudinal transcriptomic and genetic landscape of radiotherapy response in canine melanoma

“…MDM2 is a p53 negative regulator promoting tumour formation by targeting several tumour suppressors . This gene is transcriptionally regulated by p53, conversely overexpression because of amplification is reported in a variety of different tumours, including melanomas . In our study p53 mutation was not retrieved, supporting the hypothesis of a mutual exclusivity of the two mechanisms.…”

“…27,28 This gene is transcriptionally regulated by p53, conversely overexpression because of amplification is reported in a variety of different tumours, including melanomas. 14,29 In our study p53 mutation was not retrieved, supporting the hypothesis of a mutual exclusivity of the two mechanisms. Finally, loss in CDKN2A locus was observed in two dogs both at T0 and T1, and another dog acquired the deletion at disease progression confirming similarities with previous data in dog.…”

“…Recently, two extensive NGS studies have been conducted in canine MM to map the genomic landscape of this tumour but progression after therapy were not described. 14,15 In the current study, WES was performed in dogs with treatmentnaive MM at diagnosis and at disease progression to highlight the genetic mechanisms beyond progression. In addition, wholetranscriptome sequencing (RNA-seq) was performed on the same samples.…”

“…In dogs, investigations to identify global somatic mutations by next generation sequencing (NGS) were previously conducted in lymphoma and in rare congenital, retinal and neurodegenerative disorders. Recently, two extensive NGS studies have been conducted in canine MM to map the genomic landscape of this tumour but progression after therapy were not described …”

Array Comparative Genomic Hybridization Analysis Reveals Significantly Enriched Pathways in Canine Oral Melanoma

“…The syntenic human regions were then compared with published data (5,7,8,24), to detect those regions shared by both hMMs and COMs. A comparative analysis between data produced herein, and recently published studies regarding the detection of CNAs in the canine genome through several techniques (as WES, WGS, aCGH, and FISH) (8,24,27,28), was also performed.…”