Longitudinal transcriptomic and genetic landscape of radiotherapy response in canine melanoma

Abstract

Canine malignant melanoma (MM) is a highly aggressive tumour with a low survival rate and represents an ideal spontaneous model for the human counterpart. Considerable progress has been recently obtained, but the therapeutic success for canine melanoma is still challenging. Little is known about the mechanisms beyond pathogenesis and melanoma development, and the molecular response to radiotherapy has never been explored before. A faster and deeper understanding of cancer mutational processes and developing mechanisms are now possible through next generation sequencing technologies. In this study, we matched whole exome and transcriptome sequencing in four dogs affected by MM at diagnosis and at disease progression to identify possible genetic mechanisms associated with therapy failure. According to previous studies, a genetic similarity between canine MM and its human counterpart was observed. Several somatic mutations were functionally related to MAPK, PI3K/AKT and p53 signalling pathways, but located in genes other than BRAF, RAS and KIT. At disease progression, several mutations were related to therapy effects. Natural killer cell‐mediated cytotoxicity and several immune‐system‐related pathways resulted activated opening a new scenario on the microenvironment in this tumour. In conclusion, this study suggests a potential role of the immune system associated to radiotherapy in canine melanoma, but a larger sample size associated with functional studies are needed.

Prognostic value of somatic focal amplifications on chromosome 30 in canine oral melanoma

“…Nevertheless, taking into account the MI and the tumour location, the CFA 30 amplification was not any more significant, probably because of its strong association with the MI. Indeed, genes lying on this recurrent amplified region probably bring an advantage for the proliferation and progression of the tumour, such as TRPM7 involved in the MAPK pathway . Focal amplifications along CFA 10 were often found in two distinct regions covering the targeted genes MDM2 and the cycline‐dependent‐kinase CDK4 , and this association was demonstrated in a previous study .…”

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

“…MDM2 (8,27,28), CDK4 (8,28), and CDKN2A (24,27,28), which were found altered by other authors, were not identified as significantly aberrated by GISTIC algorithm in…”

“…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.…”

“…22 (8,24,27,28) together with a sigmoidal trend (a complex alternation of copy number gains followed immediately by copy number losses), in CFA 10 and 30 (8,24,28). In this study, CFA 10 and CFA 30 also showed the sigmoidal trend, and 7 of the regions found imbalanced were already reported in recent literature (Tables 2A,C) (24); with an § the syntenic regions reported by Curtin et al (5); no regions were shared with Lyu et al (7).…”

“…Several genes which have been indicated to play a significant role in the development of COMs and hMMs were involved in CNAs, comprising gains of TRPM7 (24,27), MYC (8,24), KIT (24,28), WIF1 (8), SLC27A2, GABPB1, USP8, SPPL2A, CYP19A1 (27) ( Table 4A) and losses of RB1 (8,24), LCP1, BUB1B, KNSTRN, CYSLTR2 (8), SPRED1 (24,27), and FAM98B (27) (Table 4B). On the contrary, other genes such as MDM2 (27,28) or CDK4 (8, 28), were not confirmed by our study. Finally, it is noteworthy that other genes involved in CNAs such as ADAM10, and genes belonging to gene families SNORA, SNORD, SLC25A, RPL, and RBM, have been recently shown to be highly expressed in metastatic COMs (32).…”