Canine Oral Melanoma Genomic and Transcriptomic Study Defines Two Molecular Subgroups with Different Therapeutical Targets

Cancers

Kerstin Lindblad-Toh¹  Aline Primot²  Stephanie Mottier²  Edouard Cadieu²  Sébastien Corre²  Christophe Hitte²  Thomas Derrien²  Laura Bachelot²  Armel Houel²  Benoit Hedan²  Anais Prouteau²  Camille Kergal²  Catherine André²  David Gilot²  Nadine Botherel²  Jérôme Abadie³  Laurence Cornevin⁴  Florian Cabillic⁴ 

[1] Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA;IGDR—UMR 6290, CNRS, University of Rennes 1, 35000 Rennes, France;Laboniris, Department of Biology, Pathology and Food Sciences, Oniris, 44300 Nantes, France;Laboratoire de Cytogénétique et Biologie Cellulaire, CHU de Rennes, INSERM, INRA, University of Rennes 1, Nutrition Metabolisms and Cancer, 35000 Rennes, France;

关键词: mucosal melanoma;    dog model;    oncogenes;    immune checkpoint inhibitors;    chromosomal rearrangements;    CDK4;   

DOI  :  10.3390/cancers14020276

来源: DOAJ

【 摘 要 】

Mucosal melanoma (MM) is a rare, aggressive clinical cancer. Despite recent advances in genetics and treatment, the prognosis of MM remains poor. Canine MM offers a relevant spontaneous and immunocompetent model to decipher the genetic bases and explore treatments for MM. We performed an integrative genomic and transcriptomic analysis of 32 canine MM samples, which identified two molecular subgroups with a different microenvironment and structural variant (SV) content. The overexpression of genes related to the microenvironment and T-cell response was associated with tumors harboring a lower content of SVs, whereas the overexpression of pigmentation-related pathways and oncogenes, such as TERT, was associated with a high SV burden. Using whole-genome sequencing, we showed that focal amplifications characterized complex chromosomal rearrangements targeting oncogenes, such as MDM2 or CDK4, and a recurrently amplified region on canine chromosome 30. We also demonstrated that the genes TRPM7, GABPB1, and SPPL2A, located in this CFA30 region, play a role in cell proliferation, and thus, may be considered as new candidate oncogenes for human MM. Our findings suggest the existence of two MM molecular subgroups that may benefit from dedicated therapies, such as immune checkpoint inhibitors or targeted therapies, for both human and veterinary medicine.

【 授权许可】

Unknown