Cross-species genomic landscape comparison of human mucosal melanoma with canine oral and equine melanoma

Kim Wong,David J Adams,Vivek Iyer,Geoffrey A Wood,Mark J Arends,Sionagh Smith,Hong Gyun Wu ,A K Foote ,Jerome E Dobson ,Rajiv M Patel,Iñigo Martincorena ,Elizabeth P Murchison,Paul W Harms,Iwei Yeh,Courtney R Schott,Fernando Constantino‐Casas ,Louise Van Der Weyden,Marieke L Kuijjer,Thomas Brenn,Boris C Bastian,Douglas R Fullen,Nancy M Joseph ,Carla Daniela Robles‐Espinoza

doi:10.1038/s41467-018-08081-1

Abstract

Mucosal melanoma is a rare and poorly characterized subtype of human melanoma. Here we perform a cross-species analysis by sequencing tumor-germline pairs from 46 primary human muscosal, 65 primary canine oral and 28 primary equine melanoma cases from mucosal sites. Analysis of these data reveals recurrently mutated driver genes shared between species such as NRAS, FAT4, PTPRJ, TP53 and PTEN, and pathogenic germline alleles of BRCA1, BRCA2 and TP53. We identify a UV mutation signature in a small number of samples, including human cases from the lip and nasal mucosa. A cross-species comparative analysis of recurrent copy number alterations identifies several candidate drivers including MDM2, B2M, KNSTRN and BUB1B. Comparison of somatic mutations in recurrences and metastases to those in the primary tumor suggests pervasive intra-tumor heterogeneity. Collectively, these studies suggest a convergence of some genetic changes in mucosal melanomas between species but also distinctly different paths to tumorigenesis.

Highlights

Mucosal melanoma is a rare and poorly characterized subtype of human melanoma
Dogs have been used extensively to explore the role of new therapies such as vaccination for disease management, but with the exception of analysing driver genes such as BRAF and NRAS, little is known about the genetic landscape of this malignancy and how canine and human mucosal melanomas compare[13,15,16,17]
To explore the genetic landscape of these melanomas, we generated profiles of somatic point mutations, multi-nucleotide variants, indels, and somatic copy number alterations (SCNAs) using MuTect (v1.1.7) 18, MAC (v1.2)[19], Strelka (v1.0.15)[20], and Sequenza (v2.1.2)[21], respectively, and filtered and quality controlled these variant calls as described in the Methods

Summary

Introduction

We perform a cross-species analysis by sequencing tumor-germline pairs from 46 primary human muscosal, 65 primary canine oral and 28 primary equine melanoma cases from mucosal sites. Analysis of these data reveals recurrently mutated driver genes shared between species such as NRAS, FAT4, PTPRJ, TP53 and PTEN, and pathogenic germline alleles of BRCA1, BRCA2 and TP53. Dogs have been used extensively to explore the role of new therapies such as vaccination for disease management, but with the exception of analysing driver genes such as BRAF and NRAS, little is known about the genetic landscape of this malignancy and how canine and human mucosal melanomas compare[13,15,16,17]. Equine melanomas are generally more indolent when compared with human or canine mucosal melanomas and as such represent an interesting comparator for a cross-species analysis

Objectives

Methods

Results

Conclusion