Unraveling the chaotic genomic landscape of primary and metastatic canine appendicular osteosarcoma with current sequencing technologies and bioinformatic approaches.

Shirley Chu,Obi L Griffith,Jason Kunisaki,Jason R Walker,Zachary L Skidmore,Jeffrey N Bryan,Malachi Griffith,Douglas H Thamm

doi:10.1371/journal.pone.0246443

Abstract

Osteosarcoma is a rare disease in children but is one of the most common cancers in adult large breed dogs. The mutational landscape of both the primary and pulmonary metastatic tumor in two dogs with appendicular osteosarcoma (OSA) was comprehensively evaluated using an automated whole genome sequencing, exome and RNA-seq pipeline that was adapted for this study for use in dogs. Chromosomal lesions were the most common type of mutation. The mutational landscape varied substantially between dogs but the lesions within the same patient were similar. Copy number neutral loss of heterozygosity in mutant TP53 was the most significant driver mutation and involved a large region in the middle of chromosome 5. Canine and human OSA is characterized by loss of cell cycle checkpoint integrity and DNA damage response pathways. Mutational profiling of individual patients with canine OSA would be recommended prior to targeted therapy, given the heterogeneity seen in our study and previous studies.

Highlights

Osteosarcoma (OSA) is a rare disease in humans, but it is the 8th most common cancer in children, and 30% of affected children succumb to their cancer within 5 years [1]
This study provides the first published data on whole genome sequencing (WGS), whole exome sequencing (WES) and RNA-Seq in a primary and metastatic canine osteosarcoma sample from the same patient, adding to the growing genomic database in canine osteosarcoma
Canine and human OSA share many genetic similarities, such as chromosomal instability leading to Structural variants (SVs) and genetic heterogeneity between patients and to a lesser degree between the primary and metastatic lesions within a patient

Summary

Introduction

Osteosarcoma (OSA) is a rare disease in humans, but it is the 8th most common cancer in children, and 30% of affected children succumb to their cancer within 5 years [1]. Dogs are arguably the best animal model to study human OSA because of the many similarities [4,5,6,7,8]. Both cancers are histologically similar, metastatically aggressive, and are treated with therapies that include surgery and platinumbased chemotherapy [5]. Risk factors for both canine and human OSA are large body size [2, 9, 10] and radiation therapy exposure [11, 12].

Methods

Results

Discussion

Conclusion