Whole genome and reverse protein phase array landscapes of patient derived osteosarcoma xenograft models

Abstract

Osteosarcoma is the most common primary bone malignancy in children and young adults, and it has few treatment options. As a result, there has been little improvement in survival outcomes in the past few decades. The need for models to test novel therapies is especially great in this disease since it is both rare and does not respond to most therapies. To address this, an NCI-funded consortium has characterized and utilized a panel of patient-derived xenograft models of osteosarcoma for drug testing. The exomes, transcriptomes, and copy number landscapes of these models have been presented previously. This study now adds whole genome sequencing and reverse-phase protein array profiling data, which can be correlated with drug testing results. In addition, four additional osteosarcoma models are described for use in the research community.

Figure 1

Pair-wise Pearson correlation of whole genome copy number profile from whole genome sequencing and SNP array data.

Figure 2

Copy number profiles from SNP array (top panel) and WGS data (bottom panel) for a TP53; and b RB1. Integrative Genomics Viewer panels where red indicates copy number gains while blue indicates copy number loss.

Figure 3

Copy number profiles of OS PDX models (a) and patient samples (b). Gains are displayed in red and losses displayed in blue.

Figure 4

GISTIC plots using SNP array (top panels) and WGS data (bottom panels). (a) amplification; (b) deletion.

Figure 5

Landscape of recurrently altered genes in PDX models as detected by WGS data. Each of the 21 samples shown has at least one alteration in the genes listed (altered in 100% of the samples shown). The top panel indicates the tumor mutation burden (TMB) for each model. The bottom panel illustrates the top recurrent somatic mutations along with an indication of the presence of chromothripsis (N = No, Y = Yes).

Figure 6

Chromothriptic regions in the PDX models. (a) Integrated Genomic Viewer display of the chromothriptic regions called by ShatterSeek. High confidence 1: at least 6 interleaved intrachromosomal structural variants, 7 contiguous segments oscillating between 2 copy number states, the fragment joins test, and either the chromosomal enrichment or the exponential distribution of breakpoints test. High confidence 2: at least 3 interleaved intrachromosomal structural variants and 4 or more interchromosomal structural variants, 7 contiguous segments oscillating between 2 copy number states and the fragment joins test. Low confidence: at least 6 interleaved intrachromosomal structural variants, 4, 5 or 6 adjacent segments oscillating between 2 copy number states, the fragment joins test, and either the chromosomal enrichment or the exponential distribution of breakpoints test. (b) Frequency plot of the chromosome regions in OS PDX models that have undergone chromothripsis. The frequency indicates the number of patients with chromothripsis. Left panel: High confidence 1 calls. Right panel: High confidence 2 calls.

Figure 7

RPPA analysis of osteosarcoma. a Heatmap of co-clustering scores between the RPPA data in OS PDX models and OS patients. b Heatmap of the pathway scores in the PDX models. The passage number of the PDX model is indicated after the PDX model name.