Unravelling undifferentiated soft tissue sarcomas: insights from genomics.

Shadi Hames-Fathi,Steven W G Nottley,Nischalan Pillay

doi:10.1111/his.14446

Abstract

Undifferentiated pleomorphic sarcoma now falls under the broader rubric of undifferentiated soft tissue sarcoma (USTS) in the 2020 World Health Organization classification of bone and soft tissue tumours. These rare cancers remain a diagnosis of exclusion, and show genomic complexity manifesting as extreme forms of aneuploidy and genetic rearrangement. This review covers some of the recent advances in the diagnosis and treatment of USTS based on genomic sequencing, cancer evolution and heterogeneity studies, and immunotherapy. We highlight the critical role that pathologists have to play in the diagnosis and treatment of patients with USTS, viewed through the lens of the hallmarks of cancer.

Highlights

Molecular profiling for sarcoma diagnostics is commonplace, but the complexity of interpreting newer tests such as clinical whole genome sequencing (WGS) for therapeutic purposes represents a new and significant challenge
With the development of computational analysis of digital pathological images, it is possible to statistically quantify key morphometric aspects of nuclei, such as size, shape, area, convexity, texture, and staining intensity.[13]. Such methods have shown that the extent of the pleomorphism and the large size of cells seen in undifferentiated soft tissue sarcoma (USTS) are associated with the number of whole genome doubling (WGD), by utilising a combination of copy number profiling and digital pathology image analysis algorithms.[8]
The benefit of using WGS is that structural rearrangement data can be integrated with the single-nucleotide variant (SNV) data, with data from our group showing that, without this integration, up to 50% of driver mutations in TP53, RB1 and a-thalassaemia/mental retardation syndrome X-linked protein (ATRX) would have been missed if analysis had been restricted to only coding regions of the genome.[7]

Summary

Introduction

Molecular profiling for sarcoma diagnostics is commonplace, but the complexity of interpreting newer tests such as clinical whole genome sequencing (WGS) for therapeutic purposes represents a new and significant challenge. With the development of computational analysis of digital pathological images, it is possible to statistically quantify key morphometric aspects of nuclei, such as size, shape, area, convexity, texture, and staining intensity.[13] Such methods have shown that the extent of the pleomorphism and the large size of cells seen in USTS are associated with the number of WGDs, by utilising a combination of copy number profiling and digital pathology image analysis algorithms.[8] A more established way to assess the state of WGD of a sample is to perform DNA content analysis directly by using a DNA-binding dye on nuclear suspensions and performing ploidy analysis with flow or image cytometry, which can provide a quantitative readout of the subclonal structure of a tumour[7] (Figure 2B). The mechanisms by which USTS is able to sustain such extreme levels of genomic instability remain poorly understood and cannot be explained by TP53 mutation alone, as this is a prevalent driver in many

A WGDx0 WGDx1 WGDx2 B

Discussion

Findings

Conflicts of interest