Rationale for Early Detection of EWSR1 Translocation-Associated Sarcoma Biomarkers in Liquid Biopsy

Abstract

Sarcomas are mesenchymal tumours that often arise and develop as a result of chromosomal translocations, and for several forms of sarcoma the EWSR1 gene is a frequent translocation partner. Sarcomas are a rare form of malignancy, which arguably have a proportionally greater societal burden that their prevalence would suggest, as they are more common in young people, with survivors prone to lifelong disability. For most forms of sarcoma, histological diagnosis is confirmed by molecular techniques such as FISH or RT-PCR. Surveillance after surgical excision, or ablation by radiation or chemotherapy, has remained relatively unchanged for decades, but recent developments in molecular biology have accelerated the progress towards routine analysis of liquid biopsies of peripheral blood. The potential to detect evidence of residual disease or metastasis in the blood has been demonstrated by several groups but remains unrealized as a routine diagnostic for relapse during remission, for disease monitoring during treatment, and for the detection of occult, residual disease at the end of therapy. An update is provided on research relevant to the improvement of the early detection of relapse in sarcomas with EWSR1-associated translocations, in the contexts of biology, diagnosis, and liquid biopsy.

Primary pulmonary nuclear protein of the testis midline carcinoma: case report and systematic review with pooled analysis

“…However, this malignancy is extremely rare in the lungs and mediastinum, warranting further molecular testing to confirm diagnosis. FISH testing can distinguish NMC from extraskeletal myxoid chondrosarcoma by the absence of EWSR1 breakage in NUTM1 ( 28 , 48 – 50 ). The coexpression of TTF-1 with focal or multifocal p63 is not uncommon in certain lung tumors that simultaneously express neuroendocrine markers ( 1 , 51 ), warranting consideration for the possibility of NMC.…”

Bio‐marker detection redundancy improves sensitivity

“…While LDH at unelevated levels is reasonably specific for the absence of disease, the presence of elevated LDH is not uniformly specific or sensitive for the presence or prognosis of cancer 5 . For rare sarcomas caused by chromosomal translocation, the use of LDH to detect relapse may be superseded by PCR for the fusion genes (e.g., EWSR‐FLI1 , EWSR‐ERG ) either in ctRNA or CTC 6 …”

“…5 For rare sarcomas caused by chromosomal translocation, the use of LDH to detect relapse may be superseded by PCR for the fusion genes (e.g., EWSR-FLI1, EWSR-ERG) either in ctRNA or CTC. 6 These varying methods have been improved by (1) refining the scope of a liquid biopsy, such as using personalised ctDNA PCR assays based upon tumour DNA sequencing, (2) improvements to the method of detection by means of less laborious technology (e.g., flow cytometry vs. automated enrichment of CTC and image analysis) or (3) the application of a new technique of greater specificity and sensitivity. As well as improving liquid biopsies to be inexpensive, expeditious and of greater quality (Figure 1B), another strategy is to use two different but complementary methods to improve detection.…”

Liquid Biopsy, an Everchanging Balance between Clinical Utility and Emerging Technologies

“…The search of cell-derived elements through liquid biopsy can also help to identify cases of disease recurrence, as shown for sarcomas presenting with EWSR1 -associated translocations [ 21 ]. This is a field of research that is also being explored in early stage breast cancer (eBC) and early stage CRC (eCRC).…”