Digital PCR analysis of circulating tumor DNA: a biomarker for chondrosarcoma diagnosis, prognostication, and residual disease detection

Abstract

Conventional chondrosarcoma is the most common primary bone tumor in adults. Prognosis corresponds with tumor grade but remains variable, especially for individuals with grade (G) II disease. There are currently no biomarkers available for monitoring or prognostication of chondrosarcoma. Circulating tumor DNA (ctDNA) has recently emerged as a promising biomarker for a broad range of tumor types. To date, little has been done to study the presence of ctDNA and its potential utility in the management of sarcomas, including chondrosarcoma. In this study, we have assessed ctDNA levels in a cohort of 71 patients, 32 with sarcoma, including 29 individuals with central chondrosarcoma (CS) and 39 with locally aggressive and benign bone and soft tissue tumors, using digital PCR. In patients with CS, ctDNA was detected in pretreatment samples in 14/29 patients, which showed clear correlation with tumor grade as demonstrated by the detection of ctDNA in all patients with GIII and dedifferentiated disease (n = 6) and in 8/17 patients with GII disease, but never associated with GI CS. Notably detection of ctDNA preoperatively in GII disease was associated with a poor outcome. A total of 14 patients with CS had ctDNA levels assessed at multiple time points and in most patients there was a clear reduction following surgical removal. This research lays the foundation for larger studies to assess the utility of ctDNA for chondrosarcoma diagnosis, prognostication, early detection of residual disease and monitoring disease progression.

Sarcoma treatment in the era of molecular medicine

“…The cfDNA fraction released from tumor tissues, called circulating tumor DNA (ctDNA), may reflect the genetic aberrations of cancer cells at a given time. cfDNA was recently detected in plasma of bone sarcoma (Gutteridge et al , 2017; Shukla et al , 2017; Barris et al , 2018) and STS patients (Boonstra et al , 2018; Eastley et al , 2018; Namløs et al , 2018; Ogino et al , 2018; Shulman et al , 2018). In these studies, total cfDNA levels were frequently increased in the plasma of sarcoma patients compared with the cancer‐free controls.…”

“…Interestingly, the usefulness of cfDNA analysis was demonstrated to identify TKI‐resistant mutations (Yoo et al , 2014). In a series of CHSs, ctDNA levels detected by mutated IDH1 correlated with tumor grade and prognosis (Gutteridge et al , 2017). Patient‐specific somatic alterations in cfDNA were observed in OS (Barris et al , 2018) and were associated with inferior outcomes in EwS and OS patients (Shulman et al , 2018).…”

An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing

“…A pilot study has shown that detection of IDH1 or IDH2 mutant molecules is associated with high‐grade chondrosarcoma and a worse prognosis …”

The new horizon of liquid biopsy in sarcoma: the potential utility of circulating tumor nucleic acids

“…Further studies found that the overall survival of CS patients with IDH1/IDH2 mutations was significantly lower than that of patients without IDH1/IDH2 mutations [132]. Gutteridge et al identified mutant IDH in the plasma of chondrosarcoma patients [133]. The authors demonstrated that cell-free IDH1/IDH2 could be detected in high-grade chondrosarcoma and dedifferentiated chondrosarcoma patients during the preoperative period; moreover, a high level of mutant IDH correlated with poor prognosis [133].…”

“…The authors demonstrated that cell-free IDH1/IDH2 could be detected in high-grade chondrosarcoma and dedifferentiated chondrosarcoma patients during the preoperative period; moreover, a high level of mutant IDH correlated with poor prognosis [133]. Mutant IDH1 was detected in plasma prior to traditional radiological imaging and clinical changes in patients whose tumors relapsed or metastasized during follow-up periods [133].These results indicate that mutated IDH in circulation may be a potential non-invasive biomarker to monitor chondrosarcoma patients in the clinical setting. Accumulating evidence has demonstrated that the COL2A1 [134] and exostosin glycosyltransferase (EXT1 or EXT2) genes are also frequently altered in CS [134,135].…”