Detection of circulating tumor DNA in patients with osteosarcoma

Abstract

Identification and quantification of somatic alterations in plasma-derived, circulating tumor DNA (ctDNA) is gaining traction as a non-invasive and cost effective method of disease monitoring in cancer patients, particularly to evaluate response to treatment and monitor for disease recurrence. To our knowledge, genetic analysis of ctDNA in osteosarcoma has not yet been studied. To determine whether somatic alterations can be detected in ctDNA and perhaps applied to patient management in this disease, we collected germline, tumor, and serial plasma samples from pediatric, adolescent, and young adult patients with osteosarcoma and used targeted Next Generation Sequencing (NGS) to identify somatic single nucleotide variants (SNV), insertions and deletions (INDELS), and structural variants (SV) in 7 genes commonly mutated in osteosarcoma. We demonstrate that patient-specific somatic alterations identified through comparison of tumor-germline pairs can be detected and quantified in cell-free DNA of osteosarcoma patients.

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.…”

“…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). Individual genomic EWSR1‐ETS fusion sequences can be quantified from cfDNA in EwS patients’ plasma, and as such represent suitable serum markers for therapy assessment (Krumbholz et al , 2016).…”

Novel molecular insights and new therapeutic strategies in osteosarcoma

“…The use of ctDNA can be of particular benefit as a liquid biopsy because is capable of capturing full complex OS heterogeneity and tracking genomic evolution [ 166 , 167 ]. Somatic mutations have been previously detected in cell-free DNA of patients suffering from OS by comparing tumor-germline pairs [ 168 ]. Furthermore, NGS has been applied in a study composed primarily of tumor sequencing findings capable of detecting ctDNA in half of the plasma specimen from subjects with OS, where its detection was found to be strongly linked to inferior outcomes [ 169 ].…”

Blood‐borne biomarkers of osteosarcoma: A systematic review

“…The fact remains that novel biomarkers that may be directly related to the disease processes such as the microRNAs need to perform at least as well as the non‐disease‐specific markers in terms of clinical correlation before being taken forward into prospective studies that may change clinical practice. ctDNA has received extensive attention for carcinoma, but there is only one recent small study for osteosarcoma that assessed 10 patients . Our conclusion from this review is that there is a requirement for large multicenter prospective studies in osteosarcoma that involve obtaining serial blood and tissue samples from participants in which the most promising biomarkers are evaluated with standardized laboratory techniques.…”