Treatment Response Monitoring in Patients with Advanced Malignancies Using Cell-Free SHOX2 and SEPT9 DNA Methylation in Blood

Abstract

Patients with incurable cancer usually receive palliative treatment with significant toxicity and limited efficacy. Methylation analysis of circulating cell-free DNA (ccfDNA) in blood from cancer patients represents a promising approach for minimally invasive, real-time monitoring of treatment response. Short stature homeobox 2 (SHOX2) and septin 9 (SEPT9) methylation was analyzed in N Z 8865 malignant and N Z 746 normal adjacent tissues across 33 different malignancies from The Cancer Genome Atlas. Furthermore, we performed quantitative SHOX2 and SEPT9 ccfDNA methylation analysis in plasma obtained before and consecutively during treatment from prospectively enrolled N Z 115 patients with various advanced cancers. SHOX2 and/or SEPT9 hypermethylation in malignant tissues is present in various carcinomas, sarcoma, melanoma, brain tumors, mesothelioma, and hematopoietic malignancies. Among the prospectively enrolled cancer patients, 61% (70/115) of patients had a baseline-positive blood cumulative ccfDNA methylation score (CMS) and were eligible for response monitoring. Dynamic changes of CMS during treatment were strongly associated with treatment response. A CMS increase indicated response up to 80 days before conventional monitoring. SHOX2 and SEPT9 ccfDNA methylation represents a pan-cancer biomarker and has the potential to be a powerful tool for monitoring treatment response in patients with solid tumors and lymphomas. The early identification of nonresponders might allow for a timely change of treatment regimen.

Tracking the Molecular Fingerprint of Head and Neck Cancer for Recurrence Detection in Liquid Biopsies

“…EBV ctDNA is another promising biomarker with low cost and high sensitivity for predicting disease recurrence [ 46 ]. For non-viral-driven subtypes of HNSCC, specific mutations, methylation markers, or RNA expression have been explored as biomarkers [ 24 , 26 , 50 , 51 , 52 , 53 , 56 , 57 , 64 , 67 , 68 , 69 , 79 , 80 , 81 , 82 ].…”

“…Aberrantly methylated copies of the SHOX2 and SEPT9 genes are among the liquid biopsy methylation biomarkers with the highest level of validation regarding their clinical performance [ 67 ]. After establishing the diagnostic potential of these methylated copies, de Vos and colleagues [ 68 ] evaluated their performance in monitoring disease recurrence in comparison to clinical examination or CT scan monitoring (n = 8). Four of these cases showed progressive disease.…”

What Have We Learned from Molecular Biology of Paragangliomas and Pheochromocytomas?

“…Currently, cell free (cf) DNA-based methods are increasingly employed as diagnostic or screening tools for cancer detection [144]. In the context of PPGL, with extensive candidate genetic markers, cfDNA detection maybe relevant once a causative germline or somatic mutation has been identified in the primary tumour, especially in patients with increased risk of metastatic disease.…”

Methylation Markers in Cutaneous Melanoma: Unravelling the Potential Utility of Their Tracking by Liquid Biopsy

“…As RAR-β2 is involved in the control of cell growth and apoptosis, its expression in tumor cells susceptible to its mediated apoptosis could be an important biomarker of response to biochemotherapy [ 78 ]. A recent study by de Vos and colleagues involved a large patient cohort with different malignancies from the Cancer Genome Atlas (TCGA) Research Network to test the value of two hypermethylated genes, SHOX2 , and SEPT9 , as pan-cancer biomarkers [ 188 ]. The quantitative methylation analysis of these genes has shown a correlation with treatment response: when compared to conventional monitoring, cfDNA longitudinal screening revealed an association between an increase in the methylation score (CMS, cumulative cfDNA methylation score) and non-responsiveness to treatment with an 80-day advantage.…”