Abstract
BackgroundCell-free circulating tumour-derived DNA (ctDNA) can be detected by testing for methylated BCAT1 and IKZF1 DNA, which has proven sensitivity for colorectal cancer (CRC). A prospective correlative biomarker study between presence of methylated BCAT1 and IKZF1 in tissue and blood was conducted in cases with CRC to explore how detection of such ctDNA biomarkers relates to cancer characteristics, methylation in tissue and surgical resection of the primary cancer.MethodsEnrolled patients with invasive CRC had blood collected at diagnosis, prior to any treatment or surgery (peri-diagnostic sample). A subgroup of patients also had cancer and adjacent non-neoplastic tissue collected at surgical resection, as well as a second blood sample collected within 12 months of surgery (post-surgery sample). DNA was extracted from all samples and assayed for methylated BCAT1 and IKZF1 to determine the degree of methylation in tissue and the presence of ctDNA in blood.ResultsOf 187 cases providing peri-diagnostic blood samples, tissue was available in 91, and 93 provided at least one post-surgery blood sample for marker analysis. Significant methylation of either BCAT1 or IKZF1 was seen in 86/91 (94.5%) cancer tissues, with levels independent of stage and higher than that observed in adjacent non-neoplastic specimens (P < 0.001). ctDNA methylated in BCAT1 or IKZF1 was detected in 116 (62.0%) cases at diagnosis and was significantly more likely to be detected with later stage (P < 0.001) and distal tumour location (P = 0.004). Of the 91 patients who provided pre-and post-surgery blood samples, 47 patients were ctDNA-positive at diagnosis and 35 (74.5%) became negative after tumour resection.ConclusionThis study has shown that BCAT1 and IKZF1 methylation are common events in CRC with almost all cancer tissues showing significant levels of methylation in the two genes. The presence of ctDNA in blood is stage-related and show rapid reversion to negative following surgical resection. Monitoring methylated BCAT1 and IKZF1 levels could therefore inform adequacy of surgical resection.Trial registrationAustralian New Zealand Clinical Trial Registry number 12611000318987. Registered 25 March 2011.
Highlights
Cell-free circulating tumour-derived DNA can be detected by testing for methylated Branched chain amino acid transaminase 1 (BCAT1) and IKAROS family zinc finger 1 (IKZF1) DNA, which has proven sensitivity for colorectal cancer (CRC)
Peri-diagnostic circulating tumour-derived DNA (ctDNA) status Peri-diagnostic blood samples were available for 187 cases, and 116 (62.0%, 95% confidence intervals (95%CI) 54.7–69.0) tested positive for methylated BCAT1 and/or IKZF1
When methylation changes were assessed for different clinicopathological features, similar results were seen for BCAT1 and IKZF1 except for location where BCAT1 had a higher positivity rate with distally located tumours (Table 1)
Summary
Cell-free circulating tumour-derived DNA (ctDNA) can be detected by testing for methylated BCAT1 and IKZF1 DNA, which has proven sensitivity for colorectal cancer (CRC). To achieve early detection of recurrence, patients are usually entered into a follow-up regimen including regular blood testing, radiology and colonoscopy. Better blood markers for adequacy of initial therapy should aid identification of subjects at risk of recurrence or in need of extended initial therapy such as addition of or prolongation of chemotherapy. These markers should be present in all colorectal tumours regardless of the genetic alterations and should be absent from the blood following complete surgical resection of the tumour
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