Circulating tumour DNA for monitoring colorectal cancer—a prospective cohort study to assess relationship to tissue methylation, cancer characteristics and surgical resection
Abstract Background 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). A prospective correlative biomarker study between presence of methylated BCAT1 and IKZF1 in tissue and blood w...
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| Format: | Article |
| Language: | English |
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BMC
2018-05-01
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| Series: | Clinical Epigenetics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13148-018-0500-5 |
| _version_ | 1828929373639540736 |
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| author | Erin L. Symonds Susanne K. Pedersen David H. Murray Maher Jedi Susan E. Byrne Philippa Rabbitt Rohan T. Baker Dawn Bastin Graeme P. Young |
| author_facet | Erin L. Symonds Susanne K. Pedersen David H. Murray Maher Jedi Susan E. Byrne Philippa Rabbitt Rohan T. Baker Dawn Bastin Graeme P. Young |
| author_sort | Erin L. Symonds |
| collection | DOAJ |
| description | Abstract Background 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). 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. Methods Enrolled 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. Results Of 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. Conclusion This 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 registration Australian New Zealand Clinical Trial Registry number 12611000318987. Registered 25 March 2011. |
| first_indexed | 2024-12-14T00:18:05Z |
| format | Article |
| id | doaj.art-820de594748743c1a3a69ce965684d3f |
| institution | Directory Open Access Journal |
| issn | 1868-7075 1868-7083 |
| language | English |
| last_indexed | 2024-12-14T00:18:05Z |
| publishDate | 2018-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj.art-820de594748743c1a3a69ce965684d3f2022-12-21T23:25:23ZengBMCClinical Epigenetics1868-70751868-70832018-05-0110111110.1186/s13148-018-0500-5Circulating tumour DNA for monitoring colorectal cancer—a prospective cohort study to assess relationship to tissue methylation, cancer characteristics and surgical resectionErin L. Symonds0Susanne K. Pedersen1David H. Murray2Maher Jedi3Susan E. Byrne4Philippa Rabbitt5Rohan T. Baker6Dawn Bastin7Graeme P. Young8Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University of South AustraliaClinical Genomics Pty LtdClinical Genomics Pty LtdFlinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University of South AustraliaFlinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University of South AustraliaColorectal Surgery, Division of Surgery and Perioperative Medicine, Flinders Medical CentreClinical Genomics Pty LtdFlinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University of South AustraliaFlinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University of South AustraliaAbstract Background 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). 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. Methods Enrolled 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. Results Of 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. Conclusion This 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 registration Australian New Zealand Clinical Trial Registry number 12611000318987. Registered 25 March 2011.http://link.springer.com/article/10.1186/s13148-018-0500-5Colorectal cancerBCAT1IKZF1MethylationCirculating tumour DNASurgical resection |
| spellingShingle | Erin L. Symonds Susanne K. Pedersen David H. Murray Maher Jedi Susan E. Byrne Philippa Rabbitt Rohan T. Baker Dawn Bastin Graeme P. Young Circulating tumour DNA for monitoring colorectal cancer—a prospective cohort study to assess relationship to tissue methylation, cancer characteristics and surgical resection Clinical Epigenetics Colorectal cancer BCAT1 IKZF1 Methylation Circulating tumour DNA Surgical resection |
| title | Circulating tumour DNA for monitoring colorectal cancer—a prospective cohort study to assess relationship to tissue methylation, cancer characteristics and surgical resection |
| title_full | Circulating tumour DNA for monitoring colorectal cancer—a prospective cohort study to assess relationship to tissue methylation, cancer characteristics and surgical resection |
| title_fullStr | Circulating tumour DNA for monitoring colorectal cancer—a prospective cohort study to assess relationship to tissue methylation, cancer characteristics and surgical resection |
| title_full_unstemmed | Circulating tumour DNA for monitoring colorectal cancer—a prospective cohort study to assess relationship to tissue methylation, cancer characteristics and surgical resection |
| title_short | Circulating tumour DNA for monitoring colorectal cancer—a prospective cohort study to assess relationship to tissue methylation, cancer characteristics and surgical resection |
| title_sort | circulating tumour dna for monitoring colorectal cancer a prospective cohort study to assess relationship to tissue methylation cancer characteristics and surgical resection |
| topic | Colorectal cancer BCAT1 IKZF1 Methylation Circulating tumour DNA Surgical resection |
| url | http://link.springer.com/article/10.1186/s13148-018-0500-5 |
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