Abstract
Purpose
Methylation in IKZF1 and BCAT1 are common events in colorectal cancer (CRC). They are often detected in blood as circulating tumor DNA (ctDNA) at diagnosis and disappear after surgery in most CRC patients. A prospective study was conducted to determine the relationship between detection of these markers following surgery and risk for residual disease and for recurrence.
Methods
ctDNA status with methylated BCAT1 and IKZF1 was determined within 12 months of surgical resection of CRC, and was related to presence of or risk for residual disease (margins involved, metastases present or nature of node involvement), and to recurrence-free survival.
Results
Blood was collected from 172 CRC patients after surgery and 28 (16%) were ctDNA positive. Recurrence was diagnosed in 23 of the 138 with clinical follow-up after surgery (median follow-up 23.3 months, IQR 14.3–29.5). Multivariate modeling indicated that features suggestive of residual disease were an independent predictor of post-surgery ctDNA status: cases with any of three features (close resection margins, apical node involved, or distant metastases) were 5.3 times (95% CI 1.5–18.4, p = 0.008) more likely to be ctDNA positive. Multivariate analysis showed that post-surgery ctDNA positivity was independently associated with an increased risk of recurrence (HR 3.8, 1.5–9.5, p = 0.004).
Conclusions
CRC cases positive for methylated ctDNA after surgery are at increased risk of residual disease and subsequently recurrence. This could have implications for guiding recommendations for adjuvant therapy and surveillance strategies. Randomized studies are now indicated to determine if monitoring cases with these biomarkers leads to survival benefit.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ananieva EA, Wilkinson AC (2018) Branched-chain amino acid metabolism in cancer. Curr Opin Clin Nutr Metab Care 21:64–70. https://doi.org/10.1097/MCO.0000000000000430
Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 11:726–734. https://doi.org/10.1038/nrc3130
Bettegowda C, Sausen M, Leary RJ et al (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6:224ra24–224ra24. https://doi.org/10.1126/scitranslmed.3007094
Carrillo JA, Lai A, Nghiemphu PL et al (2012) Relationship between tumor enhancement, edema, IDH1 mutational status, MGMT promoter methylation, and survival in glioblastoma. AJNR Am J Neuroradiol 33:1349–1355. https://doi.org/10.3174/ajnr.A2950
Chaumeil MM, Larson PEZ, Woods SM et al (2014) Hyperpolarized [1-13C] glutamate: a metabolic imaging biomarker of IDH1 mutational status in glioma. Can Res 74:4247–4257. https://doi.org/10.1158/0008-5472.CAN-14-0680
Cho HR, Hong B, Kim H et al (2016) Assessment of bevacizumab resistance increased by expression of BCAT1 in IDH1 wild-type glioblastoma: application of DSC perfusion MR imaging. Oncotarget 7:69606–69615. https://doi.org/10.18632/oncotarget.11901
Choi SJ, Jung SW, Huh S et al (2017) Alteration of DNA methylation in gastric cancer with chemotherapy. J Microbiol Biotechnol 27:1367–1378. https://doi.org/10.4014/jmb.1704.04035
Christofori G (2006) New signals from the invasive front. Nature 441:444–450. https://doi.org/10.1038/nature04872
Diaz LA, Williams RT, Wu J et al (2012) The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486:537–540. https://doi.org/10.1038/nature11219
Diehl F, Schmidt K, Choti MA et al (2008) Circulating mutant DNA to assess tumor dynamics. Nat Med 14:985–990. https://doi.org/10.1038/nm.1789
Edge SB, Byrd DR, Compton CC et al (2010) AJCC cancer staging manual, 7 edn. Springer, New York
Javierre BM, Rodriguez-Ubreva J, Al-Shahrour F et al (2011) Long-range epigenetic silencing associates with deregulation of ikaros targets in colorectal cancer cells. Mol Cancer Res 9:1139–1151. https://doi.org/10.1158/1541-7786.MCR-10-0515
Konishi T, Shimada Y, Hsu M et al (2018) Association of preoperative and postoperative serum carcinoembryonic antigen and colon cancer outcome. JAMA Oncol 4:309–315. https://doi.org/10.1001/jamaoncol.2017.4420
Liu Y, Chew MH, Tham CK et al (2016) Methylation of serum SST gene is an independent prognostic marker in colorectal cancer. Am J Cancer Res 6:2098–2108
Malinge S, Thiollier C, Chlon TM et al (2013) Ikaros inhibits megakaryopoiesis through functional interaction with GATA-1 and NOTCH signaling. Blood 121:2440–2451. https://doi.org/10.1182/blood-2012-08-450627
Mansfeld J, Urban N, Priebe S et al (2015) Branched-chain amino acid catabolism is a conserved regulator of physiological ageing. Nat Commun 6:10043. https://doi.org/10.1038/ncomms10043
Markowitz SD, Bertagnolli MM (2009) Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med 361:2449–2460. https://doi.org/10.1056/NEJMra0804588
Merker JD, Oxnard GR, Compton C et al (2018) Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. Arch Pathol Lab Med. https://doi.org/10.5858/arpa.2018-0901-SA
Ng SB, Chua C, Ng M et al (2017) Individualised multiplexed circulating tumour DNA assays for monitoring of tumour presence in patients after colorectal cancer surgery. Sci Rep 7:40737. https://doi.org/10.1038/srep40737
Niedzwiecki D, Bertagnolli MM, Warren RS et al (2011) Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation: results from CALGB 9581. J Clin Oncol 29:3146–3152. https://doi.org/10.1200/JCO.2010.32.5357
Noah TK, Shroyer NF (2013) Notch in the intestine: regulation of homeostasis and pathogenesis. Annu Rev Physiol 75:263–288. https://doi.org/10.1146/annurev-physiol-030212-183741
Pedersen SK, Baker RT, McEvoy A et al (2015a) A two-gene blood test for methylated DNA sensitive for colorectal cancer. PLoS One 10:e0125041. https://doi.org/10.1371/journal.pone.0125041
Pedersen SK, Symonds EL, Baker RT et al (2015b) Evaluation of an assay for methylated BCAT1 and IKZF1 in plasma for detection of colorectal neoplasia. BMC Cancer 15:654. https://doi.org/10.1186/s12885-015-1674-2
Quah H-M, Chou JF, Gonen M et al (2008) Identification of patients with high-risk stage II colon cancer for adjuvant therapy. Dis Colon Rectum 51:503–507. https://doi.org/10.1007/s10350-008-9246-z
Quentmeier A, Schlag P, Smok M, Herfarth C (1990) Re-operation for recurrent colorectal cancer: the importance of early diagnosis for resectability and survival. Eur J Surg Oncol 16:319–325
Rasmussen SL, Krarup HB, Sunesen KG et al (2016) Hypermethylated DNA as a biomarker for colorectal cancer: a systematic review. Colorectal Dis 18:549–561. https://doi.org/10.1111/codi.13336
Riccio O, van Gijn ME, Bezdek AC et al (2008) Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO 9:377–383. https://doi.org/10.1038/embor.2008.7
Rockall TA, McDonald PJ (1999) Carcinoembryonic antigen: its value in the follow-up of patients with colorectal cancer. Int J Colorectal Dis 14:73–77
Sargent D, Sobrero A, Grothey A et al (2009) Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 27:872–877. https://doi.org/10.1200/JCO.2008.19.5362
Shinkins B, Nicholson BD, Primrose J et al (2017) The diagnostic accuracy of a single CEA blood test in detecting colorectal cancer recurrence: Results from the FACS trial. PLoS One 12:e0171810. https://doi.org/10.1371/journal.pone.0171810
Song C, Pan X, Ge Z et al (2016) Epigenetic regulation of gene expression by Ikaros, HDAC1 and Casein Kinase II in leukemia. Leukemia 30:1436–1440. https://doi.org/10.1038/leu.2015.331
Su B-B, Shi H, Wan J (2012) Role of serum carcinoembryonic antigen in the detection of colorectal cancer before and after surgical resection. WJG 18:2121–2126. https://doi.org/10.3748/wjg.v18.i17.2121
Symonds EL, Pedersen SK, Baker RT et al (2016) A blood test for methylated BCAT1 and IKZF1 vs. a fecal immunochemical test for detection of colorectal neoplasia. Clin Transl Gastroenterol 7:e137. https://doi.org/10.1038/ctg.2015.67
Thewes V, Simon R, Hlevnjak M et al (2017) The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ERα-negative breast cancer. Oncogene 36:4124–4134. https://doi.org/10.1038/onc.2017.32
Thierry AR, Mouliere F, Messaoudi El S et al (2014) Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med 20:430–435. https://doi.org/10.1038/nm.3511
Tie J, Kinde I, Wang Y et al (2015) Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol 26:1715–1722. https://doi.org/10.1093/annonc/mdv177
Tie J, Wang Y, Tomasetti C et al (2016) Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med 8:346ra92–346ra92. https://doi.org/10.1126/scitranslmed.aaf6219
Tonjes M, Barbus S, Park YJ et al (2013) BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med 19:901–908. https://doi.org/10.1038/nm.3217
Vogelstein B, Papadopoulos N, Velculescu VE et al (2013) Cancer genome landscapes. Science 339:1546–1558. https://doi.org/10.1126/science.1235122
Ward PS, Patel J, Wise DR et al (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17:225–234. https://doi.org/10.1016/j.ccr.2010.01.020
Weisenberger DJ (2014) Characterizing DNA methylation alterations from The Cancer Genome Atlas. J Clin Invest 124:17–23. https://doi.org/10.1172/JCI69740
Wirtzfeld DA, Mikula L, Gryfe R et al (2009) Concordance with clinical practice guidelines for adjuvant chemotherapy in patients with stage I–III colon cancer: experience in 2 Canadian provinces. Can J Surg 52:92–97
Wittekind C, Compton CC, Greene FL, Sobin LH (2002) TNM residual tumor classification revisited. Cancer 94:2511–2516. https://doi.org/10.1002/cncr.10492
Wood LD, Parsons DW, Jones S et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318:1108–1113. https://doi.org/10.1126/science.1145720
Xu W, Yang H, Liu Y et al (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19:17–30. https://doi.org/10.1016/j.ccr.2010.12.014
Yoshikawa R, Yanagi H, Shen C-S et al (2006) ECA39 is a novel distant metastasis-related biomarker in colorectal cancer. WJG 12:5884–5889
Young GP, Pedersen SK, Mansfield S et al (2016) A cross-sectional study comparing a blood test for methylated BCAT1 and IKZF1 tumor-derived DNA with CEA for detection of recurrent colorectal cancer. Cancer Med 5:2763–2772. https://doi.org/10.1002/cam4.868
Zheng Y-H, Hu W-J, Chen B-C et al (2016) BCAT1, a key prognostic predictor of hepatocellular carcinoma, promotes cell proliferation and induces chemoresistance to cisplatin. Liver Int 36:1836–1847. https://doi.org/10.1111/liv.13178 doi
Zhu X, Asa SL, Ezzat S (2007) Ikaros Is Regulated through Multiple Histone Modifications and Deoxyribonucleic Acid Methylation in the Pituitary. Mol Endocrinol 21:1205–1215. https://doi.org/10.1210/me.2007-0053
Zhu W, Shao Y, Peng Y (2017) MicroRNA-218 inhibits tumor growth and increases chemosensitivity to CDDP treatment by targeting BCAT1 in prostate cancer. Mol Carcinog. https://doi.org/10.1002/mc.22612
Acknowledgements
GPY and CK are recipients of a grant funded by the financial support of Cancer Council SA’s Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health together with the support of the Flinders Medical Centre Foundation, its donors and partners.
Funding
This study was funded in part by the National Health and Medical Research Council (APP1006242, APP1017083) and Clinical Genomics Pty Ltd.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
GPY is a paid consultant of Clinical Genomics. SKP and DHM are paid employees of Clinical Genomics. All other authors have no conflicts of interest to declare.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Rights and permissions
About this article
Cite this article
Murray, D.H., Symonds, E.L., Young, G.P. et al. Relationship between post-surgery detection of methylated circulating tumor DNA with risk of residual disease and recurrence-free survival. J Cancer Res Clin Oncol 144, 1741–1750 (2018). https://doi.org/10.1007/s00432-018-2701-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-018-2701-x