Prognostic utility of circulating tumor DNA methylation analysis in stage IV colorectal cancer
Hirotaka Momose MD
Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Kiichi Sugimoto MD
Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
Correspondence Kiichi Sugimoto, Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Email: [email protected]
Search for more papers by this authorTakahiro Irie MD
Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
Search for more papers by this authorSachio Nomura PhD
Department of Pathology and Oncology, Juntendo University Faculty of Medicine, Tokyo, Japan
Search for more papers by this authorHisashi Ro MD
Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
Search for more papers by this authorShun Ishiyama MD
Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
Search for more papers by this authorMakoto Takahashi MD
Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
Search for more papers by this authorThomas Pisanic PhD
Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland, USA
Search for more papers by this authorKazuhiro Sakamoto MD
Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
Search for more papers by this authorHirotaka Momose MD
Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Kiichi Sugimoto MD
Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
Correspondence Kiichi Sugimoto, Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Email: [email protected]
Search for more papers by this authorTakahiro Irie MD
Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
Search for more papers by this authorSachio Nomura PhD
Department of Pathology and Oncology, Juntendo University Faculty of Medicine, Tokyo, Japan
Search for more papers by this authorHisashi Ro MD
Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
Search for more papers by this authorShun Ishiyama MD
Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
Search for more papers by this authorMakoto Takahashi MD
Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
Search for more papers by this authorThomas Pisanic PhD
Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland, USA
Search for more papers by this authorKazuhiro Sakamoto MD
Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
Search for more papers by this authorAbstract
Background and Objectives
Our aim in this study was to investigate the usefulness of circulating tumor (ct) DNA methylation analysis for predicting long-term outcomes after resection in Stage IV colorectal cancer (CRC).
Methods
Methylation analyses were performed on 95 plasma samples from patients with CRC who underwent surgery. The methylation status (relative methylation value: RMV) of CpG within the promoter region of three genes (CHFR, SOX11, and CDO1) was assessed to quantitative methylation-specific PCR (qMSP) analysis.
Results
In the patients who had undergone resection of the primary tumor and metastatic organs with curative intent, the CHFR-RMV high group had significantly worse recurrence-free survival (RFS) compared with the CHFR-RMV low group (p = 0.001). Multivariate analysis revealed that CHFR-RMV was a significant independent prognostic factor (hazard ratio = 2.63 (1.29–5.36); p = 0.008). In the patients who had undergone resection of the primary tumor with metastatic organs with curative intent after neoadjuvant systemic chemotherapy, the SOX11-RMV high group had significantly worse RFS compared with the SOX11-RMV low group (p = 0.004).
Conclusions
The current study showed the usefulness of ctDNA methylation analysis for predicting the possibility of curative resection and long-term outcomes after resection in Stage IV CRC. A future prospective study is needed to obtain more conclusive results.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| jso27824-sup-0001-Supplemental_Fig_1.jpg411 KB | Supporting information. |
| jso27824-sup-0002-Supplemental_Fig_2.jpg578.6 KB | Supporting information. |
| jso27824-sup-0003-Supplemental_Fig_3.jpg549.5 KB | Supporting information. |
| jso27824-sup-0004-20240314_Supplemental_Table_1.docx29.1 KB | Supporting information. |
| jso27824-sup-0005-20240314_Supplemental_Table_2.docx29.8 KB | Supporting information. |
| jso27824-sup-0006-20240314_Supplemental_Table_3.docx29.4 KB | Supporting information. |
| jso27824-sup-0007-20240314_Supplemental_Table_4.docx27.9 KB | Supporting information. |
| jso27824-sup-0008-20240314_Supplemental_Table_5.doc73 KB | Supporting information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics. CA Cancer J Clin. 2022; 72: 7-33.
- 2van der Geest LGM, Lam-Boer J, Koopman M, Verhoef C, Elferink MAG, de Wilt JHW. Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases. Clin Exp Metastasis. 2015; 32: 457-465.
- 3Väyrynen V, Wirta EV, Seppälä T, et al. Incidence and management of patients with colorectal cancer and synchronous and metachronous colorectal metastases: a population-based study. BJS Open. 2020; 4: 685-692.
- 4Flood MP, Das AA, Soucisse ML, et al. Synchronous liver resection, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy for colorectal liver and peritoneal metastases: a systematic review and meta-analysis. Dis Colon Rectum. 2021; 64: 754-764.
- 5Verheij FS, Soares KC, Beets GL, et al. Timing of primary tumor resection in synchronous metastatic colon cancer patients undergoing hepatic arterial infusion pump placement. Ann Surg Oncol. 2022; 29: 2044-2051.
- 6Yao YC, Chen JQ, Yin L, Lin WH, Peng JH, Fan WH. Primary tumor resection with or without metastasectomy for left- and right-sided stage IV colorectal cancer: an instrumental variable analysis. BMC Gastroenterol. 2022; 22: 114.
- 7Fonseca GM, Herman P, Faraj SF, et al. Pathological factors and prognosis of resected liver metastases of colorectal carcinoma: implications and proposal for a pathological reporting protocol. Histopathology. 2018; 72: 377-390.
- 8Miyamoto Y, Hiyoshi Y, Sawayama H, Tokunaga R, Baba H. Precision medicine for adjuvant chemotherapy of resected colorectal cancer. Ann Gastroenterol Surg. 2020; 4: 635-645.
- 9Bork U. Prognostic relevance of minimal residual disease in colorectal cancer. World J Gastroenterol. 2014; 20: 10296-10304.
- 10Gold P, Freedman SO. Specific carcinoembryonic antigens of the human digestive system. J Exp Med. 1965; 122: 467-481.
- 11A Joint National Cancer Institute of Canada/American Cancer Society I. A collaborative study of a test for carcinoembryonic antigen (CEA) in the sera of patients with carcinoma of the colon and rectum—ā joint National Cancer Institute of Canada-American Cancer Society investigation. Can Med Assoc J. 1972; 107: 25-33.
- 12Primrose JN, Perera R, Gray A, et al. Effect of 3 to 5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: the FACS randomized clinical trial. JAMA. 2014; 311: 263-270.
- 13Wang WS, Lin JK, Lin TC, et al. Carcinoembryonic antigen in monitoring of response to systemic chemotherapy in patients with metastatic colorectal cancer. Int J Colorectal Dis. 2001; 16: 96-101.
- 14Zhou H, Zhu L, Song J, et al. Liquid biopsy at the frontier of detection, prognosis and progression monitoring in colorectal cancer. Mol Cancer. 2022; 21: 86.
- 15Ignatiadis M, Sledge GW, Jeffrey SS. Liquid biopsy enters the clinic—implementation issues and future challenges. Nat Rev Clin Oncol. 2021; 18: 297-312.
- 16Okugawa Y, Grady WM, Goel A. Epigenetic alterations in colorectal cancer: emerging biomarkers. Gastroenterology. 2015; 149: 1204-1225.e12.
- 17Lao VV, Grady WM. Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol. 2011; 8: 686-700.
- 18Lam K, Pan K, Linnekamp JF, Medema JP, Kandimalla R. DNA methylation based biomarkers in colorectal cancer: a systematic review. Biochim Biophys Acta Rev Cancer. 2016; 1866: 106-120.
- 19Gao D, Herman JG, Guo M. The clinical value of aberrant epigenetic changes of DNA damage repair genes in human cancer. Oncotarget. 2016; 7: 37331-37346.
- 20Al-Hajeili M, Marshall JL, Smaglo BG. Neoadjuvant treatment for surgically resectable metastatic colorectal cancer. Oncology (Williston Park, N.Y.). 2016; 30: 10-16.
- 21Tepelenis K, Pappas-Gogos G, Ntellas P, et al. The role of preoperative chemotherapy in the management of synchronous resectable colorectal liver metastases: a meta-analysis. Curr Oncol. 2023; 30: 4499-4511.
- 22 Japanese Society for Cancer of the Colon and Rectum. Japanese classification of colorectal, appendiceal, and anal carcinoma: the 3d English edition. J Anus Rectum Colon. 2019; 3: 175-195.
- 23 JD Brierley, MK Gospodarowicz, C Wittekind, (eds). TNM Classification of Malignant Tumours, Eighth Edition. John Wiley & Sons; 2017.
- 24Hulbert A, Jusue-Torres I, Stark A, et al. Early detection of lung cancer using DNA promoter hypermethylation in plasma and sputum. Clin Cancer Res. 2017; 23: 1998-2005.
- 25Chen C, Huang X, Yin W, et al. Ultrasensitive DNA hypermethylation detection using plasma for early detection of NSCLC: a study in Chinese patients with very small nodules. Clin Epigenetics. 2020; 12: 39.
- 26Bailey VJ, Zhang Y, Keeley BP, et al. Single-tube analysis of DNA methylation with silica superparamagnetic beads. Clin Chem. 2010; 56: 1022-1025.
- 27Keeley B, Stark A, Pisanic 2nd TR, et al. Extraction and processing of circulating DNA from large sample volumes using methylation on beads for the detection of rare epigenetic events. Clin Chim Acta. 2013; 425: 169-175.
- 28Hagiwara T, Sugimoto K, Momose H, et al. CHFR-promoter-methylation status is predictive of response to irinotecan-based systemic chemotherapy in advanced colorectal cancer. Anticancer Res. 2022; 42: 697-707.
- 29Derks S, Cleven AH, Melotte V, et al. Emerging evidence for CHFR as a cancer biomarker: from tumor biology to precision medicine. Cancer Metastasis Rev. 2014; 33: 161-171.
- 30Shan T, Uyar DS, Wang LS, et al. SOX11 hypermethylation as a tumor biomarker in endometrial cancer. Biochimie. 2019; 162: 8-14.
- 31Chung W, Bondaruk J, Jelinek J, et al. Detection of bladder cancer using novel DNA methylation biomarkers in urine sediments. Cancer Epidemiol Biomarkers Prev. 2011; 20: 1483-1491.
- 32Chen M, Zhu JY, Mu WJ, Guo L. Cysteine dioxygenase type 1 (CDO1): its functional role in physiological and pathophysiological processes. Genes Diseases. 2023; 10: 877-890.
- 33Liu B, Ricarte Filho J, Mallisetty A, et al. Detection of promoter DNA methylation in urine and plasma aids the detection of Non-Small cell lung cancer. Clin Cancer Res. 2020; 26: 4339-4348.
- 34Grützmann R, Molnar B, Pilarsky C, et al. Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay. PLoS One. 2008; 3:e3759.
- 35deVos T, Tetzner R, Model F, et al. Circulating methylated SEPT9 DNA in plasma is a biomarker for colorectal cancer. Clin Chem. 2009; 55: 1337-1346.
- 36Tóth K, Sipos F, Kalmár A, et al. Detection of methylated SEPT9 in plasma is a reliable screening method for both left- and right-sided colon cancers. PLoS One. 2012; 7:e46000.
- 37Li M, Chen W, Papadopoulos N, et al. Sensitive digital quantification of DNA methylation in clinical samples. Nat Biotechnol. 2009; 27: 858-863.
- 38Yamashita K, Waraya M, Kim MS, et al. Detection of methylated CDO1 in plasma of colorectal cancer: a PCR study. PLoS One. 2014; 9:e113546.
- 39Cleven AHG, Derks S, Draht MXG, et al. CHFR promoter methylation indicates poor prognosis in stage II microsatellite stable colorectal cancer. Clin Cancer Res. 2014; 20: 3261-3271.
- 40Scolnick DM, Halazonetis TD. Chfr defines a mitotic stress checkpoint that delays entry into metaphase. Nature. 2000; 406: 430-435.
- 41Cha Y, Kim SY, Yeo HY, et al. Association of CHFR promoter methylation with treatment outcomes of irinotecan-based chemotherapy in metastatic colorectal cancer. Neoplasia. 2019; 21: 146-155.
- 42Kotani D, Oki E, Nakamura Y, et al. Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer. Nat Med. 2023; 29: 127-134.
- 43Kasi PM, Fehringer G, Taniguchi H, et al Impact of circulating tumor DNA-Based detection of molecular residual disease on the conduct and design of clinical trials for solid tumors. JCO Precis Oncol. 2022; 6:e2100181.
- 44Parikh AR, Van Seventer EE, Siravegna G, et al. Minimal residual disease detection using a plasma-only circulating tumor DNA assay in patients with colorectal cancer. Clin Cancer Res. 2021; 27: 5586-5594.
