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Methylated SEPTIN9 plasma test for colorectal cancer detection may be applicable to Lynch syndrome
  1. Megan P Hitchins1,
  2. Ingrid P Vogelaar2,
  3. Kevin Brennan2,
  4. Sigurdis Haraldsdottir2,
  5. Nianmin Zhou2,
  6. Brock Martin2,
  7. Rocio Alvarez1,
  8. Xiaopu Yuan3,
  9. Sungjin Kim4,
  10. Maha Guindi3,
  11. Andrew E Hendifar5,
  12. Matthew F Kalady6,
  13. Jennifer DeVecchio7,
  14. James M Church6,
  15. Albert de la Chapelle8,
  16. Heather Hampel8,
  17. Rachel Pearlman8,
  18. Maria Christensen9,
  19. Carrie Snyder9,
  20. Stephen J Lanspa9,
  21. Robert W Haile10,
  22. Henry T Lynch9
  1. 1Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
  2. 2Medicine, Stanford University, Stanford, California, USA
  3. 3Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
  4. 4Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
  5. 5Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Comprehensive Cancer Center, Los Angeles, California, USA
  6. 6Departments of Stem Cell and Regenerative Medicine and Colorectal Surgery, Sanford R Weiss MD Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgery Institute, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA
  7. 7Department of Stem Cell and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA
  8. 8Department of Internal Medicine and the Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
  9. 9Hereditary Cancer Center, Creighton University, Omaha, Nebraska, USA
  10. 10Department of Medicine, Research Center for Health Equity, Cedars-Sinai Medical Center, Los Angeles, California, USA
  1. Correspondence to Dr Megan P Hitchins; megan.hitchins{at}


Objective The plasma-based methylated SEPTIN9 (mSEPT9) is a colorectal cancer (CRC) screening test for adults aged 50–75 years who are at average risk for CRC and have refused colonoscopy or faecal-based screening tests. The applicability of mSEPT9 for high-risk persons with Lynch syndrome (LS), the most common hereditary CRC condition, has not been assessed. This study sought preliminary evidence for the utility of mSEPT9 for CRC detection in LS.

Design Firstly, SEPT9 methylation was measured in LS-associated CRC, advanced adenoma, and subject-matched normal colorectal mucosa tissues by pyrosequencing. Secondly, to detect mSEPT9 as circulating tumor DNA, the plasma-based mSEPT9 test was retrospectively evaluated in LS subjects using the Epi proColon 2.0 CE assay adapted for 1mL plasma using the “1/1 algorithm”. LS case groups included 20 peri-surgical cases with acolonoscopy-based diagnosis of CRC (stages I-IV), 13 post-surgical metastatic CRC, and 17 pre-diagnosis cases. The control group comprised 31 cancer-free LS subjects.

Results Differential hypermethylation was found in 97.3% (36/37) of primary CRC and 90.0% (18/20) of advanced adenomas, showing LS-associated neoplasia frequently produce the mSEPT9 biomarker. Sensitivity of plasma mSEPT9 to detect CRC was 70.0% (95% CI, 48%-88%)in cases with a colonoscopy-based CRC diagnosis and 92.3% (95% CI, 64%-100%) inpost-surgical metastatic cases. In pre-diagnosis cases, plasma mSEPT9 was detected within two months prior to colonoscopy-based CRC diagnosis in 3/5 cases. Specificity in controls was 100% (95% CI 89%-100%).

Conclusion These preliminary findings suggest mSEPT9 may demonstrate similar diagnostic performance characteristics in LS as in the average-risk population, warranting a well-powered prospective case–control study.

  • colorectal cancer
  • lynch syndrome
  • plasma
  • circulating tumor dna

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  • RWH and HTL contributed equally.

  • Contributors MPH and RWH contributed to the concept and design, and supervised the study. MPH, IPV, SH, NZ, BM, RA, XY, MG, AEH, MFK, JDV, JMC, AdelaC, HH, RP, MC, CS, SJL, and HTL contributed to the acquisition of data. MPH, IPV, KB, BM, SJL, RWH, and HTL contributed to the analysis and interpretation of data. MPH, KB and SK contributed to statistical analyses. MPH, IPV, KB, SK, and RWH contributed to drafting of the manuscript. All authors provided critical review of the manuscript. MPH was responsible for critical revision of the manuscript.

  • Funding This project was funded in part by the Chen-Yang Foundation, the Liz’s Legacy fund through Kicks for a Cure, the Samuel Oschin Comprehensive Cancer Center at Cedars-Sinai Medical Center, and by revenue from Nebraska's excise tax on cigarettes awarded to Creighton University through the Nebraska Department of Health & Human Services (DHHS). HTL is partially funded through the Charles F and Mary C Heider Chair in Cancer Research, which he holds at Creighton University. We acknowledge support from the Biobank & Translational Research Core at CSMC, which was funded in part through institutional support and in part through NIH grant G20 RR030860.

  • Disclaimer The contents represent the views of the authors and do not necessarily represent the official views of the State of Nebraska or DHHS.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval The Hereditary Cancer Center, Creighton University (No 05-13877), The Icelandic Population-based Cancer Registry (Icelandic National Bioethics Committee No VSNb2013010033/03.15 and Data Protection Authority No 2013010109TS), The Ohio State University Comprehensive Cancer Center from the prior ‘Columbus-area HNPCC-study’ and ‘Ohio State Colorectal Cancer Prevention Initiative’ (No 2019C0064), The Cleveland Clinic, Ohio (No 2884), and Cedars-Sinai Medical Center (CSMC), California (No Pro00049624). Designated use of the retrospectively collected samples from these sources for SEPT9 methylation testing was subsequently approved by the Icelandic National Bioethics Committee (No 13-024 S1), Stanford University (No 120715 NOT-H3), and CSMC (No Pro00051525).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Data are available upon reasonable request.