Methylated SEPTIN9 plasma test for colorectal cancer detection may be applicable to Lynch syndrome

Megan P. Hitchins*, Ingrid P. Vogelaar, Kevin Brennan, Sigurdis Haraldsdottir, Nianmin Zhou, Brock Martin, Rocio Alvarez, Xiaopu Yuan, Sungjin Kim, Maha Guindi, Andrew E. Hendifar, Matthew F. Kalady, Jennifer Devecchio, James M. Church, Albert De La Chapelle, Heather Hampel, Rachel Pearlman, Maria Christensen, Carrie Snyder, Stephen J. LanspaRobert W. Haile, Henry T. Lynch

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


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.

Original languageEnglish
Article numbere000299
JournalBMJ Open Gastroenterology
Issue number1
Publication statusPublished - 1 May 2019

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Other keywords

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


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