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. Lanspa & 2 others Robert W. Haile, Henry T. Lynch

Research output: Contribution to journalArticle

Abstract

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 (US)
Article numbere000299
JournalBMJ Open Gastroenterology
Volume6
Issue number1
DOIs
StatePublished - May 1 2019

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Hereditary Nonpolyposis Colorectal Neoplasms
Colorectal Neoplasms
Colonoscopy
Adenoma
Neoplasms
Early Detection of Cancer
Methylation
Case-Control Studies
Mucous Membrane
Biomarkers

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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Methylated SEPTIN9 plasma test for colorectal cancer detection may be applicable to Lynch syndrome. / Hitchins, Megan P.; Vogelaar, Ingrid P.; Brennan, Kevin; Haraldsdottir, Sigurdis; Zhou, Nianmin; Martin, Brock; Alvarez, Rocio; Yuan, Xiaopu; Kim, Sungjin; Guindi, Maha; Hendifar, Andrew E.; Kalady, Matthew F.; Devecchio, Jennifer; Church, James M.; De La Chapelle, Albert; Hampel, Heather; Pearlman, Rachel; Christensen, Maria; Snyder, Carrie; Lanspa, Stephen J.; Haile, Robert W.; Lynch, Henry T.

In: BMJ Open Gastroenterology, Vol. 6, No. 1, e000299, 01.05.2019.

Research output: Contribution to journalArticle

Hitchins, MP, Vogelaar, IP, Brennan, K, Haraldsdottir, S, Zhou, N, Martin, B, Alvarez, R, Yuan, X, Kim, S, Guindi, M, Hendifar, AE, Kalady, MF, Devecchio, J, Church, JM, De La Chapelle, A, Hampel, H, Pearlman, R, Christensen, M, Snyder, C, Lanspa, SJ, Haile, RW & Lynch, HT 2019, 'Methylated SEPTIN9 plasma test for colorectal cancer detection may be applicable to Lynch syndrome', BMJ Open Gastroenterology, vol. 6, no. 1, e000299. https://doi.org/10.1136/bmjgast-2019-000299
Hitchins, Megan P. ; Vogelaar, Ingrid P. ; Brennan, Kevin ; Haraldsdottir, Sigurdis ; Zhou, Nianmin ; Martin, Brock ; Alvarez, Rocio ; Yuan, Xiaopu ; Kim, Sungjin ; Guindi, Maha ; Hendifar, Andrew E. ; Kalady, Matthew F. ; Devecchio, Jennifer ; Church, James M. ; De La Chapelle, Albert ; Hampel, Heather ; Pearlman, Rachel ; Christensen, Maria ; Snyder, Carrie ; Lanspa, Stephen J. ; Haile, Robert W. ; Lynch, Henry T. / Methylated SEPTIN9 plasma test for colorectal cancer detection may be applicable to Lynch syndrome. In: BMJ Open Gastroenterology. 2019 ; Vol. 6, No. 1.
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abstract = "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.",
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T1 - Methylated SEPTIN9 plasma test for colorectal cancer detection may be applicable to Lynch syndrome

AU - Hitchins, Megan P.

AU - Vogelaar, Ingrid P.

AU - Brennan, Kevin

AU - Haraldsdottir, Sigurdis

AU - Zhou, Nianmin

AU - Martin, Brock

AU - Alvarez, Rocio

AU - Yuan, Xiaopu

AU - Kim, Sungjin

AU - Guindi, Maha

AU - Hendifar, Andrew E.

AU - Kalady, Matthew F.

AU - Devecchio, Jennifer

AU - Church, James M.

AU - De La Chapelle, Albert

AU - Hampel, Heather

AU - Pearlman, Rachel

AU - Christensen, Maria

AU - Snyder, Carrie

AU - Lanspa, Stephen J.

AU - Haile, Robert W.

AU - Lynch, Henry T.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

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