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; Robert W. Haile; Henry T. Lynch

doi:10.1136/bmjgast-2019-000299

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 journal › Article › peer-review

6 Citations (Scopus)

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 language	English
Article number	e000299
Journal	BMJ Open Gastroenterology
Volume	6
Issue number	1
DOIs	https://doi.org/10.1136/bmjgast-2019-000299
Publication status	Published - 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
SEPTIN9

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10.1136/bmjgast-2019-000299

Cite this

Hitchins, M. P., Vogelaar, I. P., Brennan, K., Haraldsdottir, S., Zhou, N., Martin, B., Alvarez, R., Yuan, X., Kim, S., Guindi, M., Hendifar, A. E., Kalady, M. F., Devecchio, J., Church, J. M., De La Chapelle, A., Hampel, H., Pearlman, R., Christensen, M., Snyder, C., ... Lynch, H. T. (2019). Methylated SEPTIN9 plasma test for colorectal cancer detection may be applicable to Lynch syndrome. BMJ Open Gastroenterology, 6(1), [e000299]. https://doi.org/10.1136/bmjgast-2019-000299

@article{723780e355f042f2bcb7a09826c045da,

title = "Methylated SEPTIN9 plasma test for colorectal cancer detection may be applicable to Lynch syndrome",

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.",

keywords = "circulating tumor DNA, colorectal cancer, lynch syndrome, plasma, SEPTIN9",

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

note = "Funding Information: Funding This project was funded in part by the Chen-Yang Foundation, the Liz{\textquoteright}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: {\textcopyright} 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.",

year = "2019",

month = may,

day = "1",

doi = "10.1136/bmjgast-2019-000299",

language = "English",

volume = "6",

journal = "BMJ Open Gastroenterology",

issn = "2054-4774",

publisher = "BMJ Publishing Group",

number = "1",

}

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

TY - JOUR

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.

N1 - 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.

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.

KW - circulating tumor DNA

KW - colorectal cancer

KW - lynch syndrome

KW - plasma

KW - SEPTIN9

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DO - 10.1136/bmjgast-2019-000299

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AN - SCOPUS:85067055409

SN - 2054-4774

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JO - BMJ Open Gastroenterology

JF - BMJ Open Gastroenterology

IS - 1

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ER -

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

Abstract

Bibliographical note

Other keywords

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