Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors - A prospective study and guidelines for clinical testing

Kristyn Galbraith; Varshini Vasudevaraja; Jonathan Serrano; Guomiao Shen; Ivy Tran; Nancy Abdallat; Mandisa Wen; Seema Patel; Misha Movahed-Ezazi; Arline Faustin; Marissa Spino-Keeton; Leah Geiser Roberts; Ekrem Maloku; Steven A. Drexler; Benjamin L. Liechty; David Pisapia; Olga Krasnozhen-Ratush; Marc Rosenblum; Seema Shroff; Daniel R. Boué; Christian Davidson; Qinwen Mao; Mariko Suchi; Paula North; Amanda Hopp; Annette Segura; Jason A. Jarzembowski; Lauren Parsons; Mahlon D. Johnson; Bret Mobley; Wesley Samore; Declan McGuone; Pallavi P. Gopal; Peter D. Canoll; Craig Horbinski; Joseph M. Fullmer; Midhat S. Farooqui; Murat Gokden; Nitin R. Wadhwani; Timothy E. Richardson; Melissa Umphlett; Nadejda M. Tsankova; John C. Dewitt; Chandra Sen; Dimitris G. Placantonakis; Donato Pacione; Jeffrey H. Wisoff; Eveline Teresa Hidalgo; David Harter; Christopher M. William; Christine Cordova; Sylvia C. Kurz; Marissa Barbaro; Daniel A. Orringer; Matthias A. Karajannis; Erik P. Sulman; Sharon L. Gardner; David Zagzag; Aristotelis Tsirigos; Jeffrey C. Allen; John G. Golfinos; Matija Snuderl

doi:10.1093/noajnl/vdad076

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors - A prospective study and guidelines for clinical testing

Kristyn Galbraith, Varshini Vasudevaraja, Jonathan Serrano, Guomiao Shen, Ivy Tran, Nancy Abdallat, Mandisa Wen, Seema Patel, Misha Movahed-Ezazi, Arline Faustin, Marissa Spino-Keeton, Leah Geiser Roberts, Ekrem Maloku, Steven A. Drexler, Benjamin L. Liechty, David Pisapia, Olga Krasnozhen-Ratush, Marc Rosenblum, Seema Shroff, Daniel R. BouéChristian Davidson, Qinwen Mao, Mariko Suchi, Paula North, Amanda Hopp, Annette Segura, Jason A. Jarzembowski, Lauren Parsons, Mahlon D. Johnson, Bret Mobley, Wesley Samore, Declan McGuone, Pallavi P. Gopal, Peter D. Canoll, Craig Horbinski, Joseph M. Fullmer, Midhat S. Farooqui, Murat Gokden, Nitin R. Wadhwani, Timothy E. Richardson, Melissa Umphlett, Nadejda M. Tsankova, John C. Dewitt, Chandra Sen, Dimitris G. Placantonakis, Donato Pacione, Jeffrey H. Wisoff, Eveline Teresa Hidalgo, David Harter, Christopher M. William, Christine Cordova, Sylvia C. Kurz, Marissa Barbaro, Daniel A. Orringer, Matthias A. Karajannis, Erik P. Sulman, Sharon L. Gardner, David Zagzag, Aristotelis Tsirigos, Jeffrey C. Allen, John G. Golfinos, Matija Snuderl

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

Original language	American English
Article number	vdad076
Journal	Neuro-Oncology Advances
Volume	5
Issue number	1
DOIs	https://doi.org/10.1093/noajnl/vdad076
State	Published - Jan 1 2023
Externally published	Yes

ASJC Scopus subject areas

Surgery
Oncology
Clinical Neurology

Keywords

DNA methylation
central nervous system tumors
guidelines
molecular
tumor classification

Access to Document

10.1093/noajnl/vdad076

Cite this

Galbraith, K., Vasudevaraja, V., Serrano, J., Shen, G., Tran, I., Abdallat, N., Wen, M., Patel, S., Movahed-Ezazi, M., Faustin, A., Spino-Keeton, M., Roberts, L. G., Maloku, E., Drexler, S. A., Liechty, B. L., Pisapia, D., Krasnozhen-Ratush, O., Rosenblum, M., Shroff, S., ... Snuderl, M. (2023). Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors - A prospective study and guidelines for clinical testing. Neuro-Oncology Advances, 5(1), Article vdad076. https://doi.org/10.1093/noajnl/vdad076

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title = "Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors - A prospective study and guidelines for clinical testing",

abstract = "Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14\%), 78 cases (5\%) did not classify with any class, and in an additional 110 (7\%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86\%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18\%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.",

keywords = "DNA methylation, central nervous system tumors, guidelines, molecular, tumor classification",

author = "Kristyn Galbraith and Varshini Vasudevaraja and Jonathan Serrano and Guomiao Shen and Ivy Tran and Nancy Abdallat and Mandisa Wen and Seema Patel and Misha Movahed-Ezazi and Arline Faustin and Marissa Spino-Keeton and Roberts, \{Leah Geiser\} and Ekrem Maloku and Drexler, \{Steven A.\} and Liechty, \{Benjamin L.\} and David Pisapia and Olga Krasnozhen-Ratush and Marc Rosenblum and Seema Shroff and Bou{\'e}, \{Daniel R.\} and Christian Davidson and Qinwen Mao and Mariko Suchi and Paula North and Amanda Hopp and Annette Segura and Jarzembowski, \{Jason A.\} and Lauren Parsons and Johnson, \{Mahlon D.\} and Bret Mobley and Wesley Samore and Declan McGuone and Gopal, \{Pallavi P.\} and Canoll, \{Peter D.\} and Craig Horbinski and Fullmer, \{Joseph M.\} and Farooqui, \{Midhat S.\} and Murat Gokden and Wadhwani, \{Nitin R.\} and Richardson, \{Timothy E.\} and Melissa Umphlett and Tsankova, \{Nadejda M.\} and Dewitt, \{John C.\} and Chandra Sen and Placantonakis, \{Dimitris G.\} and Donato Pacione and Wisoff, \{Jeffrey H.\} and \{Teresa Hidalgo\}, Eveline and David Harter and William, \{Christopher M.\} and Christine Cordova and Kurz, \{Sylvia C.\} and Marissa Barbaro and Orringer, \{Daniel A.\} and Karajannis, \{Matthias A.\} and Sulman, \{Erik P.\} and Gardner, \{Sharon L.\} and David Zagzag and Aristotelis Tsirigos and Allen, \{Jeffrey C.\} and Golfinos, \{John G.\} and Matija Snuderl",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.",

year = "2023",

month = jan,

day = "1",

doi = "10.1093/noajnl/vdad076",

language = "American English",

volume = "5",

journal = "Neuro-Oncology Advances",

issn = "2632-2498",

publisher = "Oxford University Press",

number = "1",

}

Galbraith, K, Vasudevaraja, V, Serrano, J, Shen, G, Tran, I, Abdallat, N, Wen, M, Patel, S, Movahed-Ezazi, M, Faustin, A, Spino-Keeton, M, Roberts, LG, Maloku, E, Drexler, SA, Liechty, BL, Pisapia, D, Krasnozhen-Ratush, O, Rosenblum, M, Shroff, S, Boué, DR, Davidson, C, Mao, Q, Suchi, M, North, P, Hopp, A, Segura, A, Jarzembowski, JA, Parsons, L, Johnson, MD, Mobley, B, Samore, W, McGuone, D, Gopal, PP, Canoll, PD, Horbinski, C, Fullmer, JM, Farooqui, MS, Gokden, M, Wadhwani, NR, Richardson, TE, Umphlett, M, Tsankova, NM, Dewitt, JC, Sen, C, Placantonakis, DG, Pacione, D, Wisoff, JH, Teresa Hidalgo, E, Harter, D, William, CM, Cordova, C, Kurz, SC, Barbaro, M, Orringer, DA, Karajannis, MA, Sulman, EP, Gardner, SL, Zagzag, D, Tsirigos, A, Allen, JC, Golfinos, JG & Snuderl, M 2023, 'Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors - A prospective study and guidelines for clinical testing', Neuro-Oncology Advances, vol. 5, no. 1, vdad076. https://doi.org/10.1093/noajnl/vdad076

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors - A prospective study and guidelines for clinical testing. / Galbraith, Kristyn; Vasudevaraja, Varshini; Serrano, Jonathan et al.
In: Neuro-Oncology Advances, Vol. 5, No. 1, vdad076, 01.01.2023.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors - A prospective study and guidelines for clinical testing

AU - Galbraith, Kristyn

AU - Vasudevaraja, Varshini

AU - Serrano, Jonathan

AU - Shen, Guomiao

AU - Tran, Ivy

AU - Abdallat, Nancy

AU - Wen, Mandisa

AU - Patel, Seema

AU - Movahed-Ezazi, Misha

AU - Faustin, Arline

AU - Spino-Keeton, Marissa

AU - Roberts, Leah Geiser

AU - Maloku, Ekrem

AU - Drexler, Steven A.

AU - Liechty, Benjamin L.

AU - Pisapia, David

AU - Krasnozhen-Ratush, Olga

AU - Rosenblum, Marc

AU - Shroff, Seema

AU - Boué, Daniel R.

AU - Davidson, Christian

AU - Mao, Qinwen

AU - Suchi, Mariko

AU - North, Paula

AU - Hopp, Amanda

AU - Segura, Annette

AU - Jarzembowski, Jason A.

AU - Parsons, Lauren

AU - Johnson, Mahlon D.

AU - Mobley, Bret

AU - Samore, Wesley

AU - McGuone, Declan

AU - Gopal, Pallavi P.

AU - Canoll, Peter D.

AU - Horbinski, Craig

AU - Fullmer, Joseph M.

AU - Farooqui, Midhat S.

AU - Gokden, Murat

AU - Wadhwani, Nitin R.

AU - Richardson, Timothy E.

AU - Umphlett, Melissa

AU - Tsankova, Nadejda M.

AU - Dewitt, John C.

AU - Sen, Chandra

AU - Placantonakis, Dimitris G.

AU - Pacione, Donato

AU - Wisoff, Jeffrey H.

AU - Teresa Hidalgo, Eveline

AU - Harter, David

AU - William, Christopher M.

AU - Cordova, Christine

AU - Kurz, Sylvia C.

AU - Barbaro, Marissa

AU - Orringer, Daniel A.

AU - Karajannis, Matthias A.

AU - Sulman, Erik P.

AU - Gardner, Sharon L.

AU - Zagzag, David

AU - Tsirigos, Aristotelis

AU - Allen, Jeffrey C.

AU - Golfinos, John G.

AU - Snuderl, Matija

PY - 2023/1/1

Y1 - 2023/1/1

N2 - Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

AB - Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

KW - DNA methylation

KW - central nervous system tumors

KW - guidelines

KW - molecular

KW - tumor classification

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U2 - 10.1093/noajnl/vdad076

DO - 10.1093/noajnl/vdad076

M3 - Article

SN - 2632-2498

VL - 5

JO - Neuro-Oncology Advances

JF - Neuro-Oncology Advances

IS - 1

M1 - vdad076

ER -

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors - A prospective study and guidelines for clinical testing

Abstract

ASJC Scopus subject areas

Keywords

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