DNA methylation profiling to predict recurrence risk in meningioma: Development and validation of a nomogram to optimize clinical management

Farshad Nassiri, Yasin Mamatjan, Suganth Suppiah, Jetan H. Badhiwala, Sheila Mansouri, Shirin Karimi, Olli Saarela, Laila Poisson, Irina Gepfner-Tuma, Jens Schittenhelm, Ho Keung Ng, Houtan Noushmehr, Patrick Harter, Peter Baumgarten, Michael Weller, Matthias Preusser, Christel Herold-Mende, Marcos Tatagiba, Ghazaleh Tabatabai, Felix SahmAndreas Von Deimling, Kenneth Aldape, Karolyn Au, Jill Barnhartz-Sloan, Wenya Linda Bi, Priscilla K. Brastianos, Nicholas Butowski, Carlos Carlotti, Michael D. Cusimano, Francesco Dimeco, Katharine Drummond, Ian F. Dunn, Evanthia Galanis, Caterina Giannini, Roland Goldbrunner, Brent Griffith, Rintaro Hashizume, C. Oliver Hanemann, Christel Herold-Mende, Craig Horbinski, Raymond Y. Huang, David James, Michael D. Jenkinson, Christine Jungk, Timothy J. Kaufman, Boris Krischek, Daniel Lachance, Christian Lafougère, Ian Lee, Jeff C. Liu, Yasin Mamatjan, Tathiane M. Malta, Christian Mawrin, Michael McDermott, David Munoz, Farshad Nassiri, Houtan Noushmehr, Ho Keung Ng, Arie Perry, Farhad Pirouzmand, Laila M. Poisson, Bianca Pollo, David Raleigh, Felix Sahm, Andrea Saladino, Thomas Santarius, Christian Schichor, David Schultz, Nils O. Schmidt, Warren Selman, Andrew Sloan, Julian Spears, James Snyder, Suganth Suppiah, Ghazaleh Tabatabai, Marcos Tatagiba, Daniela Tirapelli, Joerg C. Tonn, Derek Tsang, Michael A. Vogelbaum, Andreas Von Deimling, Patrick Y. Wen, Tobias Walbert, Manfred Westphal, Adriana M. Workewych, Gelareh Zadeh, Gelareh Zadeh, Kenneth D. Aldape*

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. Methods: DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. Results: The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03-0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8-7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22-0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3-11.1, P < 0.001) with clinical implications. Conclusions: The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.

Original languageEnglish (US)
Article numbernoz061
Pages (from-to)901-910
Number of pages10
JournalNeuro-oncology
Volume21
Issue number7
DOIs
StatePublished - Jul 11 2019

Fingerprint

Nomograms
DNA Fingerprinting
Meningioma
DNA Methylation
Recurrence
Adjuvant Radiotherapy
Standard of Care
Area Under Curve
Survival
Patient Selection
Neoplasms
Observation

Keywords

  • meningioma
  • methylation
  • nomogram
  • predictor
  • recurrence

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Nassiri, F., Mamatjan, Y., Suppiah, S., Badhiwala, J. H., Mansouri, S., Karimi, S., ... Aldape, K. D. (2019). DNA methylation profiling to predict recurrence risk in meningioma: Development and validation of a nomogram to optimize clinical management. Neuro-oncology, 21(7), 901-910. [noz061]. https://doi.org/10.1093/neuonc/noz061
Nassiri, Farshad ; Mamatjan, Yasin ; Suppiah, Suganth ; Badhiwala, Jetan H. ; Mansouri, Sheila ; Karimi, Shirin ; Saarela, Olli ; Poisson, Laila ; Gepfner-Tuma, Irina ; Schittenhelm, Jens ; Ng, Ho Keung ; Noushmehr, Houtan ; Harter, Patrick ; Baumgarten, Peter ; Weller, Michael ; Preusser, Matthias ; Herold-Mende, Christel ; Tatagiba, Marcos ; Tabatabai, Ghazaleh ; Sahm, Felix ; Von Deimling, Andreas ; Aldape, Kenneth ; Au, Karolyn ; Barnhartz-Sloan, Jill ; Bi, Wenya Linda ; Brastianos, Priscilla K. ; Butowski, Nicholas ; Carlotti, Carlos ; Cusimano, Michael D. ; Dimeco, Francesco ; Drummond, Katharine ; Dunn, Ian F. ; Galanis, Evanthia ; Giannini, Caterina ; Goldbrunner, Roland ; Griffith, Brent ; Hashizume, Rintaro ; Hanemann, C. Oliver ; Herold-Mende, Christel ; Horbinski, Craig ; Huang, Raymond Y. ; James, David ; Jenkinson, Michael D. ; Jungk, Christine ; Kaufman, Timothy J. ; Krischek, Boris ; Lachance, Daniel ; Lafougère, Christian ; Lee, Ian ; Liu, Jeff C. ; Mamatjan, Yasin ; Malta, Tathiane M. ; Mawrin, Christian ; McDermott, Michael ; Munoz, David ; Nassiri, Farshad ; Noushmehr, Houtan ; Ng, Ho Keung ; Perry, Arie ; Pirouzmand, Farhad ; Poisson, Laila M. ; Pollo, Bianca ; Raleigh, David ; Sahm, Felix ; Saladino, Andrea ; Santarius, Thomas ; Schichor, Christian ; Schultz, David ; Schmidt, Nils O. ; Selman, Warren ; Sloan, Andrew ; Spears, Julian ; Snyder, James ; Suppiah, Suganth ; Tabatabai, Ghazaleh ; Tatagiba, Marcos ; Tirapelli, Daniela ; Tonn, Joerg C. ; Tsang, Derek ; Vogelbaum, Michael A. ; Von Deimling, Andreas ; Wen, Patrick Y. ; Walbert, Tobias ; Westphal, Manfred ; Workewych, Adriana M. ; Zadeh, Gelareh ; Zadeh, Gelareh ; Aldape, Kenneth D. / DNA methylation profiling to predict recurrence risk in meningioma : Development and validation of a nomogram to optimize clinical management. In: Neuro-oncology. 2019 ; Vol. 21, No. 7. pp. 901-910.
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title = "DNA methylation profiling to predict recurrence risk in meningioma: Development and validation of a nomogram to optimize clinical management",
abstract = "Background: Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. Methods: DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. Results: The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95{\%} CI: 0.03-0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95{\%} CI: 1.8-7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95{\%} CI: 0.22-0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95{\%} CI: 5.3-11.1, P < 0.001) with clinical implications. Conclusions: The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.",
keywords = "meningioma, methylation, nomogram, predictor, recurrence",
author = "Farshad Nassiri and Yasin Mamatjan and Suganth Suppiah and Badhiwala, {Jetan H.} and Sheila Mansouri and Shirin Karimi and Olli Saarela and Laila Poisson and Irina Gepfner-Tuma and Jens Schittenhelm and Ng, {Ho Keung} and Houtan Noushmehr and Patrick Harter and Peter Baumgarten and Michael Weller and Matthias Preusser and Christel Herold-Mende and Marcos Tatagiba and Ghazaleh Tabatabai and Felix Sahm and {Von Deimling}, Andreas and Kenneth Aldape and Karolyn Au and Jill Barnhartz-Sloan and Bi, {Wenya Linda} and Brastianos, {Priscilla K.} and Nicholas Butowski and Carlos Carlotti and Cusimano, {Michael D.} and Francesco Dimeco and Katharine Drummond and Dunn, {Ian F.} and Evanthia Galanis and Caterina Giannini and Roland Goldbrunner and Brent Griffith and Rintaro Hashizume and Hanemann, {C. Oliver} and Christel Herold-Mende and Craig Horbinski and Huang, {Raymond Y.} and David James and Jenkinson, {Michael D.} and Christine Jungk and Kaufman, {Timothy J.} and Boris Krischek and Daniel Lachance and Christian Lafoug{\`e}re and Ian Lee and Liu, {Jeff C.} and Yasin Mamatjan and Malta, {Tathiane M.} and Christian Mawrin and Michael McDermott and David Munoz and Farshad Nassiri and Houtan Noushmehr and Ng, {Ho Keung} and Arie Perry and Farhad Pirouzmand and Poisson, {Laila M.} and Bianca Pollo and David Raleigh and Felix Sahm and Andrea Saladino and Thomas Santarius and Christian Schichor and David Schultz and Schmidt, {Nils O.} and Warren Selman and Andrew Sloan and Julian Spears and James Snyder and Suganth Suppiah and Ghazaleh Tabatabai and Marcos Tatagiba and Daniela Tirapelli and Tonn, {Joerg C.} and Derek Tsang and Vogelbaum, {Michael A.} and {Von Deimling}, Andreas and Wen, {Patrick Y.} and Tobias Walbert and Manfred Westphal and Workewych, {Adriana M.} and Gelareh Zadeh and Gelareh Zadeh and Aldape, {Kenneth D.}",
year = "2019",
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doi = "10.1093/neuonc/noz061",
language = "English (US)",
volume = "21",
pages = "901--910",
journal = "Neuro-Oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
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Nassiri, F, Mamatjan, Y, Suppiah, S, Badhiwala, JH, Mansouri, S, Karimi, S, Saarela, O, Poisson, L, Gepfner-Tuma, I, Schittenhelm, J, Ng, HK, Noushmehr, H, Harter, P, Baumgarten, P, Weller, M, Preusser, M, Herold-Mende, C, Tatagiba, M, Tabatabai, G, Sahm, F, Von Deimling, A, Aldape, K, Au, K, Barnhartz-Sloan, J, Bi, WL, Brastianos, PK, Butowski, N, Carlotti, C, Cusimano, MD, Dimeco, F, Drummond, K, Dunn, IF, Galanis, E, Giannini, C, Goldbrunner, R, Griffith, B, Hashizume, R, Hanemann, CO, Herold-Mende, C, Horbinski, C, Huang, RY, James, D, Jenkinson, MD, Jungk, C, Kaufman, TJ, Krischek, B, Lachance, D, Lafougère, C, Lee, I, Liu, JC, Mamatjan, Y, Malta, TM, Mawrin, C, McDermott, M, Munoz, D, Nassiri, F, Noushmehr, H, Ng, HK, Perry, A, Pirouzmand, F, Poisson, LM, Pollo, B, Raleigh, D, Sahm, F, Saladino, A, Santarius, T, Schichor, C, Schultz, D, Schmidt, NO, Selman, W, Sloan, A, Spears, J, Snyder, J, Suppiah, S, Tabatabai, G, Tatagiba, M, Tirapelli, D, Tonn, JC, Tsang, D, Vogelbaum, MA, Von Deimling, A, Wen, PY, Walbert, T, Westphal, M, Workewych, AM, Zadeh, G, Zadeh, G & Aldape, KD 2019, 'DNA methylation profiling to predict recurrence risk in meningioma: Development and validation of a nomogram to optimize clinical management', Neuro-oncology, vol. 21, no. 7, noz061, pp. 901-910. https://doi.org/10.1093/neuonc/noz061

DNA methylation profiling to predict recurrence risk in meningioma : Development and validation of a nomogram to optimize clinical management. / Nassiri, Farshad; Mamatjan, Yasin; Suppiah, Suganth; Badhiwala, Jetan H.; Mansouri, Sheila; Karimi, Shirin; Saarela, Olli; Poisson, Laila; Gepfner-Tuma, Irina; Schittenhelm, Jens; Ng, Ho Keung; Noushmehr, Houtan; Harter, Patrick; Baumgarten, Peter; Weller, Michael; Preusser, Matthias; Herold-Mende, Christel; Tatagiba, Marcos; Tabatabai, Ghazaleh; Sahm, Felix; Von Deimling, Andreas; Aldape, Kenneth; Au, Karolyn; Barnhartz-Sloan, Jill; Bi, Wenya Linda; Brastianos, Priscilla K.; Butowski, Nicholas; Carlotti, Carlos; Cusimano, Michael D.; Dimeco, Francesco; Drummond, Katharine; Dunn, Ian F.; Galanis, Evanthia; Giannini, Caterina; Goldbrunner, Roland; Griffith, Brent; Hashizume, Rintaro; Hanemann, C. Oliver; Herold-Mende, Christel; Horbinski, Craig; Huang, Raymond Y.; James, David; Jenkinson, Michael D.; Jungk, Christine; Kaufman, Timothy J.; Krischek, Boris; Lachance, Daniel; Lafougère, Christian; Lee, Ian; Liu, Jeff C.; Mamatjan, Yasin; Malta, Tathiane M.; Mawrin, Christian; McDermott, Michael; Munoz, David; Nassiri, Farshad; Noushmehr, Houtan; Ng, Ho Keung; Perry, Arie; Pirouzmand, Farhad; Poisson, Laila M.; Pollo, Bianca; Raleigh, David; Sahm, Felix; Saladino, Andrea; Santarius, Thomas; Schichor, Christian; Schultz, David; Schmidt, Nils O.; Selman, Warren; Sloan, Andrew; Spears, Julian; Snyder, James; Suppiah, Suganth; Tabatabai, Ghazaleh; Tatagiba, Marcos; Tirapelli, Daniela; Tonn, Joerg C.; Tsang, Derek; Vogelbaum, Michael A.; Von Deimling, Andreas; Wen, Patrick Y.; Walbert, Tobias; Westphal, Manfred; Workewych, Adriana M.; Zadeh, Gelareh; Zadeh, Gelareh; Aldape, Kenneth D.

In: Neuro-oncology, Vol. 21, No. 7, noz061, 11.07.2019, p. 901-910.

Research output: Contribution to journalArticle

TY - JOUR

T1 - DNA methylation profiling to predict recurrence risk in meningioma

T2 - Development and validation of a nomogram to optimize clinical management

AU - Nassiri, Farshad

AU - Mamatjan, Yasin

AU - Suppiah, Suganth

AU - Badhiwala, Jetan H.

AU - Mansouri, Sheila

AU - Karimi, Shirin

AU - Saarela, Olli

AU - Poisson, Laila

AU - Gepfner-Tuma, Irina

AU - Schittenhelm, Jens

AU - Ng, Ho Keung

AU - Noushmehr, Houtan

AU - Harter, Patrick

AU - Baumgarten, Peter

AU - Weller, Michael

AU - Preusser, Matthias

AU - Herold-Mende, Christel

AU - Tatagiba, Marcos

AU - Tabatabai, Ghazaleh

AU - Sahm, Felix

AU - Von Deimling, Andreas

AU - Aldape, Kenneth

AU - Au, Karolyn

AU - Barnhartz-Sloan, Jill

AU - Bi, Wenya Linda

AU - Brastianos, Priscilla K.

AU - Butowski, Nicholas

AU - Carlotti, Carlos

AU - Cusimano, Michael D.

AU - Dimeco, Francesco

AU - Drummond, Katharine

AU - Dunn, Ian F.

AU - Galanis, Evanthia

AU - Giannini, Caterina

AU - Goldbrunner, Roland

AU - Griffith, Brent

AU - Hashizume, Rintaro

AU - Hanemann, C. Oliver

AU - Herold-Mende, Christel

AU - Horbinski, Craig

AU - Huang, Raymond Y.

AU - James, David

AU - Jenkinson, Michael D.

AU - Jungk, Christine

AU - Kaufman, Timothy J.

AU - Krischek, Boris

AU - Lachance, Daniel

AU - Lafougère, Christian

AU - Lee, Ian

AU - Liu, Jeff C.

AU - Mamatjan, Yasin

AU - Malta, Tathiane M.

AU - Mawrin, Christian

AU - McDermott, Michael

AU - Munoz, David

AU - Nassiri, Farshad

AU - Noushmehr, Houtan

AU - Ng, Ho Keung

AU - Perry, Arie

AU - Pirouzmand, Farhad

AU - Poisson, Laila M.

AU - Pollo, Bianca

AU - Raleigh, David

AU - Sahm, Felix

AU - Saladino, Andrea

AU - Santarius, Thomas

AU - Schichor, Christian

AU - Schultz, David

AU - Schmidt, Nils O.

AU - Selman, Warren

AU - Sloan, Andrew

AU - Spears, Julian

AU - Snyder, James

AU - Suppiah, Suganth

AU - Tabatabai, Ghazaleh

AU - Tatagiba, Marcos

AU - Tirapelli, Daniela

AU - Tonn, Joerg C.

AU - Tsang, Derek

AU - Vogelbaum, Michael A.

AU - Von Deimling, Andreas

AU - Wen, Patrick Y.

AU - Walbert, Tobias

AU - Westphal, Manfred

AU - Workewych, Adriana M.

AU - Zadeh, Gelareh

AU - Zadeh, Gelareh

AU - Aldape, Kenneth D.

PY - 2019/7/11

Y1 - 2019/7/11

N2 - Background: Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. Methods: DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. Results: The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03-0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8-7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22-0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3-11.1, P < 0.001) with clinical implications. Conclusions: The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.

AB - Background: Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. Methods: DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. Results: The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03-0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8-7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22-0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3-11.1, P < 0.001) with clinical implications. Conclusions: The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.

KW - meningioma

KW - methylation

KW - nomogram

KW - predictor

KW - recurrence

UR - http://www.scopus.com/inward/record.url?scp=85071162289&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071162289&partnerID=8YFLogxK

U2 - 10.1093/neuonc/noz061

DO - 10.1093/neuonc/noz061

M3 - Article

C2 - 31158293

AN - SCOPUS:85071162289

VL - 21

SP - 901

EP - 910

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - 7

M1 - noz061

ER -