Universität zu Köln

Rosswog, Carolina, Schmidt, Rene, Oberthuer, Andre, Juraeva, Dilafruz, Brors, Benedikt ORCID: 0000-0001-5940-3101, Engesser, Anne, Kahlert, Yvonne, Volland, Ruth, Bartenhagen, Christoph, Simon, Thorsten, Berthold, Frank, Hero, Barbara, Faldum, Andreas and Fischer, Matthias (2017). Molecular Classification Substitutes for the Prognostic Variables Stage, Age, and MYCN Status in Neuroblastoma Risk Assessment. Neoplasia, 19 (12). S. 982 - 991. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1476-5586

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Abstract

BACKGROUND: Current risk stratification systems for neuroblastoma patients consider clinical, histopathological, and genetic variables, and additional prognostic markers have been proposed in recent years. We here sought to select highly informative covariates in a multistep strategy based on consecutive Cox regression models, resulting in a risk score that integrates hazard ratios of prognostic variables. METHODS: A cohort of 695 neuroblastoma patients was divided into a discovery set (n = 75) for multigene predictor generation, a training set (n = 411) for risk score development, and a validation set (n = 209). Relevant prognostic variables were identified by stepwise multivariable L1-penalized least absolute shrinkage and selection operator (LASSO) Cox regression, followed by backward selection in multivariable Cox regression, and then integrated into a novel risk score. RESULTS: The variables stage, age, MYCN status, and two multigene predictors, NB-th24 and NB-th44, were selected as independent prognostic markers by LASSO Cox regression analysis. Following backward selection, only the multigene predictors were retained in the final model. Integration of these classifiers in a risk scoring system distinguished three patient subgroups that differed substantially in their outcome. The scoring system discriminated patients with diverging outcome in the validation cohort (5-year event-free survival, 84.9 +/- 3.4 vs 63.6 +/- 14.5 vs 31.0 +/- 5.4; P < .001), and its prognostic value was validated by multivariable analysis. CONCLUSION: We here propose a translational strategy for developing risk assessment systems based on hazard ratios of relevant prognostic variables. Our final neuroblastoma risk score comprised two multigene predictors only, supporting the notion that molecular properties of the tumor cells strongly impact clinical courses of neuroblastoma patients.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rosswog, Carolina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, Rene UNSPECIFIED UNSPECIFIED UNSPECIFIED Oberthuer, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Juraeva, Dilafruz UNSPECIFIED UNSPECIFIED UNSPECIFIED Brors, Benedikt UNSPECIFIED orcid.org/0000-0001-5940-3101 UNSPECIFIED Engesser, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Kahlert, Yvonne UNSPECIFIED UNSPECIFIED UNSPECIFIED Volland, Ruth UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartenhagen, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Simon, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Berthold, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Hero, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Faldum, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-209500
DOI:	10.1016/j.neo.2017.09.006
Journal or Publication Title:	Neoplasia
Volume:	19
Number:	12
Page Range:	S. 982 - 991
Date:	2017
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1476-5586
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language YOUNG-ADULTS; STRATIFICATION; EXPRESSION; GENE; ADOLESCENTS; ALK; REARRANGEMENTS; AMPLIFICATION; ACTIVATION; PREDICTION Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/20950