Higher Mixed lineage Kinase Domain-like protein (MLKL) is associated with worst overall survival in adult-type diffuse glioma patients

Introduction Recently, the search for novel molecular markers in adult-type diffuse gliomas has grown substantially, yet with few novel breakthroughs. As the presence of a necrotic center is a differential diagnosis for more aggressive entities, we hypothesized that genes involved in necroptosis may play a role in tumor progression. Aim Given that MLKL is the executioner of the necroptotic pathway, we evaluated whether this gene would help to predict prognosis of adult gliomas patients. Methods We analyzed a publicly available retrospective cohort (n = 530) with Kaplan Meier survival analysis (p<0.0001) and both uni- and multivariate Cox regression models. Results We determined that MLKL is an independent predictive prognostic marker for overall survival in these patients (HR: 2.56, p<0.001), even when controlled by the CNS5 gold-standard markers, namely IDH mutation and 1p/19q Codeletion (HR: 1.68, p = 0.013). These findings were confirmed in a validation cohort (n = 325), using the same cutoff value. Interestingly, higher expression of MLKL is associated with worse clinical outcome for adult-type diffuse glioma patients, which is opposite to what was found in other cell cancer types, suggesting that necroptosis undertakes an atypical detrimental role in glioma progression.

[1]  Xing Zhang,et al.  Pyroptosis in Cancer: Friend or Foe? , 2021, Cancers.

[2]  G. Reifenberger,et al.  The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. , 2021, Neuro-oncology.

[3]  Pieter Wesseling,et al.  cIMPACT‐NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT‐Utrecht meeting on future CNS tumor classification and grading , 2020, Brain pathology.

[4]  E. Victor,et al.  RIPK3 is a novel prognostic marker for lower grade glioma and further enriches IDH mutational status subgrouping , 2020, Journal of Neuro-Oncology.

[5]  Christina M Bebber,et al.  Ferroptosis in Cancer Cell Biology , 2020, Cancers.

[6]  M. J. van den Bent,et al.  Survival of diffuse astrocytic glioma, IDH1/2-wildtype, with molecular features of glioblastoma, WHO grade IV: a confirmation of the cIMPACT-NOW criteria. , 2019, Neuro-oncology.

[7]  K. Kalchev,et al.  RIPK3 expression as a potential predictive and prognostic marker in metastatic colon cancer. , 2019, Clinical and investigative medicine. Medecine clinique et experimentale.

[8]  G. Reifenberger,et al.  cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV” , 2018, Acta Neuropathologica.

[9]  Tao Jiang,et al.  Comprehensive RNA-seq transcriptomic profiling in the malignant progression of gliomas , 2017, Scientific Data.

[10]  P. Schirmacher,et al.  Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB , 2016, Oncogene.

[11]  G. Reifenberger,et al.  The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary , 2016, Acta Neuropathologica.

[12]  T. Vanden Berghe,et al.  An outline of necrosome triggers , 2016, Cellular and Molecular Life Sciences.

[13]  Z. Yang,et al.  Cancer therapy in the necroptosis era , 2016, Cell Death and Differentiation.

[14]  D. Green,et al.  Sequential Engagement of Distinct MLKL Phosphatidylinositol-Binding Sites Executes Necroptosis. , 2016, Molecular cell.

[15]  L. Mei,et al.  Mixed lineage kinase domain-like protein is a prognostic biomarker for cervical squamous cell cancer. , 2015, International journal of clinical and experimental pathology.

[16]  J. Bertin,et al.  Absence of RIPK3 predicts necroptosis resistance in malignant melanoma , 2015, Cell Death and Disease.

[17]  Steven J. M. Jones,et al.  Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. , 2015, The New England journal of medicine.

[18]  Alexander R. Pico,et al.  Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. , 2015, The New England journal of medicine.

[19]  D. Green,et al.  Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis , 2015, Cell Death and Differentiation.

[20]  A. Thorburn,et al.  Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics , 2015, Cell Research.

[21]  Qiang Z Yu,et al.  Apoptosis, autophagy, necroptosis, and cancer metastasis , 2015, Molecular Cancer.

[22]  M. Kvansakul,et al.  The Bcl-2 family: structures, interactions and targets for drug discovery , 2014, Apoptosis.

[23]  J. Akers,et al.  RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas , 2014, Genome research.

[24]  M. Bertrand,et al.  MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. , 2014, Cell reports.

[25]  Ling He,et al.  Low expression of mixed lineage kinase domain-like protein is associated with poor prognosis in ovarian cancer patients , 2013, OncoTargets and therapy.

[26]  S. Fulda.  The mechanism of necroptosis in normal and cancer cells , 2013, Cancer biology & therapy.

[27]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[28]  Peter Vandenabeele,et al.  Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. , 2013, Immunity.

[29]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[30]  S. Fulda,et al.  Targeting IAP proteins for therapeutic intervention in cancer , 2012, Nature Reviews Drug Discovery.

[31]  Ji Luo,et al.  Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis , 2012, Proceedings of the National Academy of Sciences.

[32]  W. Kaiser,et al.  DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. , 2012, Cell host & microbe.

[33]  Simone Fulda,et al.  Targeting IAP proteins for therapeutic intervention in cancer , 2012, Nature Reviews Drug Discovery.

[34]  Xiaodong Wang,et al.  Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase , 2012, Cell.

[35]  Helmut Kettenmann,et al.  The brain tumor microenvironment , 2011, Glia.

[36]  R A Knight,et al.  Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012 , 2011, Cell Death and Differentiation.

[37]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[38]  K. Hoang-Xuan,et al.  All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2 , 2010, Neurology.

[39]  S. Fulda.  Tumor resistance to apoptosis , 2009, International journal of cancer.

[40]  P. Burger,et al.  Identification of der(1;19)(q10;p10) in Five Oligodendrogliomas Suggests Mechanism of Concurrent 1p and 19q Loss , 2006, Journal of neuropathology and experimental neurology.

[41]  J. Niederkorn.  See no evil, hear no evil, do no evil: the lessons of immune privilege , 2006, Nature Immunology.

[42]  K. O'Byrne,et al.  Tumor necrosis correlates with angiogenesis and is a predictor of poor prognosis in malignant mesothelioma. , 2003, Chest.

[43]  Raymond Sawaya,et al.  Necrosis and Glioblastoma: A Friend or a Foe? A Review and a Hypothesis , 2002, Neurosurgery.

[44]  D. Louis,et al.  Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. , 1998, Journal of the National Cancer Institute.

[45]  G. Reifenberger,et al.  Announcing cIMPACT-NOW: the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy , 2016, Acta Neuropathologica.

[46]  Kimberly Young,et al.  Cancer-Induced Inflammation , 2016 .

[47]  Berthold Lausen,et al.  Maximally selected rank statistics , 1992 .