title: Cyclin-dependent kinase pathway aberrations in diverse malignancies: clinical and molecular characteristics.
abstract: Aberrations in the cyclin-dependent kinase (CDK) pathways that regulate the cell cycle restriction point contribute to genomic instability and tumor proliferation, and can be targeted by recently developed CDK inhibitors. We therefore investigated the clinical correlates of CDK4/6 and CDKN2A/B abnormalities in diverse malignancies. Patients with various cancers who underwent molecular profiling by targeted next generation sequencing (Foundation Medicine; 182 or 236 cancer-related genes) were reviewed. Of 347 patients analyzed, 79 (22.8%) had aberrant CDK 4/6 or CDKN2A/B. Only TP53 mutations occurred more frequently than those in CDK elements. Aberrations were most frequent in glioblastomas (21/26 patients; 81%) and least frequent in colorectal cancers (0/26 patients). Aberrant CDK elements were independently associated with EGFR and ARID1A gene abnormalities (P < 0.0001 and p = 0.01; multivariate analysis). CDK aberrations were associated with poor overall survival (univariate analysis; HR[95% CI] = 2.09 [1.35-4.70]; p = 0.004). In multivariate analysis, PTEN and TP53 aberrations were independently associated with poorer survival (HR = 4.83 and 1.92; P < 0.0001 and p = 0.01); CDK aberrations showed a trend toward worse survival (HR = 1.67; p = 0.09). There was also a trend toward worse progression-free survival (PFS) with platinum-containing regimens in patients with abnormal CDK elements (3.5 versus 5.0 months, p = 0.13). In conclusion, aberrations in the CDK pathway were some of the most common in cancer and independently associated with EGFR and ARID1A alterations. Patients with abnormal CDK pathway genes showed a trend toward poorer survival, as well as worse PFS on platinum-containing regimens. Further investigation of the prognostic and predictive impact of CDK alterations across cancers is warranted.
authors.affiliation: a Center for Personalized Cancer Therapy and Division of Hematology and Oncology ; Department of Medicine; UC San Diego Moores Cancer Center ; La Jolla , CA USA.
authors.forename: Shumei
authors.initials: S
authors.lastname: Kato
authors.forename: Maria
authors.initials: M
authors.lastname: Schwaederle
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Daniels
authors.forename: David
authors.initials: D
authors.lastname: Piccioni
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Bazhenova
authors.forename: Kelly
authors.initials: K
authors.lastname: Shimabukuro
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Parker
authors.forename: Paul
authors.initials: P
authors.lastname: Fanta
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C112476:ARID1A protein, human; D000970:Antineoplastic Agents; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: CDK4/6; CDKN2A/B; cancer; cyclin-Dependent Kinase; next generation sequencing