title: Cell-Cycle Gene Alterations in 4,864 Tumors Analyzed by Next-Generation Sequencing: Implications for Targeted Therapeutics.
abstract: Alterations in the cyclin-dependent kinase (CDK)-retinoblastoma (RB) machinery disrupt cell-cycle regulation and are being targeted in drug development. To understand the cancer types impacted by this pathway, we analyzed frequency of abnormalities in key cell-cycle genes across 4,864 tumors using next-generation sequencing (182 or 236 genes; Clinical Laboratory Improvement Amendments laboratory). Aberrations in the cell-cycle pathway were identified in 39% of cancers, making this pathway one of the most commonly altered in cancer. The frequency of aberrations was as follows: CDKN2A/B (20.1% of all patients), RB1 (7.6%), CCND1 (6.1%), CCNE1 (3.6%), CDK4 (3.2%), CCND3 (1.8%), CCND2 (1.7%), and CDK6 (1.7%). Rates and types of aberrant cell-cycle pathway genes differed between cancer types and within histologies. Analysis of coexisting and mutually exclusive genetic aberrations showed that CCND1, CCND2, and CCND3 aberrations were all positively associated with CDK6 aberrations [OR and P values, multivariate analysis: CCND1 and CDK6 (OR = 3.5; P < 0.0001), CCND2 and CDK6 (OR = 4.3; P = 0.003), CCND3 and CDK6 (OR = 3.6; P = 0.007)]. In contrast, RB1 alterations were negatively associated with multiple gene anomalies in the cell-cycle pathway, including CCND1 (OR = 0.25; P = 0.003), CKD4 (OR = 0.10; P = 0.001), and CDKN2A/B (OR = 0.21; P < 0.0001). In conclusion, aberrations in the cell-cycle pathway were very common in diverse cancers (39% of 4,864 neoplasms). The frequencies and types of alterations differed between and within tumor types and will be informative for drug development strategies. Mol Cancer Ther; 15(7); 1682-90. ©2016 AACR.
authors.affiliation: Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, La Jolla, California.
authors.forename: Teresa
authors.initials: T
authors.lastname: Helsten
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. shumei.kato@gmail.com.
authors.forename: Shumei
authors.initials: S
authors.lastname: Kato
authors.affiliation: Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, La Jolla, California.
authors.forename: Maria
authors.initials: M
authors.lastname: Schwaederle
authors.affiliation: N-of-One, Inc., Lexington, Massachusetts.
authors.forename: Brett N
authors.initials: BN
authors.lastname: Tomson
authors.affiliation: N-of-One, Inc., Lexington, Massachusetts.
authors.forename: Timon P H
authors.initials: TP
authors.lastname: Buys
authors.affiliation: N-of-One, Inc., Lexington, Massachusetts.
authors.forename: Sheryl K
authors.initials: SK
authors.lastname: Elkin
authors.affiliation: N-of-One, Inc., Lexington, Massachusetts.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Carter
authors.affiliation: Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, La Jolla, California.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D014644:Genetic Variation; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins