CDK4 Alterations Research Articles

Verification and Mechanism Exploration of CDK4 Alterations on Influencing Radiotherapy Sensitivity in Small Cell Lung Cancer

In this study, we aimed to explore the changes of functional phenotype before and after radiotherapy through vitro and vivo experiments. The potential pathway was preliminarily clarified. Firstly, the relationships between the prognosis and the expression of CDK4 protein in SCLC patients treated with definitive chemoradiotherapy were explored. Then the stable overexpressed/knockdown CDK4 and negative control transfecting SCLC cell lines were established to monitor the changes of cell proliferation, migration, invasion, apoptosis and cell cycle after increasing radiation doses according to a cell counting kit assay, transwell cell migration and invasion assay, apoptosis cell cycle assay and BALB/c mouse model of subcutaneously transplanted tumor. The potential signal pathways were confirmed via KEGG pathway enrichment analysis and western blot. Compared with patients with lower CDK4 protein expression, prognosis of those with high CDK4 protein expression was decreased significantly (p < 0.05). The cell activity, migration and invasion ability of overexpression/knockdown CDK4 and negative control group were all decreased with increasing radiation doses, but the activity, migration and invasion ability of cells with overexpression CDK4 was stronger after same dose X-ray irradiation (p<0.01). For group with knockdown CDK4, it showed lower cell activity, migration and invasion than negative control group. After X-ray irradiation, the apoptotic ratio of all groups increased. And cells with overexpressed CDK4 displayed significantly reduced apoptosis, less G0/G1 phase cells, and improved M phase cells than the control group. In addition, compared with negative control group, gross tumor volume of overexpression CDK4 group decreased much smaller after X-ray irradiation. H1339 cells with overexpression CDK4 and negative control group were sequenced by transcriptomic sequencing before and after radiotherapy. Taken together, differential genes were consistently enriched in MAPK pathway. Western blot showed that, compared with the negative control group, overexpression CDK4 group of H1339 and SW1271 cells after radiotherapy all showed significant changes on pERK proteins in the ERK pathway increased significantly (P<0.001). In this study, the overexpression/knockdown CDK4 and negative control group were successfully constructed in H1339 and SW1271 cells, revealing the radiotherapy resistance of CDK4 alterations in vitro and in vivo experiment. And CDK4 alterations was shown to promote radiotherapy resistance through phosphorylation of MAPK/ERK signaling pathway in SCLC.

Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large-Scale Data to Inform Therapeutic Directions.

BackgroundWe describe the landscape of cyclin and interactive gene pathway alterations in 190,247 solid tumors.MethodsUsing comprehensive genomic profiling (315 genes, >500× coverage), samples were analyzed for alterations in activating/sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1), hormone genes (estrogen receptor 1 [ESR1], androgen receptor [AR]), and co‐alterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1).ResultsAlterations in at least one cyclin activating/sensitizing gene occurred in 24% of malignancies. Tumors that frequently harbored at least one cyclin alteration were brain gliomas (47.1%), esophageal (40.3%) and bladder cancer (37.9%), and mesotheliomas (37.9%). The most frequent alterations included CDKN2A (13.9%) and CDKN2B loss (12.5%). Examples of unique patterns of alterations included CCND1 amplification in breast cancer (17.3%); CDK4 alterations in sarcomas (12%); CCND2 in testicular cancer (23.4%), and SMARCB1 mutations in kidney cancer (3% overall, 90% in malignant rhabdoid tumors). Alterations in resistance genes RB1 and CCNE1 affected 7.2% and 3.6% of samples. Co‐occurrence analysis demonstrated a lower likelihood of concomitant versus isolated alterations in cyclin activating/sensitizing and resistance genes (odds ratio [OR], 0.35; p < .001), except in colorectal, cervical, and small intestine cancers. AR and cyclin activating/sensitizing alterations in prostate cancer co‐occurred more frequently (vs. AR alterations and wild‐type cyclin activating/sensitizing alterations) (OR, 1.79; p < .001) as did ESR1 and cyclin activating/sensitizing alterations in breast (OR, 1.62; p < .001) and cervical cancer (OR, 4.08; p = .04) (vs. ESR1 and cyclin wild‐type activating/sensitizing alterations).ConclusionCyclin pathway alterations vary according to tumor type/histology, informing opportunities for targeted therapy, including for rare cancers.Implications for PracticeCyclin pathway genomic abnormalities are frequent in human solid tumors, with substantial variation according to tumor site and histology. Opportunities for targeted therapy emerge with comprehensive profiling of this pathway.

CDKN2A and CDK4 alterations in melanoma patients and primary melanomas from Latvia

CDKN2A and CDK4 alterations in melanoma patients and primary melanomas from Latvia

Investigation of germline PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 alterations in familial glioma.

Epidemiological studies suggest that some familial aggregations of glioma may be due to inherited predisposition. Many genes involved in familial cancers are frequently altered in the corresponding sporadic forms. We have investigated several genes known to be altered in sporadic gliomas for their potential contribution to familial glioma. Fifteen glioma patients with a family history of brain tumors were identified through the Mayo Clinic Department of Neurology (nine diffuse astrocytomas, two oligodendrogliomas, two mixed oligoastrocytomas, one pilocytic astrocytoma, and one pineal glioma). Eleven of the propositi had one or more first degree relative with a glioma. Lymphocyte DNA was derived from each of the patients and analyzed by polymerase chain reaction (PCR) and direct sequencing of the PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 genes. In addition, fluorescence in situ hybridization (FISH) was performed on EBV-transformed lymphocytes from each affected individual to detect germline copy number of the p16(INK4A)/p14(ARF) tumor suppressor region. A p53 germline point mutation was identified in one family with some findings of Li-Fraumeni syndrome, and a hemizygous germline deletion of the p16(INK4A)/p14(ARF) tumor suppressor region was demonstrated by FISH in a family with history of both astrocytoma and melanoma. Thus, whereas germ-line mutations of PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 are not common events in familial glioma, outside of familial cancer syndromes, point mutations of p53 and hemizygous deletions and other rearrangements of the p16(INK4A)/p14(ARF) tumor suppressor region may account for a subset of familial glioma cases. Collectively, these data lend genetic support to the heritable nature of some cases of glioma.