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Cutaneous Malignant Melanoma
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The CDKN2A (cyclin-dependent kinase inhibitor 2A) gene on chromosome 9p21.3 spans 27.5 kb with four exons (1β, 1α, 2, and 3) and encodes two proteins, p16 (by exon 1α, exon 2, and exon 3) and p14ARF (by exon 1 β, exon 2, and exon 3, an alternate reading frame protein product of the CDKN2A locus) [7,8].
Future perspectives in peritoneal malignancy
Published in Tom Cecil, John Bunni, Akash Mehta, A Practical Guide to Peritoneal Malignancy, 2019
Ioanna Panagiotopoulou, Alexios Tzivanakis, Tom Cecil
The most frequently mutated tumour suppressor genes detected in malignant mesothelioma are the cyclin-dependent kinase inhibitor 2A/alternative reading frame (CDKN2A/ARF), neurofibromatosis type 2 (NF2) and BRCA-1 associated protein-1 (BAP-1) [49]. CDKN2A encodes p16INK4a that controls the cell cycle via the cyclin-dependent kinase 4/cyclin D-retinoblastoma protein pathway [49,53, 54]. The ARF gene encodes p14ARF that, in turn, regulates p53. Therefore, a deletion of CDKN2A and ARF results in the inactivation of two tumour suppressor pathways [49]. The NF2 gene encodes a tumour suppressor protein named merlin that mediates inhibition of cell proliferation via the mTOR pathway. Therefore, NF2 loss of function in mesothelioma results in upregulated mTOR activity and increased cell proliferation [49,55]. BAP1 encodes a nuclear ubiquitin C-terminal hydrolase that is an enzyme involved in numerous processes such as cell proliferation, DNA repair and transcription regulation [49,55]. BAP1 enhances the BRCA-1 mediated inhibition of cell proliferation by acting on the host cell factor-1 transcriptional scaffolding subunit [49].
Biological individualisation of radiotherapy
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Catharine M.L. West, Robert G. Bristow, Adrian C. Begg
The prevalence of HPV-associated head and neck cancer rose dramatically over the past 20 years and the first decade of the twenty-first century saw a rapid increase in studies of HPV in head and neck cancer. HPV is associated in particular with oropharyngeal cancers and a good prognosis. There is debate over the best way of assessing HPV positivity – the main approaches used are PCR assays, in situ hybridisation and immunohistochemistry for p16 expression. PCR is often considered the gold standard probably because of its use in cervical screening. PCR can measure DNA or E6/E7 mRNA, which indicate the presence of HPV but do not distinguish integrated and episomal forms of the virus. In situ hybridisation shows viral integration but is technically difficult. The p16 is a protein involved in cell-cycle regulation that is encoded by cyclin-dependent kinase inhibitor 2A (CDKN2A), which is a tumour suppressor gene. The immunohistochemistry of p16 is straightforward, widely available and considered a rapid screening method for HPV positivity. The p16 is considered to be a marker that could be used for individualisation of treatment possibly alone or followed by PCR and/or in situ hybridisation to determine the presence of the virus.
Investigational drugs for the treatment of thymic cancer: a focus on phase 1 and 2 clinical trials
Published in Expert Opinion on Investigational Drugs, 2022
Fabio Conforti, Laura Pala, Tommaso De Pas, Yongfeng He, Giuseppe Giaccone
Aberrations in cell-cycle, particularly in the cyclin dependent kinase (CDK) 4–6/Rb pathway, are involved in the pathogenesis of TETs [41,42]. Recurrent deletions of the cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) gene, encoding for p16 protein, have been found in TETs. Reduced expression of p21 and p27 proteins characterizes up to 70% of TETs. These alterations cause CDK overactivation and deregulation of cell cycle [41,42]. This is the rationale underpinning two trials, the CDKO-125A-006 and 007 trials, that tested the antitumor activity of milciclib in patients with TCs and B3-TMs. Milciclib is an inhibitor of several cyclin dependent kinases including CDK1, CDK4, CDK5, and CDK7[43]. The 006 trial included 72 patients who received only one previous line of therapy, and the majority (i.e. 72%) had TC. The 007 trial enrolled 30 patients heavily pretreated with multiple chemotherapy lines and 57% had B3-TMs. The ORR observed was less than 5% in both trials. However, a potentially valuable cytostatic effect of milciclib has been reported in both trials: up to 83% of patients achieved disease control lasting at least 6 weeks and the median PFS was 6.8 months (95%CI, 4.1–8.7) in the 006 trial and 9.7 months (95%CI, 4.1–17.4) in the 007 trial[43]. Both studies had the unusual endpoint of 3-month PFS which was met and have not been reported as full publications as yet.
Emerging immune checkpoint inhibitors for the treatment of head and neck cancers
Published in Expert Opinion on Emerging Drugs, 2020
Sarah E. Green, Michael G. McCusker, Ranee Mehra
A recent abstract, presented at ASCO 2020, evaluated the relationship between TP53 and cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations and increased TMB [141]. Of 1010 HPV-negative HNSCC tumor samples tested, 60% were positive for loss of function (LOF) TP53 mutations and 20% had damaging CDKN2A mutations present. Mean TMB was noted to be higher in tumors with LOF TP53 mutations or CDKN2A mutations and was highest in tumors with damaging mutations in both genes [141]. Despite very high infiltration of immune cells in HNSCC tumors, there are a number of mechanisms of innate resistance as well as adapted resistance that are affecting response rates of ICIs. Cancer cells can increase immunosuppressive cytokines, down-regulate T cells through activation of inhibitory CTLA-4 and PD-1, and cause T cell tolerance due to the overexpression of antigens as a result of abnormalities or deficiencies of tumor HLA class I expression [142,143]. Extrinsic mechanisms of resistance to ICIs include T cell exhaustion, and T cell phenotype change resulting in loss of cytotoxic activity [144].
Clinical and prognostic effects of CDKN2A, CDKN2B and CDH13 promoter methylation in ovarian cancer: a study using meta-analysis and TCGA data
Published in Biomarkers, 2019
Liang Xia, Wenzhu Zhang, Li Gao
The PubMed, Embase, EBSCO and Cochrane Library databases were systematically searched to identify all available studies using the following key words and search terms updated to 21 January 2019: ‘CDKN2A OR p16 OR INK4a OR cyclin-dependent kinase inhibitor 2A’, ‘CDKN2B OR INK4B OR cyclin-dependent kinase inhibitor 2B OR p15’, ‘CDH13 OR H-cadherin OR T-cadherin OR cadherin-13’, ‘ovarian OR ovary’, ‘cancer OR carcinoma OR tumor OR neoplasm’, ‘methylation OR DNA methylation OR hypermethylation OR epigenetic silencing OR epigenetic inactivation’. In addition, a manual search from reference lists of all eligible studies was also conducted to get additional articles. The present study was conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement criteria (Moher et al. 2009).