Exome Sequencing with Validations and Expression of p16/CDKN2A Shows no Association with HPV in Oral Cancers.

PURPOSE: Despite many studies attributing HPV infection to oropharyngeal tumorigenesis, its involvement in non-oropharyngeal cancers is ambiguous. We have evaluated the mutation profile of p16 along with protein expression and correlated it with the HPV status in oral cancers. METHODS: Somatic mutations in p16 were studied by exome sequencing (n=25) and validated by Sequenom Mass spectrometry (n=50).  Expression of p16 was studied by immunohistochemistry (IHC) and correlated with HPV16/18 status evaluated by PCR, and IHC (n=221) in oral cancers. RESULTS: Out of 25 oral cancer patients' samples sequenced by Exome sequencing, p16 mutations were found in 4 samples (16%). All the p16 mutations were identified in patients with cancers in the site of gingivobuccal complex and not tongue subsite. All the 4 patients with p16 mutations had failed treatment, and showed a significantly poor disease-free survival. Insilico analysis of the types of p16 mutations showed mutated, truncated p16 protein having an increased intrinsic disorder, and all the mutations involved truncation post arginine. Validation of the p16 mutations by mass spectrometry showed 8/50 (16%) of patients harbouring pArg80Ter mutation, of which 7/8 (87.5%) had failed treatment.  Overexpression of p16 in >70% of the tumour cells was found in 21.4% (26/121) OSCC patients, 6.75% (5/74) OPML patients and p16 expression was significantly correlated (p=0.001; χ2 = 25.601) to the grade. All the samples were studied for HPV presence by PCR and IHC. We found that none of the p16 positive tumours showing expression in >70% of the tumour cells harbored HPV both by PCR as well as IHC. CONCLUSION: Our study emphasises the importance of p16 in oral cancers, and shows that oral cancer is not HPV associated and p16 expression is not a surrogate marker for HPV.

Transcriptional cyclin-dependent kinases as the mediators of inflammation-a review.

Cyclin-dependent kinases (CDKs) belong to the serine/threonine kinase family, and their unique interactions with a variety of cyclin complexes influence its catalytic activity to ensure unimpaired cell cycle progression. In addition to their cell cycle regulatory roles, it is becoming increasingly clear that the CDKs can have multiple functional roles like transcription, epigenetic regulation, metabolism, stem cell self-renewal, neuronal functions, and in spermatogenesis. Further in addition, recent reports suggest that CDKs have a remarkable regulatory role in influencing the pro-inflammatory functions of various cytokines during the clinical inflammatory responses. CDKs initiate the inflammatory responses by triggering the activity of prominent pro-inflammatory transcription factors such as nuclear factor kappa B (NF-kB), signal transducer and activator of transcription 3 (STAT3), and activator protein 1 (AP-1). The transcriptional CDKs (tCDKs) is crucial for organizing various transcription events and associated processes such as RNA capping, splicing, 3' end formation, and chromatin remodeling. Although the in-depth mechanism of certain mammalian CDKs is explored with respect to inflammation, the role of other tCDKs or any synergistic play among the members still remains unexplored. Until today, there is only supportive and palliative care available most of the inflammatory disorders, and thus it is the right time to explore novel pharmacological targets. In this regard, we focus on the pathophysiological role of CDK7, CDK8 and CDK9 and their impact on the development of inflammatory disorders within the mammals. Additionally, we discuss the potential trends of having tCDKs as a therapeutic target for fine-tuning inflammatory disorders.