Biological individualisation of radiotherapy
Michael C. Joiner, Albert J. van der Kogel in Basic Clinical Radiobiology, 2018
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.
Epigenetic mechanisms in bone development
Nicholas C. Harvey, Cyrus Cooper in Osteoporosis: a lifecourse epidemiology approach to skeletal health, 2018
Previous array analysis of umbilical cord samples from the Princess Anne Hospital Cohort and the Southampton Women’s Survey (8) identified an association between offspring fat mass and methylation at another locus, CDKN2A (8,18,19). The CDKN2A locus encodes two cell cycle inhibitors: p14ARF and P16INK4a, which play roles in cellular senescence and ageing. The CDKN2A locus also encodes the long non-coding RNA ANRIL (antisense non-coding RNA in the INK4 locus), a 3834bp transcript which can negatively regulate p16INK4a. SNPs within the CDKN2A locus, particularly those located within ANRIL, have been associated with cardiovascular disease, diabetes and frailty (20), and DNA methylation at this locus has recently been demonstrated to vary with age (21).
Familial Pancreatic Cancer
Dongyou Liu in Handbook of Tumor Syndromes, 2020
The CDKN2A (cyclin-dependent kinase inhibitor 2A) gene on chromosome 9p21.3 is a 27.5 kb DNA and encodes a 156 aa, 16 kDa protein (p16), that functions as a negative regulator of the G1-to-S transition in the cell cycle through strong interaction with CDK4 and CDK6, and also as a tumor suppressor through interaction with, and sequestration of the E3 ubiquitin-protein ligase MDM2 in the nucleolus, which induces degradation of tumor suppressor protein p53, and enhances p53-dependent transactivation and apoptosis. Mutation/deletion (or hypermethylation of the promoter region) in the CDKN2A gene inactivates p16, and results in stimulation of the proliferative activity in >90% of pancreatic cancer. Some pancreatic cancer with intact CDKN2A may have somatic mutations in other cell-cycle regulators (e.g., FBXW7 or ANAPC2) [12]. CDKN2A mutations are also observed in cutaneous malignant melanoma, and melanoma-pancreatic cancer syndrome.
Butyrate-Induced In Vitro Colonocyte Differentiation Network Model Identifies ITGB1, SYK, CDKN2A, CHAF1A, and LRP1 as the Prognostic Markers for Colorectal Cancer Recurrence
Published in Nutrition and Cancer, 2019
Nirmalya Dasgupta, Bhupesh Kumar Thakur, Abhijit Chakraborty, Santasabuj Das
CDKN2A (p16), an inhibitor of cyclin-dependent kinase inhibitor, functions as an important tumor suppressor. Concordant with this, we found that increased expression of CDKN2A was associated with poor prognosis, which was consistent across three different cohorts (Total N = 492; Table 4). Further analysis with TCGA-COAD datasets showed very similar results to our GEO-microarray based models. CDKN2A is over-expressed in COAD and the expression is gradually increased with advancing stage of the disease (Supplementary Figs. S5 and S7). APC and TP53 mutations represented higher expression levels of CDKN2A, which is consistent with our in vitro differentiation model (Supplementary Fig. S6). In agreement with our previous results, TCGA-COAD dataset showed that higher expression of CDKN2A was associated with poor survival (HR =2; p = 0.0066).
Therapeutic trends in pancreatic ductal adenocarcinoma (PDAC)
Published in Expert Opinion on Investigational Drugs, 2019
Sreenivasa Chandana, Hani M. Babiker, Daruka Mahadevan
There are several common gene mutations, involved in the process of PDAC carcinogenesis. Most important frequent gene mutations include, KRAS, CDKN2A, TP53, and SMAD4. Gain of function mutations in codons 12, 13, and 61 in KRAS lead to activation of downstream signaling via the mitogen-activated protein kinase (MAPK) pathway. This increases cell survival and carcinogenesis in PDAC. CDKN2A is a cyclin-dependent kinase inhibitor that regulates the cell cycle G1-S phase transition. Inactivation of CDKN2A gene via inactivating mutations/deletions or hypermethylation leads to dysregulation of the cell cycle and carcinogenesis. TP53 is a tumor suppressor gene responsible for management of cellular stress and guard genomic stability in cells. Different mutations in TP53 are frequent in many solid tumors, including PDAC. SMAD4 gene encodes for a transcription factor that regulates transforming growth factor-beta (TGF-B) and bone morphogenetic protein (BMP) signaling pathways. Mutations in SMAD4 plays a role in malignant stromagenesis in PDAC. Genetically engineered mouse models with one or more of the above driver gene mutations were developed, but unfortunately, these models did not accurately predict the human disease process and response to chemotherapy or stroma directed therapy [4,5].
CDKN2A genetic testing in melanoma-prone families in Sweden in the years 2015–2020: implications for novel national recommendations
Published in Acta Oncologica, 2021
Maria Pissa, Teo Helkkula, Frida Appelqvist, Gustav Silander, Åke Borg, Jenny Pettersson, Jan Lapins, Kari Nielsen, Veronica Höiom, Hildur Helgadottir
In 2015, a working group appointed by SMSG, the Swedish Network for Familial Melanoma (SweFam), updated the recommendations for CDKN2A testing (Figure 1). These criteria were published in the Swedish National Guidelines for Melanoma and are still the recommended criteria for testing [36]. To summarize, in these guidelines, CDKN2A genetic testing is recommended in families that have three or more related cases of melanoma and/or pancreatic cancer. In families with two melanomas diagnoses, testing is recommended if the cases are first-degree relatives and at least one of the cases was under the age of 55 years at diagnosis. Further, in individuals with three or more multiple primary melanomas and no relatives with melanoma or pancreatic cancer, testing is recommended if the first melanoma was diagnosed before the age of 55 years. CDKN2A genetic testing is recommended, from the age of 18, to first-degree relatives of identified carriers. Carriers are, from the age of 18 years, recommended dermatologic surveillance and, from the age of 40 years, MRI screening for pancreatic cancer. Although the pancreatic MRI screening in carriers of CDKN2A PVs needs further evaluation, there are studies that indicate that it is beneficial, with more individuals diagnosed with resectable cancers and better survival outcomes compared to pancreatic cancer cases in the normal population [37,38]. The carriers are also counseled regarding UV exposure habits, skin self-exams and the importance of abstaining from tobacco smoking.
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