The tumour suppressor ARF (alternative reading frame) is encoded by the INK4a (inhibitor of cyclin-dependent kinase 4)/ARF locus, which is frequently altered in human tumours. ARF binds MDM2 (murine ...double minute 2) and releases p53 from inhibition by MDM2, resulting in stabilization, accumulation and activation of p53. Recently, ARF has been found to associate with other proteins, but, to date, little is known about ARF-associated proteins that are implicated in post-translational regulation of ARF activity. Using a yeast two-hybrid screen, we have identified a novel protein, LZAP (LXXLL/leucine-zipper-containing ARF-binding protein), that interacts with endogenous ARF in mammalian cells. In the present study, we show that LZAP reversed the ability of ARF to inhibit HDM2's ubiquitin ligase activity towards p53, but simultaneously co-operated with ARF, maintaining p53 stability and increasing p53 transcriptional activity. Expression of LZAP, in addition to ARF, increased the percentage of cells in the G1 phase of the cell cycle. Expression of LZAP also caused activation of p53 and a p53-dependent G1 cell-cycle arrest in the absence of ARF. Taken together, our data suggest that LZAP can regulate ARF biochemical and biological activity. Additionally, LZAP has p53-dependent cell-cycle effects that are independent of ARF.
Recent advancements in computational power, machine learning, and artificial intelligence technology have enabled automated evaluation of medical images to generate quantitative diagnostic and ...prognostic biomarkers. Such objective biomarkers are readily available and have the potential to improve personalized treatment, precision medicine, and patient selection for clinical trials. In this article, we explore the merits of the most recent addition to the "-omics" concept for the broader field of head and neck cancer - "Radiomics". This review discusses radiomics studies focused on (molecular) characterization, classification, prognostication and treatment guidance for head and neck squamous cell carcinomas (HNSCC). We review the underlying hypothesis, general concept and typical workflow of radiomic analysis, and elaborate on current and future challenges to be addressed before routine clinical application.
Recent studies have revealed the mutational signatures underlying the somatic evolution of cancer, and the prevalences of associated somatic genetic variants. Here we estimate the intensity of ...positive selection that drives mutations to high frequency in tumors, yielding higher prevalences than expected on the basis of mutation and neutral drift alone. We apply this approach to a sample of 525 head and neck squamous cell carcinoma exomes, producing a rank-ordered list of gene variants by selection intensity. Our results illustrate the complementarity of calculating the intensity of selection on mutations along with tallying the prevalence of individual substitutions in cancer: while many of the most prevalently-altered genes were heavily selected, their relative importance to the cancer phenotype differs from their prevalence and from their P value, with some infrequent variants exhibiting evidence of strong positive selection. Furthermore, we extend our analysis of effect size by quantifying the degree to which mutational processes (such as APOBEC mutagenesis) contributes mutations that are highly selected, driving head and neck squamous cell carcinoma. We calculate the substitutions caused by APOBEC mutagenesis that make the greatest contribution to cancer phenotype among patients. Lastly, we demonstrate via in vitro biochemical experiments that the APOBEC3B protein can deaminate the cytosine bases at two sites whose mutant states are subject to high net realized selection intensities-PIK3CA E545K and E542K. By quantifying the effects of mutations, we deepen the molecular understanding of carcinogenesis in head and neck squamous cell carcinoma.
Objectives/Hypothesis:
To examine the role of HPV status in the etiology, prognosis, and treatment of head and neck squamous cell carcinoma in early larynx malignancies.
Study Design:
Retrospective.
...Methods:
Thirty‐eight cases of T1 or carcinoma in situ (CIS) laryngeal lesions were examined for the presence of human papilloma virus (HPV) using an inclusive polymerase chain reaction (PCR)/hybridization technique capable of identifying 37 HPV subtypes.
Results:
HPV DNA was detected in 6 (16%) of the 38 lesions, representing HPV types 16, 26, 31, 39, and 52, and p16 tumor suppressor protein expression was confirmed in 10 representative cases. This HPV prevalence is higher than that noted in many previous laryngeal cancer studies, possibly due to the relatively large panel of subtypes screened for in this study. Identification of HPV‐26, which has been associated with uterine cervical cancer, in an early laryngeal cancer specimen represents the first evidence of this subtype in a laryngeal carcinoma. Consistent with reports focusing on head and neck squamous cell carcinoma (HNSCC) arising from other subsites within the upper aerodigestive tract, patients with HPV‐positive laryngeal carcinomas were of younger age and were somewhat less likely to have a history of tobacco use, although the latter of the two findings did not reach statistical significance.
Conclusions:
Our findings emphasize the presence of a broad spectrum of HPV types in a relevant proportion of early laryngeal cancers, and together with evidence of an association of HPV tumor status with a more favorable clinical course, provide a rationale for the routine HPV testing of small larynx lesions. Laryngoscope, 2009
Mechanism of radiosensitivity of normal tissues, a key factor in determining the toxic side effects of cancer radiotherapy, is not fully understood. We recently demonstrated that deficiency of ...mitochondrial tumor suppressor, Fus1, increases radiosensitivity at the organismal, tissue and cellular levels. Since Fus1-deficient mice and cells exhibit high levels of oxidative stress, we hypothesized that dysregulation of cellular antioxidant defenses may contribute to the increased radiosensitivity. To address this potential mechanism, we treated the Fus1 KO mice with an inhibitor of pathogenic oxidative reactions, pyridoxamine (PM). Treatment with PM ameliorated IR-induced damage to GI epithelium of Fus1 KO mice and significantly increased the survival of irradiated mice. In cultured Fus1 KO epithelial cells, IR-induced oxidative stress was enhanced because of inadequate cellular antioxidant defenses, such as low levels and/or activities of cytochrome C, Sod 2 and STAT3. This resulted in dysregulation of IR-induced DNA-damage response and DNA synthesis. Treatment of Fus1 KO cells with PM or Sod 2 mimetic Tempol normalized the oxidative stress response, thus compensating to a significant degree for inadequate antioxidant response. Our findings using Fus1 KO radiosensitive mice suggest that radiosensitivity is mediated via dysregulation of antioxidant response and defective redox homeostasis.
Objective
To examine the prevalence and predictors of patient-reported barriers to care among survivors of head and neck squamous cell carcinoma and the association with health-related quality of ...life (HRQOL) outcomes.
Study Design
Retrospective cohort study.
Setting
Outpatient oncology clinic at an academic tertiary care center.
Methods
Data were obtained from the UNC Health Registry/Cancer Survivorship Cohort. Barriers to care included self-reported delays in care and inability to obtain needed care due to cost. HRQOL was measured with validated questionnaires: general (PROMIS) and cancer specific (FACT-GP).
Results
The sample included 202 patients with head and neck squamous cell carcinoma with a mean age of 59.6 years (SD, 10.0). Eighty-two percent were male and 87% were White. Sixty-two patients (31%) reported at least 1 barrier to care. Significant predictors of a barrier to care in unadjusted analysis included age ≤60 years (P = .007), female sex (P = .020), being unmarried (P = .016), being uninsured (P = .047), and Medicaid insurance (P = .022). Patients reporting barriers to care had significantly worse physical and mental HRQOL on the PROMIS questionnaires (P < .001 and P = .002, respectively) and lower cancer-specific HRQOL on the FACT-GP questionnaire (P < .001), which persisted across physical, social, emotional, and functional domains. There was no difference in 5-year OS (75.3% vs 84.1%, P = .177) or 5-year CSS (81.6% vs 85.4%, P = .542) in patients with and without barriers to care.
Conclusion
Delay- and affordability-related barriers are common among survivors of head and neck cancer and appear to be associated with significantly worse HRQOL outcomes. Certain sociodemographic groups appear to be more at risk of patient-reported barriers to care.
Objective
Oral cavity cancer is the most common malignant disease of the head and neck. The natural course of the disease is poorly characterized and unavailable for patient consideration during ...initial treatment planning. Our primary objective was to outline this natural history, with a secondary aim of identifying predictors of treatment refusal.
Study Design
Retrospective review of adult patients with oral cavity cancer who refused surgery that was recommended by their physician in the National Cancer Database.
Methods
Demographic, tumor, and survival variables were included in the analyses. Multivariate Cox regressions as well as univariate Kaplan‐Meier analyses were conducted.
Results
Patients who were older, uninsured, had government insurance, or had more advanced disease were more likely to go untreated. Survival among untreated patients was poor, but there was a small proportion of patients surviving long term. Five‐year survival rates ranged from 31.1% among early‐stage patients to 12.6% among stage 4 patients.
Conclusion
Although the natural course of oral cavity cancer carries a poor prognosis, there are a number of patients with longer‐than‐expected survival. The survival estimates may provide supplemental information for patients deciding whether to pursue treatment. In addition to age and extent of disease, system factors such as insurance status and facility case volume are associated with a patient's likelihood of refusing treatment.
Level of Evidence
4. Laryngoscope, 128:664–669, 2018
PDF
