Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twentyfive cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter-and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.cancer | head and neck | papilloma virus | genome rearrangement | integration sites H ead and neck cancer (HNC) is a heterogeneous group of tumors characterized by a common anatomic origin, and most such tumors develop from within the mucosa and are classified as head and neck squamous cell carcinomas (HNSCCs) (1). HNSCC, the sixth most common cancer diagnosed worldwide and the eighth most common cause of cancer death (2), is frequently associated with human papillomavirus (HPV) infection (3, 4). Depending on the anatomic site of the tumor, HPV prevalence is estimated at 23-36% (5). HPV-positive HNSCCs form a distinct subset of HNCs that differs from HPV-negative HNSCCs in tumor biology and clinical characteristics, including superior clinical outcomes (6-9).The molecular pathogenesis of HPV-driven HNSCC also seems distinct from HPV-negative tumors, with previous studies showing a divergent spectrum of alterations in gene expression, mutations, amplifications, and deletions as well as distinct epigenome alterations (10-15). HPV is known to drive tumorigenesis through the actions of its major oncoproteins E6 and E7, which target numerous cellular pathways, including inactivation of p53 and the retinoblastoma (Rb) protein (16-18). Together with E5, they also play an important role in immune evasion, being involved in both innate and adaptive immunity (19,20).Initially after infection, HPV is identified in circular extrachromosomal particles or episomes. A critical step in progression to cancer is the integration of viral DNA into the host cell Significance A significant proportion of head and neck cancer is driven by human papil...
The ESAS-r retains core elements of the ESAS, with improved interpretation and clarity of symptom intensity assessment. It represents the next generation of ESAS development, with further validation recommended for drowsiness, appetite, and well-being.
Symptom intensity in cancer and palliative care patients is frequently assessed using a 0-10 ranking score. Results are then often grouped into verbal categories (mild, moderate, or severe) to guide therapy. Numerical cutpoints separating these categories are often variable, with previous work suggesting different cutpoints across different symptoms, which is unwieldy for clinical use. The Edmonton Symptom Assessment Symptom (ESAS) assesses nine common symptoms using this 0-10 scale. The primary aim of this study was to examine the relationship between the numerical and verbal scores using the ESAS and to identify a single cutpoint to separate severe from nonsevere symptomatology. A second goal was to similarly identify a cutpoint to separate moderate or severe from none or mild symptom intensity. Consenting patients (n=400) completed both a standard ESAS and an identical form that replaced 0-10 with none, mild, moderate, and severe. Receiver operating characteristic curves were generated to identify the best fit between sensitivity and specificity. For the "severe" ranking, six symptoms had a best fit of 7, with sensitivity for the remaining three symptoms still greater than 80%. For the combined grouping of moderate or severe, results were less uniform. A cutpoint of either 4 or 5 would be supported by our data, with a greater sensitivity using 4 and improved specificity using 5 as the cutpoint. Across all ESAS symptoms, then, 7 or higher represents a severe symptom by patient definition, whereas a cutpoint of either 4 or 5 could reasonably define combined moderate and severe symptoms.
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