Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy associated with molecular heterogeneity, locoregional spread, resistance to therapy and relapse after initial treatment. Increasing evidence suggests that master developmental pathways with key roles in adult tissue homeostasis, including Hippo and Wnt/β-catenin signaling, are dysregulated in the initiation and progression of HNSCC. However, a comprehensive investigation into the crosstalk between these pathways is currently lacking, and may prove crucial to the discovery of novel targets for HNSCC therapy. More recent evidence points to the tumor microenvironment, mainly comprising cancer-associated fibroblasts (CAFs), as capable of influencing tumor cell behavior and promoting invasive HNSCC phenotypes. Nonetheless, current methods to screen for CAF markers in tumors are restricted to targeted immunostaining experiments with limited success and robustness across tissue types. The Cancer Genome Atlas network has generated multi-tiered molecular profiles for over 10,000 tumors spanning more than two dozen different cancer types, providing an unprecedented opportunity for the application and development of integrative methods aimed at the in silico interrogation of experimentally-derived signatures. These multi-omic profiles further enable one to link genomic anomalies, including somatic mutations and DNA copy number alterations, with phenotypic effects driven by pathogenic pathway activity. Effectively querying this vast amount of information to help elucidate subsets of functionally and clinically-relevant oncogenic drivers, however, remains an ongoing challenge. To address these issues, I first investigate the effects of oncogenic pathway perturbation in HNSCC using experimental models coupled with in vitro genome-wide transcriptional profiling. Next, I describe a new computational approach for the unbiased identification of CAF markers in HNSCC solely using bulk tumor RNA-sequencing information. Lastly, I have developed Candidate Driver Analysis or CaDrA - a statistical framework that allows one to query genetic and epigenetic alterations for candidate drivers of signature activity within a given disease context. Collectively, this work offers new perspectives on the molecular cues underlying HNSCC development, while simultaneously highlighting the power of integrative genomics methods capable of accelerating the discovery of novel targets for cancer diagnosis and therapy.

abstract: Recent studies have shown that human papillomavirus (HPV) plays a role in development of cancers, one of which is head and neck cancer. There is strong and consistent molecular evidence demonstrating that human papillomavirus (HPV) is an etiological cause of these oropharyngeal cancers. Despite the introduction of HPV vaccines, there is still an increase in human papillomavirus associated OPC (HPVOPC) and it is expected that the incidence of head and neck cancer, specifically oropharyngeal cancer (OPC) will increase. The aim of this study is to utilize human papillomavirus (HPV) seropositivity for rapid detection of HPV early specific antigen-antibodies using a lateral flow assay. Human papillomavirus (HPV) 16 proteins of interest, E7, E6 and CE2 were expressed and purified in E. coli for detection of specific antibodies using lateral flow assay because viral and host factors impact the serologic responses to HPV early antigens in HPV-positive oropharyngeal cancer. 17 samples and 5 controls with already known antibody reactivity from ELISA analysis were selected for HPV serologic responses. The lateral flow strip was evaluated for its color band intensity using Image J software. Peak area was used to quantify the color intensity of the lateral flow strip. Out of the 17 samples, 11 (64.7%) showed high antibody levels to E7, 12 (70.6%) showed high Ab levels to E6 and 6 (35.3%) showed high Ab levels to CE2. Correlation coefficient between antibody detection by sight and ELISA for E7, CE2 and E6 were 0.6614, 0.4845 and 0.2372 respectively and correlation coefficient between lateral flow assay and ELISA for E7, CE2 and E6 were 0.3480, 0.1716 and 0.1644 respectively. This further proves patients or samples with HPV 16 oropharyngeal cancer have detectable antibodies to early E7, E6 and E2 proteins, which are potential biomarkers for HPV-associated oropharyngeal cancer. / Dissertation/Thesis / Masters Thesis Molecular and Cellular Biology 2019

Bakgrund: Huvud- och halscancer leder till olika förändringar som påverkar patienten fysiskt och psykiskt samt påverkar vardagen och livssituationen. Sjuksköterskan har en central roll för dessa patienter då dennes uppgift är att främja hälsa genom att bidra med stödåtgärder. Mer kunskap om hur patienterna upplevelser förändringar efter huvud- och halscancer krävs för att kunna ge adekvata omvårdnadsåtgärder.Syfte: Syftet var att beskriva patienters upplevelser av förändringar i utseende och funktion under och efter behandling av huvud- och halscancer. Metod: En litteraturöversikt med kvalitativa artiklar genomfördes utifrån tolv artiklar från databaserna Medline och Cinahl. Dataanalysen genomfördes enligt Fribergs femstegsmodell. Resultat: Litteraturöversiktens resultat bestod av tre kategorier och sju subkategorier. Kategorierna var förändringar av kroppens funktioner, förändringar i utseende och förändringar i sociala sammanhang. Resultatet visade att patienterna upplevde svårigheter att äta och konsekvenserna det ledde till. Patienterna upplevde också utseendeförändringar och att deras sociala liv påverkades.Slutsats: Patienternas liv förändrades negativt på olika sätt och ur olika aspekter. De hade svårigheter att äta, drabbades av utseendeförändringar och upplevde en påverkan på deras sociala liv. Sjuksköterskor kan erbjuda adekvata omvårdnadsinsatser till dessa patienter genom att vara lyhörd kring de förändringar som huvud- och halscancer medför. / Background: Head and neck cancer (HHC) leads to various changes which affect the patient physically and psychologically, but also the life situation. Nurses have a central role in promoting health and providing support to this patient group. More knowledge about patients’ experiences of changes after HHC is needed to offer adequate nursing interventions.Aim: The aim was to describe patients' experiences of changes in appearance and function during and after treatment for head and neck cancer. Method: A literature review with qualitative articles was carried out based on twelve articles retrieved from Medline and Cinahl. The data analysis was carried out according to Friberg's five-step model. Result: The result of the literature review consists of three categories and seven subcategories. The categories were Changes in the body's functions, Changes in appearance, and Changes in social contexts. The results showed that HHC patients experienced difficulties in eating and the consequences it led to. It also showed how patients experienced negative changes in their appearance. Furthermore, the patients experienced a negative impact on their social life.Conclusion: The patients' lives changed in different ways and from different aspects in a negative way. The patients had difficulties eating, suffered from changes in appearance, and experienced an impact on their social life. Nurses can offer adequate nursing interventions to these patients by being responsive to the changes.

Introduction: Oropharyngeal cancer (OPC) is a highly prevalent malignancy worldwideaffecting the tonsils, the soft palette and the base of the tongue. OPC has a high risk ofrecurrence. Patients are offered a 5-year follow-up program in order to discover earlyrecurrences. However, there exists some controversy regarding the benefit of this follow-up indetecting early recurrences. Objective: The primary aim of this study was to investigate whether recurrences of OPC weredetected in patient-initiated appointments or during routine follow-up. The secondary aim wasto compare the survival between these groups. Method and materials: This study is a retrospective cohort study regarding recurrencedetection among patients diagnosed with OPC. The Örebro Head- and neck cancer registerwas used to identify patients with recurrence of OPC. Additional data was collected frommedical records. Results: A total of 75 patients were included. Routine follow-up detected 50.7% ofrecurrences while patient-initiated visits detected 42.7% of recurrences. No statisticallysignificant difference was found in survival between these groups Conclusion: In contradiction to our hypothesis most of the recurrences were detected atroutine follow-up. There was no statistically significant difference in survival between thetwo ways of detection. These results indicate that our current follow-up program has animportance in detecting early recurrences and should not be altered.

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Background: Radiation therapy used for head and neck cancer patients cause many side effects in the oral cavity and above all affects the salivary glands. Complaint of dry mouth (xerostomia) and hyposalivation are common as well as swallowing difficulty (dysphagia) even after the cancer is remitted.  Aim: The aim of the study is to examine the correlation between hyposalivation and xerostomia in patients undergoing radiotherapy.   Methods: Six patients undergoing radiotherapy for head and neck cancer at Norrlands University Hospital participated in the study. A questionnaire regarding xerostomia was answered and a collection of stimulated as well as unstimulated saliva was taken.  Results: Regarding the stimulated salivary flowrate, one out six patients was below the limit of hyposalivation. Three out of six patients were below the limit of hyposalivation with reference to the unstimulated salivary output. The questionnaire regarding xerostomia showed that all patients experienced dry mouth symptoms to varying degrees. The questions concerning the dryness of the tongue and the amount of saliva in the mouth had the highest rating.  Conclusion: Regarding the patients that participated in this study, a correlation is shown between xerostomia and unstimulated salivary output. However, due to the lack of participants in the study, no firm conclusion can be drawn.

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Background: Head and neck cancer (HNC)-specific symptoms have a substantial impact on health-related quality of life. The aim of this study was to determine whether self-reported dysphagia, voice problems and pain of HNC patients changed over time and whether specific clinical or sociodemographic variables were associated with these symptoms. Methods: HNC patients (n = 299) in an outpatient setting answered questionnaires (Eating Assessment Tool-10; questions from the EORTC QLQ-C30 and EORTC H&N35) on dysphagia, voice problems and pain, collected with the software “OncoFunction” at three different timepoints (t1–t3) after diagnosis. The mean score changes from t1 to t3 were expressed in terms of effect sizes d. The impact of sociodemographic and clinical factors on the course of the variables was tested with multivariate analyses of variance. Results: Dysphagia, voice impairment and pain in HNC survivors significantly improved over a period of approximately 14 months after diagnosis. Tumor site, stage, treatment modality, occupational state and ECOG state were significantly correlated with self-reported functional outcome. The pain level of the HNC patients was rather low. Conclusions: Patients suffer from functional impairments after HNC treatment, but an improvement in self-reported symptoms could be demonstrated within this time period.

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