| 1. |
- de Flon, Caroline Haglund, et al.
(författare)
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High Levels of FGF11 Correlate with Poor Survival in Patients with Human Papillomavirus (HPV)-Positive Oropharyngeal Squamous Cell Carcinoma
- 2023
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 15:7
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Tidskriftsartikel (refereegranskat)abstract
- To better identify patients with human papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC) and a poor prognosis after treatment, we compared the gene expression in tumours from patients with a poor or a favourable prognosis in a case-control setting. The results were thereafter validated in two separate cohorts on the RNA and protein levels. High RNA or protein expression of FGF11 was correlated with a poor patient survival in all three cohorts. Taken together, the data imply that FGF11 may play a major role in the prognosis of patients and that FGF11 could serve as a prognostic marker in HPV-positive oropharyngeal cancer.Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favourable prognosis. It has therefore been suggested that treatment should be individualized and separated by HPV status. However, additional prognostic markers are still needed before treatment can be individualized for this patient group. For this purpose, all patients diagnosed with HPV and p16-positive OPSCC in Stockholm 2000-2009, identified as having a partial/nonresponse to treatment and having viable tumour cells in their neck specimen with material available were categorized as cases. These were matched to controls (complete responders), and the differences in the gene expression were analysed. Two separate verification cohorts were identified including patients with HPV- and p16-positive OPSCC, and the data from the case-control study were verified by qPCR and immunohistochemistry (IHC) in the respective cohorts. A separation of gene expression in correlation with survival was observed in the case-control study, and FGF11 expression was identified as significantly differently expressed between the two groups. The prognostic role of FGF11 was validated in the two cohorts on the RNA and protein levels, respectively. Taken together, our findings suggest that FGF11 may indicate a poor prognosis in HPV-positive OPSCC and may serve as a prognostic biomarker.
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| 2. |
- Mints, Michael, et al.
(författare)
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Tumour inflammation signature and expression of S100A12 and HLA class I improve survival in HPV-negative hypopharyngeal cancer
- 2021
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Hypopharyngeal squamous cell carcinoma (HPSCC) has a very poor prognosis. Local surgery may increase survival, but is often avoided due to significant post-op co-morbidities. Since prognostic markers are lacking, the aim was to find predictive biomarkers that identify patients whose response to oncological treatment is poor and who may benefit from primary surgery to increase survival. Pretreatment biopsies from 23 HPSCC patients, 3 human papillomavirus (HPV) positive and 20 HPV-negative, were analyzed for expression of 750 mRNAs using the Nanostring nCounter IO360 panel in relation to 3-year survival. Validation was performed through immunohistochemistry (IHC) for HLA class I and S100A12 in 74 HPV-negative HPSCC samples. Clustering identified a subset of HPV-negative HPSCC with favorable prognosis and a gene expression signature overexpressing calgranulins and immune genes, distinct from that of HPV-positive HPSCC. Enrichment analysis showed immune signaling, including the tumor inflammation signature, to be enriched in surviving patients. IHC validation confirmed high S100A12 and HLA class I expression to correlate with survival in HPV-negative HPSCC. This shows that immune activity is strongly related to survival in HPV-negative HPSCC. Enrichment of the tumor inflammation signature indicates a potential benefit of immunotherapy. Low expression of both HLA class I and S100A12 could be used to select patients for local surgery.
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| 3. |
- Sivars, Lars, et al.
(författare)
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Cell-Free Human Papillomavirus DNA Is a Sensitive Biomarker for Prognosis and for Early Detection of Relapse in Locally Advanced Cervical Cancer
- 2024
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Ingår i: Clinical Cancer Research. - : American Association For Cancer Research (AACR). - 1078-0432 .- 1557-3265. ; 30:13, s. 2764-2771
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Human papillomavirus (HPV) is the cause of the majority of cervical cancer cases and has been showed to be released as cell-free tumor DNA (ctHPV DNA) into the circulation. Here, we analyze if ctHPV DNA could be used as a prognostic biomarker and/or to detect relapse earlier than traditional methods in locally advanced cervical cancer (LACC).Experimental Design: A total of 74 patients with LACC were included; 66of 74 were positive for 13 high-risk HPV types on a bead-based assay of tumor biopsy samples. HPV-type-specific droplet digital PCR assays were developed. Longitudinal plasma samples were then analyzed for the biopsy-verified HPV type for each patient. In total, 418 plasma samples were analyzed. Patients were followed for a median of 37 months. Results were correlated to tumor and clinical characteristics.Results: Of the pretreatment plasma samples, 92.4% were positive for ctHPV DNA. Persistent ctHPV DNA in end-of-treatment, early follow-up (1-2 months after end-of-treatment), or tumor evaluation (3-4 months after end-of-treatment) plasma was correlated with worse progression-free survival (P < 0.001) compared with if ctHPV DNA was not found. The positive predictive value of ctHPV status at early follow-up for predicting disease progression was 87.5%, and the negative predictive value was 89.3%. ctHPV DNA was found in plasma before relapse was diagnosed using radiology in all patients (n = 10) who experienced relapse after complete clinical response to treatment with a median 315 days lead time.Conclusions: ctHPV DNA in follow-up plasma is a promising prognostic biomarker in patients with LACC, useful for analysis of response to therapy and for early detection of relapse.
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| 4. |
- Zupancic, Mark
(författare)
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Diagnostic and prognostic markers in primarily non-smoking related head and neck cancer
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Head and neck cancer (HNC) includes cancers of the oral cavity, the pharynx (i.e., the nasopharynx, the oropharynx, and the hypopharynx), the larynx, the nasal cavity, the paranasal sinuses, and the salivary glands. Traditional risk factors are smoking, alcohol, opium, betel chewing, and virus infections, such as human papillomaviruses (HPV) and Epstein-Barr Virus (EBV). These viruses play a major role in some cancers, and it is evident that the aetiology of different HNC types differs. In Sweden, HNC risk profiles have changed in the past decades due to a decrease of smoking in both men and women, while an increase in HPV-related cases has been noted. This increase is anticipated to continue for some decades, until the introduction of the HPV vaccine will hopefully prevent most of them. This thesis has therefore focused on HNC primarily not associated with smoking. It includes studies on oropharyngeal squamous cell carcinoma (OPSCC) and HPV-related multiphenotypic sinonasal carcinoma (HMSC) in a broader context. Finally, we also studied adenoid cystic carcinoma (AdCC), where the aetiology is mainly unknown, and the diagnostics are still very challenging. In Paper I we investigated the relationship between the presence of HPV DNA and p16INK4a (p16) overexpression and prognosis of different OPSCC subsites. We found that the presence of HPV DNA and p16 overexpression were favourable prognostic markers in the tonsillar and base of tongue cancer subsites (TSCC and BOTSCC, respectively) but not in other OPSCC cancer subsites (otherOPSCC). We also showed the importance of testing for both HPV DNA and p16 expression status for better prognostication. In Paper II we investigated a possible prognostic role of psoriasin expression, examined by immunohistochemistry in base of tongue cancer. In this pilot study we could show that low psoriasin expression was a favourable prognostic marker in HPV-positive (HPV+) BOTSCC. Paper III includes a systematic literature review of studies on HMSC and the presence of different HPV types in these tumours and their various locations. The data indicated that HPV+ tumours with such characteristics may not only be located within the sinonasal region. In Paper IV we initially investigated whether the presence of HPV and human polyomaviruses (HPyVs) played a role in the prognosis of adenoid cystic carcinoma (AdCC) where the aetiology is still mainly unknown. In addition, we wanted to examine whether the presence of these viruses could play a diagnostic role. HPyVs did however not have a major role in the aetiology of AdCC, as no case was positive for HPyV. Of 68 patients analysed, there were three HPV+ AdCC cases, but upon re-examination their pathology was more similar to HMSC. This suggested that HMSC may not be limited to the sinonasal region. Furthermore, our findings indicated that the presence of HPV could be used in diagnostics when distinguishing between AdCC and HMSC. In Paper V we investigated a large cohort of AdCC patients (155 cases) regarding clinical presentation, treatment, and survival. We found that subsite (major salivary glands), early stage (stage I-II), and multimodal treatment were positive prognostic factors, while age, gender, perineural growth, or negative surgical margins did not influence clinical outcome. In conclusion we were able to show that the presence of HPV DNA and p16 overexpression were favourable prognostic markers in TSCC and BOTSCC but not in otherOPSCC. In addition, low psoriasin expression was found to be a positive prognostic marker for HPV+ BOTSCC. In the systematic literature review of HMSC we disclosed that this tumour entity could also arise at sites outside the sinonasal area. Furthermore, we could show that neither HPyVs nor HPV played a major role in AdCC, but that presence of HPV could be of differential diagnostic value, especially in the sinonasal area. The final paper describing a large AdCC patient cohort confirmed that commonly used prognostic factors, e.g., gender, age, and smoking history did not correlate with survival, notably in this study neither did perineural invasion nor radical surgery of the tumour primary.
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| 5. |
- Zupancic, Mark, et al.
(författare)
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Human papillomavirus (HPV) load is higher in HPVDNA/p16 positive than in HPVDNA positive/p16 negative oropharyngeal squamous cell carcinoma but does not differ significantly between various subsites or correlate to survival
- 2024
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Ingår i: Oral Oncology. - : Elsevier. - 1368-8375 .- 1879-0593. ; 151
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivePatients with human papillomavirus DNA positive (HPVDNA+) and p16ink4a overexpressing (p16+) oropharyngeal squamous cell carcinoma (OPSCC), especially those with cancer in the tonsillar and base of tongue subsites as compared to other OPSCC subsites have a better outcome than those with only HPVDNA+ or only p16+ cancer. Likewise having a high viral load has been suggested to be a positive prognostic factor. We therefore hypothesized, that HPV viral load could vary depending on OPSCC subsite, as well as with regard to whether the cancer was HPVDNA+ and p16+, or only HPVDNA+, or only p16+ and that this affected outcome.Material and methodsTo address these issues HPV viral load was determined by HPV digital droplet (dd) PCR in tumor biopsies with previously known HPVDNA/p16 status from 270 OPSCC patients diagnosed 2000–2016 in Stockholm, Sweden. More specifically, of these patients 235 had HPVDNA+/p16+, 10 had HPVDNA+/p16-, 13 had HPVDNA-/p16+ and 12 had HPVDNA-/p16- cancer.ResultsWe found that HPVDNA+/p16+ OPSCC had a significantly higher viral load than HPVDNA+/p16- OPSCC. Moreover, there was a tendency for a higher viral load in the tonsillar and base of tongue OPSCC subsites compared to the other subsites and for a low viral load to correlate to a better clinical outcome but none of these tendencies reached statistical significance.ConclusionTo conclude, the mean viral load in HPVDNA+/p16+ OPSCC was higher than in HPVDNA+/p16- OPSCC, but there was no statistically significant difference in viral load depending on OPSCC subsite or on clinical outcome.
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