| 1. |
- Bersani, Cinzia, et al.
(författare)
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A model using concomitant markers for predicting outcome in human papillomavirus positive oropharyngeal cancer
- 2017
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Ingår i: Oral Oncology. - : Elsevier. - 1368-8375 .- 1879-0593. ; 68, s. 53-59
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Head-neck cancer therapy has become intensified. With radiotherapy alone, 3-year disease-free survival (DFS) is 80% for HPV-positive TSCC/BOTSCC and better for patients with favorable characteristics, suggesting therapy could be tapered for some, decreasing side-effects. Therefore, we built a model to predict progression-free survival for patients with HPV-positive TSCC and BOTSCC. Material and methods: TSCC/BOTSCC patients treated curatively between 2000 and 2011, with HPV16 DNA/E7 mRNA positive tumors examined for CD8(+) TILs, HPV16 mRNA and HLA class I expression were included. Patients were split randomly 65/35 into training and validation sets, and LASSO regression was used to select a model in the training set, the performance of which was evaluated in the validation set. Results: 258 patients with HPV DNA/E7 mRNA positive tumors could be included, 168 and 90 patients in the respective sets. No treatment improved prognosis compared to radiotherapy alone. CD8(+) TIL counts and young age were the strongest predictors of survival, followed by T-stage <3 and presence of HPV16 E2 mRNA. The model had an area under curve (AUC) of 76%. A model where the presence of three of four of these markers defined good prognosis captured 56% of non-relapsing patients with a positive predictive value of 98% in the validation set. Furthermore, the model identified 35% of our cohort that was over-treated and could safely have received de-escalated therapy. Conclusion: CD8(+) TIL counts, age, T-stage and E2 expression could predict progression-free survival, identifying patients eligible for randomized trials with milder treatment, potentially reducing side effects without worsening prognosis.
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| 2. |
- Bersani, Cinzia, et al.
(författare)
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Targeted sequencing of tonsillar and base of tongue cancer and human papillomavirus positive unknown primary of the head and neck reveals prognostic effects of mutated FGFR3
- 2017
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:21, s. 35339-35350
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Human papillomavirus positive (HPV+) tonsillar cancer (TSCC), base of tongue cancer (BOTSCC) and unknown primary cancer of the head and neck (HNCUP) have better outcome than corresponding HPV- cancers. To find predictive markers for response to treatment, and correlations and differences in mutated oncogenes and suppressor genes between HPV+ TSCC/BOTSSCC and HPV+ HNCUP and HPV- TSCC/BOTSCC targeted next-generation sequencing was performed of frequently mutated regions in 50 cancer related genes.PATIENTS AND METHODS: DNA from 348 TSCC/BOTSCC and 20 HNCUP from patients diagnosed 2000-2011, was sequenced by the Ion Proton sequencing platform using the Ion AmpliSeq Cancer Hotspot Panel v2 to identify frequently mutated regions in 50 cancer related genes. Ion Torrent Variant Caller software was used to call variants.RESULTS: 279 HPV+ TSCC/BOTSCC, 46 HPV- TSCC/BOTSCC and 19 HPV+ HNCUP samples qualified for further analysis. Mutations/tumor were fewer in HPV+ TSCC/BOTSCC and HNCUP, compared to HPV- tumors (0.92 vs. 1.32 vs. 1.68). Differences in mutation frequency of TP53 and PIK3CA were found between HPV+ TSCC/BOTSCC and HNCUP and HPV- TSCC/BOTSCC. In HPV+ TSCC/BOTSCC presence of FGFR3 mutations correlated to worse prognosis. Other correlations to survival within the groups were not disclosed.CONCLUSIONS: In HPV+ TSCC/BOTSCC mutation of PIK3CA was most frequently observed, while TP53 mutations dominated in HPV- TSCC/BOTSCC. In HPV+ TSCC/ BOTSCC and HNCUP, mutations/tumor were similar in frequency and fewer compared to that in HPV- TSCC/BOTSCC. Notably, FGFR3 mutations in HPV+ TSCC/BOTSCC indicated worse prognosis.
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| 3. |
- Cheng, Liqin, et al.
(författare)
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Vaginal microbiota and human papillomavirus infection among young Swedish women
- 2020
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Ingår i: npj Biofilms and Microbiomes. - : Springer Science and Business Media LLC. - 2055-5008. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Human papillomavirus (HPV) infection is one of the most common sexually transmitted diseases. To define the HPV-associated microbial community among a high vaccination coverage population, we carried out a cross-sectional study with 345 young Swedish women. The microbial composition and its association with HPV infection, including 27 HPV types, were analyzed. Microbial alpha-diversity was found significantly higher in the HPV-infected group (especially with oncogenic HPV types and multiple HPV types), compared with the HPV negative group. The vaginal microbiota among HPV-infected women was characterized by a larger number of bacterial vaginosis-associated bacteria (BVAB), Sneathia, Prevotella, and Megasphaera. In addition, the correlation analysis demonstrated that twice as many women with non-Lactobacillus-dominant vaginal microbiota were infected with oncogenic HPV types, compared with L. crispatus-dominated vaginal microbiota. The data suggest that HPV infection, especially oncogenic HPV types, is strongly associated with a non-Lactobacillus-dominant vaginal microbiota, regardless of age and vaccination status.
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| 4. |
- Du, Juan, et al.
(författare)
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Prevalence of Oral Human Papillomavirus Infection among Youth, Sweden
- 2012
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Ingår i: Emerging Infectious Diseases. - : Centers for Disease Control and Prevention. - 1080-6040 .- 1080-6059. ; 18:9, s. 1468-1471
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Tidskriftsartikel (refereegranskat)abstract
- Human papillomavirus (HPV) causes cervical, head, and neck cancers. We studied 483 patients at a youth clinic in Stockholm, Sweden, and found oral HPV prevalence was 9.3% and significantly higher for female youth with than without cervical HPV infection (p = 0.043). Most oral HPV types matched the co-occurring cervical types.
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| 5. |
- Lindquist, David, et al.
(författare)
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Intense CD44 expression is a negative prognostic factor in tonsillar and base of tongue cancer
- 2012
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Ingår i: Anticancer Research. - : International Institute of Anticancer Research. - 0250-7005 .- 1791-7530. ; 32:1, s. 153-161
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with tonsillar and base of tongue cancer, which are human papillomavirus (HPV) positive, have a better clinical outcome than those with HPV-negative tumors. The identification of additional predictive markers for response to therapy could still be of great use.MATERIALS AND METHODS: Tumor markers CD44, p16, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), E-cadherin, cyclooxygenase-2 (COX 2), Ki-67, and p27 were analyzed by immunochemistry, and HPV status was tested by polymerase chain reaction (PCR) in tumors from 73 patients and correlated to survival.RESULTS: High intensity CD44 staining (p=0.006) and high EGFR expression (p=0.026) were indicators of poor prognosis, while high p16 expression (p=0.021) and younger age (p=0.002) were positive prognostic markers for disease-specific survival. Furthermore, staining of CD44 (p=0.026) and age (p=0.002) were shown to be strong prognostic markers in multivariate analysis, which should be evaluated further for possible use in clinical practice.
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| 6. |
- Ährlund-Richter, Andreas
(författare)
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Studies on human papillomavirus (HPV) and other markers in the development and prognosis of HPV associated cancer
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Human papilloma virus (HPV) is a risk factor for anogenital and oropharyngeal cancer (OPSCC) and commonly transmitted sexually although most infections are cleared without adverse effects. Notably, the past decades the incidences of HPV positive (HPV+), but not HPV negative (HPV-) tonsillar and base of tongue cancer (TSCC and BOTSCC), the two major OPSCC subtypes have both increased. For this reason, we wanted to follow HPV-prevalence. Before HPV vaccination a high prevalence of HPV was shown in the cervix and oral cavity of youth aged 15-23 years at a youth clinic in Stockholm 2008-2010, but later, with rising vaccine coverage, a decrease of HPV vaccine types was observed between 2013-2015. In parallel, in the mid-2010s many studies showed a link between vaginal microbiota and obstetric outcomes, inflammatory disease, as well as sexually transmitted disease. A few years later, several meta-studies and one DNA sequencing study abroad, showed an association between HPV prevalence and microbiota. In this context, of note, most HPV associated anogenital cancers go through three stages of development, pre-malignant stages, dysplasia, high-grade dysplasia/cancer in situ, to malignant stages, invasive cancer, and metastatic cancer. However, these stages are not well studied in HPV+ TSCC and BOTSCC and although there have been many biomarker studies in these tumours additional ones would be of use to better individualize treatment of these cancers. The aim of this thesis was therefore to follow up some of these findings. Approaches: In paper I, we followed up the HPV vaccination coverage and HPV prevalence at a youth clinic in Stockholm, to investigate vaccine effects. In paper II, we investigated possible effects of HPV status, age and vaccination status on the vaginal microbiota of women in a cohort from Uppsala and Stockholm. In paper III, we analysed and compared gene expression in high-grade dysplasia and invasive cancer in HPV+ and HPV- TSCCC/BOTSCC with particular emphasis on HPV status. In paper IV, we did whole-exome-sequencing on primary tumours of HPV+ TSCC/BOTSCC patients with and without recurrences, to identify similarities and differences between the groups as well as to identify markers of prognostic significance or candidates for targeted therapy. Results: In paper I, the proportion of HPV vaccinated women increased from 10.7% 2008-2010 to 82.1% 2017-2018. HPV-vaccine types were reduced overall and more in vaccinated than in unvaccinated women, but other high-risk HPV types still remained high. In paper II, microbial alpha-diversity was significantly higher for HPV+ compared to HPV-patients. Twice as many HPV+ than HPV- women had non-lactobacillus dominant vaginal microbiota compared to L. crispatus dominated vaginal microbiota and oncogenic HPVs were associated with non-lactobacillus dominant vaginal microbiota. In paper III, invasive and non-invasive tumours gene-expression were compared using immunohistochemistry (IHC) and RNA-panels. Forty genes showed differential expression, e.g. SPARC, psoriasin I, collagen-1 and galectin-1 and HPV+ and HPV- dysplasia was similarly differentiated from invasive cancer. In paper IV, a high-impact deletion on CDC27 was observed only in primaries of patients with relapse and 3 variants and 26 mutated genes, were present > 30% of all primaries regardless of prognosis. Conclusions: The presented studies in this thesis reaffirm the efficacy of the HPV vaccine programs in Stockholm, but with a remaining continuous prevalence of nonvaccine HR-HPV types. The results also suggest an influence from the HPV status on the vaginal microbiota make up. Furthermore, the data suggest that that HPV+ and HPVTSCC/BOTSCC although not identical also likely have similar dysplastic cancer stages. Finally, there are differences between the mutational profiles of HPV+ TSCC/BOTSCC that re-occur compared to those that do not re-occur, but also here there are genes that are similarly altered in primary tumours of patients that are cured or that relapse.
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| 7. |
- Ährlund-Richter, Andreas, et al.
(författare)
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Whole-exome sequencing of HPV positive tonsillar and base of tongue squamous cell carcinomas reveals a global mutational pattern along with relapse-specific somatic variants
- 2022
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- To identify predictive/targetable markers in human papillomavirus positive (HPV+) ton-sillar and base of tongue cancer (TSCC/BOTSCC), whole-exome sequencing (WES) of tumours of patients with/without recurrence was performed. Forty primary tumours and adjacent normal tissue were separated by micro-dissection from formalin-fixed paraffin-embedded tissue from patients treated with curative intent 2000–2014 at Karolinska University Hospital. Successful sequencing was obtained in primary tumours of 18 patients without and primaries of 17 with local or distant recurrence, as well as in 10 corresponding recurrences (i.e., five local relapses and five distant metas-tases) from these 17 patients. One variant—a high-impact deletion in the CDC27 gene—was observed only in primaries of 5/17 patients that had a recurrence after full treatment but in none of those without recurrence. In addition, 3 variants and 26 mutated genes, including CDC27, BCLAF1 and AQP7, were present in at least 30% of all primary tumours independent of prognosis. To conclude, a CDC27 deletion was specific and found in ~30% of samples from patients with a local relapse/distant metastasis and could, therefore, potentially be a prospective marker to predict prognosis. Commonly mutated genes, such as BCLAF1, should be further studied in the context of targeted therapy.
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