Patients with early stage oropharyngeal squamous cell carcinoma can be identified with label-free serum proteomics
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Synapt MS
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Blood Serum
SUBMITTER: 
Sakari Joenväärä
LAB HEAD: Suvi Renkonen
PROVIDER: PXD008445 | Pride | 2018-07-11
REPOSITORIES: Pride
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Patients with early-stage oropharyngeal cancer can be identified with label-free serum proteomics.
Tuhkuri Anna A Saraswat Mayank M Mäkitie Antti A Mattila Petri P Silén Robert R Dickinson Amy A Carpén Timo T Tohmola Tiialotta T Joenväärä Sakari S Renkonen Suvi S
British journal of cancer 20180702 2
<h4>Background</h4>The increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC) is mainly related to human papillomavirus (HPV) infection. As OPSCCs are often diagnosed at an advanced stage, mortality and morbidity remain high. There are no diagnostic biomarkers for early detection of OPSCC.<h4>Methods</h4>Serum from 25 patients with stage I-II OPSCC, and 12 healthy controls, was studied with quantitative label-free proteomics using ultra-definition MS<sup>E</sup>. Statistical analy ...[more]
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Project description:This is the proteomics part of the above project. Purpose: No blood-based biomarkers to detect OPSCC early before symptoms develop or before clinically visible. Diagnosis is solely based on histology of a visible tumour. Most OPSCC patients are diagnosed at an advanced stage, which leads to significant morbidity and poor survival. If high-risk patients were identified with blood-based biomarkers before clear clinical manifestations, tumours could be detected and treated at an earlier stage. Causes of OPSCC include smoking, alcohol misuse, and human papillomavirus (HPV). Tumours are separated according to WHO recommendations into HPV+ OPSCC and HPV- OPSCC using the proxy histological marker p16. We additionally separated our patients into these groups to determine whether the serum glycopeptides would differ between HPV+ and HPV- tumours, as these are distinct clinical entities. Patients and Methods: Pre-treatment sera from 74 patients with OPSCC (including 26 p16- tumours and 48 p16+ tumours) and 12 controls were used, collected between the years 2012 and 2015 at the Department of Otorhinolaryngology – Head and Neck Surgery, Helsinki University Hospital, Helsinki, Finland. Samples were grouped as follows: early stage p16+ OPSCC (stage I only), early stage p16- OPSCC (stage I-II), p16+ (any stage), p16- (any stage), controls. In-parallel quantitative bulk serum proteomics and serum glycopeptidomics were performed. Results: We identified 78 bulk proteins in the serum, of which 33 significantly differed between early-stage p16- OPSCC and controls, 22 between early-stage p16+ OPSCC and controls, 1 between early-stage p16+ and early-stage p16- OPSCCs, and 30 between all p16+ and p16- OPSCCs. We identified glycopeptides from proteins including but not limited to alpha-1-antitrypsin, haptoglobin, and Immunoglobulin heavy constant alpha 1, and compared these with the protein expression levels in each comparison. Conclusions: We have identified novel serum glycopeptide biomarkers detect early-stage OPSCCs, to be evaluated further as a diagnostic panel to detect preclinical OPSCC in at-risk patients.
2024-01-26 | PXD016727 | Pride
Project description:This is the glycopeptide part of the above project. Purpose: No blood-based biomarkers to detect OPSCC early before symptoms develop or before clinically visible. Diagnosis is solely based on histology of a visible tumour. Most OPSCC patients are diagnosed at an advanced stage, which leads to significant morbidity and poor survival. If high-risk patients were identified with blood-based biomarkers before clear clinical manifestations, tumours could be detected and treated at an earlier stage. Causes of OPSCC include smoking, alcohol misuse, and human papillomavirus (HPV). Tumours are separated according to WHO recommendations into HPV+ OPSCC and HPV- OPSCC using the proxy histological marker p16. We additionally separated our patients into these groups to determine whether the serum glycopeptides would differ between HPV+ and HPV- tumours, as these are distinct clinical entities. Patients and Methods: Pre-treatment sera from 74 patients with OPSCC (including 26 p16- tumours and 48 p16+ tumours) and 12 controls were used, collected between the years 2012 and 2015 at the Department of Otorhinolaryngology – Head and Neck Surgery, Helsinki University Hospital, Helsinki, Finland. Samples were grouped as follows: early stage p16+ OPSCC (stage I only), early stage p16- OPSCC (stage I-II), p16+ (any stage), p16- (any stage), controls. In-parallel quantitative bulk serum proteomics and serum glycopeptidomics were performed. Results: We identified 78 bulk proteins in the serum, of which 33 significantly differed between early-stage p16- OPSCC and controls, 22 between early-stage p16+ OPSCC and controls, 1 between early-stage p16+ and early-stage p16- OPSCCs, and 30 between all p16+ and p16- OPSCCs. We identified glycopeptides from proteins including but not limited to alpha-1-antitrypsin, haptoglobin, and Immunoglobulin heavy constant alpha 1, and compared these with the protein expression levels in each comparison. Conclusions: We have identified novel serum glycopeptide biomarkers detect early-stage OPSCCs, to be evaluated further as a diagnostic panel to detect preclinical OPSCC in at-risk patients.
2024-01-26 | PXD016709 | Pride
Project description:Purpose No blood biomarkers to detect early OSCC without clinical signs exist - diagnosis is solely based on histology of a visible tumor. Most OSCC patients are diagnosed at advanced stage, which leads to significant morbidity and poor survival. If high-risk patients were identified with blood-based biomarkers before clear clinical manifestations, tumors could be detected and treated at earlier stage. Patients and Methods Serum samples were collected from patients with OSCC at the Department of Otorhinolaryngology – Head and Neck Surgery, Helsinki University Hospital (Finland). Age and gender matched healthy individuals served as controls. Quantitative proteomic analysis with mass spectrometry was performed. Results We quantified 388 proteins in the serum samples. A complete separation between cases and controls was seen based on the protein expression profiles. With statistical analyses, we identified a set of eight proteins that most reliably separated OSCC patients from healthy individuals. Although the tumor stages varied from I to IVa, this set of proteins was able to identify all OSCCs and thus is sensitive for detecting even early tumors. Conclusion We are the first to suggest a set of serum biomarkers to be evaluated further as a diagnostic panel to detect preclinical OSCC in risk patients.
2018-04-25 | PXD005263 | Pride
Project description:Colorectal cancer (CRC) is the third most common cancer worldwide. Increased levels of C-reactive protein (CRP), which occur during local and systemic inflammation, have been linked to poor prognosis in CRC patients. on the other hand there are no biomarkers associated with 5 year survival of CRC patients. We divided the serum samples into either high (>30 mg/L) or low CRP (<30 mg/L) or long and short 5-year survival. In this study, we have quantified 256 proteins with two or more unique peptides. Data were further analyzed by ANOVA, principal component analysis (PCA), Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA)-modeling and OPLS-DA-associated S-plot. Pathway analysis was performed using Integrated Molecular Pathway Level Analysis (IMPaLa) and Ingenuity Pathway Analysis (IPA). We propose several proteins associated with prognosis and survival in patients with CRC.
2018-03-26 | PXD008583 | Pride
Project description:The global rise of HPV(+) oropharyngeal squamous cell carcinoma (OPSCC) has generated considerable interest underlying its etiology and management. Despite an overall decline in head and neck malignancies, the incidence in OPSCC has by contrast sharply risen, with HPV(+) subtypes now comprising 80% of all OPSCC.1,2 Relative to HPV(-) OPSCC, HPV(+) patients are more responsive to chemoradiation and harbor a 52% risk-of-death reduction.3 Despite this distinct outcome, treatment regimens remain the same for all OPSCC subtypes (smoking-driven and virus-driven), rather than an adaptive approach to what most consider distinct diseases. The short-term effects (e.g., mucositis, odynophagia) and long-term toxicities (e.g., xerostomia, dysphagia, ototoxicity) from treatment substantially affect quality of life, and rival the impact of the cancer itself. Recently published as well as ongoing trials are actively examining deintensification approaches2,4-9, with the goal of diminishing treatment sequelae for HPV(+) subtypes. While deintensification may decrease chemoradiation-related toxicities, it nonetheless may also undertreat a meaningful percentage of HPV(+) patients who may then recur. In examining national trials, 19% of HPV(+) patients had disease progression after therapy, with a two-year survival rate of 60%.10 Current methods to ascertain HPV status involve p16 staining. However, on comparison with gold standard E6/E7 expression by qPCR, p16 harbored a 15% false positivity rate11, suggesting limited utility as a sole biomarker for deintensification. Improved molecular stratification would greatly enhance the clinician’s ability to precisely tailor treatment while minimizing the risk of jeopardizing outcomes. One approach encompasses in-depth proteomic profiling of HPV(+) OPSCC to reveal distinct protein expression profiles and delineate clinically relevant upstream pathways. In turn, these proteomic differences may distinguish higher-risk disease (cases predisposed to recurrence that may benefit from treatment intensification) from lower-risk phenotypes (cases whose treatment response is sufficiently robust to warrant deintensification). Here, two HPV(+) OPSCC cohorts stratified by treatment response are compared via a hybrid data dependent acquisition/data independent acquisition (DDA/DIA) approach via mass spectrometry. We focused on detection of low-abundance proteins to highlight proteomic signatures that can be potentially exploited for treatment stratification.
2022-05-05 | PXD028618 | Pride
Project description:Head and neck squamous cell carcinomas are heterogeneous neoplasms that show clinical and biological differences in association with the human papillomavirus (HPV). To provide adequate therapeutic strategies, biological and clinical characterization is essential to stratify patients based on prognostic and predictive factors. Reports on HNSCC are scarce in Mexico, thus in the present study, we analyze 414 cases of HNSCC, including those of the oropharynx (OPSCC), larynx (LASCC), and oral cavity (OCSCC). We determined the presence of HPV and p16 expression. Global expression profiles were analyzed with Affymetrix HTA 2.0 microarray in 25 selected cases HPV+/p16+ versus HPV-/p16-. In our study we analyze 25 samples derived from HNSCC patients. 18 samples were HPV-/p16- and 7 HPV+/p16+. We compared the HPV-/p16- versus the HPV+/p16+ and identified differentially expressed RNAs with a fold change greater than 1.5 or less than -1.5. These data were used to obtain 98 genes that are differentially expressed in absence of HPV. The present study offers information regarding clinical and molecular characteristics of HNSCC, both associated and unassociated with HPV, in Mexican patients.
2021-12-01 | GSE181805 | GEO
Project description:Nowadays, risk stratification for oropharyngeal squamous cell carcinoma (OPSCC) is based on HPV status, tobacco smoking, and tumor stage. Although HPV positivity represents a strong prognostic factor for both reduced risk of relapse, and improved survival, there is a subset of HPV-positive OPSCC patients who still experience poor outcomes. Furthermore, HPV-negative OPSCC patients, who have an even higher risk of relapse within two years from the end of the treatment, are still lacking suitable prognostic biomarkers for clinical outcome. In this scenario, inclusion of new biomarkers that differentiate OPSCC patients with a diverse prognosis is urgently needed. Since genes encoding for epigenetic regulators have been frequently found mutated in several tumors, including OPSCC, it is expected that epigenetic changes may play a major role in OPSCC pathogenesis and response to therapy. Consistently, HPV oncoproteins have been also demonstrated to impact on epigenetic pattern by interacting with different epigenetic regulators, thus affecting the chromatin landscape of OPSCC HPV-positive cells. Along this line, we have recently demonstrated the methylation levels of the “Long interspersed nucleotide element-1” (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was different between HPV16-positive and -negative OPSCC patients. In particular, the lowest level of LINE-1 element methylation was observed in HPV16-negative OPSCC patients who relapsed within 24 months, thus indicating the overall level of genomic DNA methylation may have an impact on early OPSCC relapse risk. Despite these promising initial data, the influence of LINE1 methylation levels on OPSCC survival is not yet well defined. We retrospectively reviewed a cohort of 156 patients with stage III–IVB (AJCC TNM 7th Ed.) OPSCC. Forty patients were diagnosed and treated at Treviso Regional Hospital, and 116 at National Cancer Institute of Aviano and/or Pordenone Hospital. All patients were managed with curative intent with elective radiotherapy ± chemotherapy or surgery ± adjuvant (chemo)radiotherapy, in accordance with current clinical practice. Genomic DNA was extracted from OPSCC formalin-fixed paraffin-embedded tissues. The quantification of HPV16 DNA was performed by real-time quantitative PCR by using specific primers for the amplification of a region spanning the E6 genes of the HPV16 genome, whereas the methylation status of LINE1 repetitive sequences was evaluated by real-time quantitative Methylation-Specific PCR. The impact of genome-wide methylation patterns on progression-free survival (PFS) and overall survival (OS) was assessed using Kaplan-Meier analyses. Optimal cut-points for LINE-1 were search through a recursive algorithm which estimates the predictive value for PFS (Harrell's c-index) for each possible couple of LINE-1 values; optimal cut-points were defined as those which maximized Harrell's c-index. Multivariate hazard risk (HR) and corresponding confidence intervals (CI) were calculated according to Cox proportional hazard model adjusting for gender, age, TNM stage, and HPV status.The median follow up was 30 months (interquartile range: 17-72 months) Considering all cases, PFS and OS were respectively 64.6% and 71.8% at 2 years, and 49.5% and 53.7% at 5 years. HPV DNA prevalence was 28.8% (45/156). Compared to HPV-negative patients, HPV-positive ones had a better outcome in terms of PFS at 2 (81.0% vs. 58.2%) and 5 years (70.9% vs 41.6%; p=0.003), as well as in terms of OS (5-year OS: 74.1 vs. 45.9%, respectively; p=0.003). LINE-1 methylation level was significantly higher in HPV-positive OPSCC patients than in HPV-negative ones (median, 66.9% and 48.7% respectively; p<0.001). Three patterns of LINE-1 methylation status were indentified according to PFS: high ≥55%, medium 35-54%, low <35%. The same cut-points were identified from the analysis on OS. Analyzing all patients, PFS at 2 years was 75.9% in the high methylation group, 62.0% in the intermediate group, and 41.6% in the low methylation group (p≤0.001). Compared to LINE-1≥55%, multivariate HR were 1.66 (95% CI: 0.92-2.99) for LINE-1 35-54% and 2.84 (95% CI: 1.51-5.37) for LINE-1<35%. Moreover, OS at 2 and 5 years was significantly better in the high methylation group (p<0.001), with HRs of death similar to those for PFS. It is worth noting that the level of LINE-1 remained a prognostic factor for both PFS (p= 0.004) and of OS (p=0.011) when we restricted the analysis to HPV-negative patients. Among these patients, the multivariate HRs for LINE-1<35% were 2.87 (95% CI: 1.49-5.52) for PFS and 2.86 (1.43-5.74) for OS. In HPV-positive group, respect to patients with LINE-1 <55%, cases with a LINE-1≥55% have had better trend in terms of PFS and OS, but this difference was not statistically significant (p=0.112; p= 0.113), mainly due to small sample size. Between HPV-positive patients, only one had a methylation of LINE-1 < 35%. LINE-1 methylation has been identified as a molecular marker of prognosis for stage III-IV OPSCC patients, becoming a promising biomarker to be integrated in current prognostic factors (e.g., stage, HPV status, tobacco smoking) to refine the comprehensive clinical management of OPSCC. This is of particular clinical relevance for HPV-positive OPSCC patients, since this marker may help in indentify the subset of these patients with bad prognosis. However, further validation in a prospective study is needed for its application in daily clinical practice.
2022-07-14 | E-MTAB-11152 | biostudies-arrayexpress
Project description:Nowadays, risk stratification for oropharyngeal squamous cell carcinoma (OPSCC) is based on HPV status, tobacco smoking, and tumor stage. Although HPV positivity represents a strong prognostic factor for both reduced risk of relapse, and improved survival, there is a subset of HPV-positive OPSCC patients who still experience poor outcomes. Furthermore, HPV-negative OPSCC patients, who have an even higher risk of relapse within two years from the end of the treatment, are still lacking suitable prognostic biomarkers for clinical outcome. In this scenario, inclusion of new biomarkers that differentiate OPSCC patients with a diverse prognosis is urgently needed. Since genes encoding for epigenetic regulators have been frequently found mutated in several tumors, including OPSCC, it is expected that epigenetic changes may play a major role in OPSCC pathogenesis and response to therapy. Consistently, HPV oncoproteins have been also demonstrated to impact on epigenetic pattern by interacting with different epigenetic regulators, thus affecting the chromatin landscape of OPSCC HPV-positive cells. Along this line, we have recently demonstrated the methylation levels of the “Long interspersed nucleotide element-1” (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was different between HPV16-positive and -negative OPSCC patients. In particular, the lowest level of LINE-1 element methylation was observed in HPV16-negative OPSCC patients who relapsed within 24 months, thus indicating the overall level of genomic DNA methylation may have an impact on early OPSCC relapse risk. Despite these promising initial data, the influence of LINE1 methylation levels on OPSCC survival is not yet well defined. We retrospectively reviewed a cohort of 156 patients with stage III–IVB (AJCC TNM 7th Ed.) OPSCC. Forty patients were diagnosed and treated at Treviso Regional Hospital, and 116 at National Cancer Institute of Aviano and/or Pordenone Hospital. All patients were managed with curative intent with elective radiotherapy ± chemotherapy or surgery ± adjuvant (chemo)radiotherapy, in accordance with current clinical practice. Genomic DNA was extracted from OPSCC formalin-fixed paraffin-embedded tissues. The quantification of HPV16 DNA was performed by real-time quantitative PCR by using specific primers for the amplification of a region spanning the E6 genes of the HPV16 genome, whereas the methylation status of LINE1 repetitive sequences was evaluated by real-time quantitative Methylation-Specific PCR. The impact of genome-wide methylation patterns on progression-free survival (PFS) and overall survival (OS) was assessed using Kaplan-Meier analyses. Optimal cut-points for LINE-1 were search through a recursive algorithm which estimates the predictive value for PFS (Harrell's c-index) for each possible couple of LINE-1 values; optimal cut-points were defined as those which maximized Harrell's c-index. Multivariate hazard risk (HR) and corresponding confidence intervals (CI) were calculated according to Cox proportional hazard model adjusting for gender, age, TNM stage, and HPV status.The median follow up was 30 months (interquartile range: 17-72 months) Considering all cases, PFS and OS were respectively 64.6% and 71.8% at 2 years, and 49.5% and 53.7% at 5 years. HPV DNA prevalence was 28.8% (45/156). Compared to HPV-negative patients, HPV-positive ones had a better outcome in terms of PFS at 2 (81.0% vs. 58.2%) and 5 years (70.9% vs 41.6%; p=0.003), as well as in terms of OS (5-year OS: 74.1 vs. 45.9%, respectively; p=0.003). LINE-1 methylation level was significantly higher in HPV-positive OPSCC patients than in HPV-negative ones (median, 66.9% and 48.7% respectively; p<0.001). Three patterns of LINE-1 methylation status were indentified according to PFS: high ≥55%, medium 35-54%, low <35%. The same cut-points were identified from the analysis on OS. Analyzing all patients, PFS at 2 years was 75.9% in the high methylation group, 62.0% in the intermediate group, and 41.6% in the low methylation group (p≤0.001). Compared to LINE-1≥55%, multivariate HR were 1.66 (95% CI: 0.92-2.99) for LINE-1 35-54% and 2.84 (95% CI: 1.51-5.37) for LINE-1<35%. Moreover, OS at 2 and 5 years was significantly better in the high methylation group (p<0.001), with HRs of death similar to those for PFS. It is worth noting that the level of LINE-1 remained a prognostic factor for both PFS (p= 0.004) and of OS (p=0.011) when we restricted the analysis to HPV-negative patients. Among these patients, the multivariate HRs for LINE-1<35% were 2.87 (95% CI: 1.49-5.52) for PFS and 2.86 (1.43-5.74) for OS. In HPV-positive group, respect to patients with LINE-1 <55%, cases with a LINE-1≥55% have had better trend in terms of PFS and OS, but this difference was not statistically significant (p=0.112; p= 0.113), mainly due to small sample size. Between HPV-positive patients, only one had a methylation of LINE-1 < 35%. LINE-1 methylation has been identified as a molecular marker of prognosis for stage III-IV OPSCC patients, becoming a promising biomarker to be integrated in current prognostic factors (e.g., stage, HPV status, tobacco smoking) to refine the comprehensive clinical management of OPSCC. This is of particular clinical relevance for HPV-positive OPSCC patients, since this marker may help in indentify the subset of these patients with bad prognosis. However, further validation in a prospective study is needed for its application in daily clinical practice.
2023-02-21 | E-MTAB-12032 | biostudies-arrayexpress
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2023-04-13 | PXD023009 | Pride
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2011-03-30 | E-GEOD-26221 | biostudies-arrayexpress