A Prognostic Gene Expression Signature for Oropharyngeal Squamous Cell Carcinoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE171898 | GEO | 2021/04/13
REPOSITORIES: GEO
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Project description:Background: Human papillomavirus-16 (HPV) causes the majority of oropharyngeal squamous cell carcinomas (OPSCC), especially tonsillar and base of tongue cancer. HPV-positive cancer patients have better clinical outcomes than HPV-negative patients and several groups have suggested de-intensification of treatment schedules in order to avoid unnecessary side effects in the former group. Current TNM classification falls short in predicting OPSCC patients’ prognosis highlighting the unmet need for novel biomarkers. Here we tested the expression and the prognostic role of microRNAs (miRs) in relation to HPV status and clinical outcome in 220 patients with OPSCC distributed in three independent cohorts. Methods: MiR expression was assessed in three cohorts of OPSCC patients by NanoString nCounter Technology (training; n=78), Real-Time PCR (validation; n=93) and miR-Sequencing (TCGA; n=51). In-Situ Hybridization was used to define miR localization. Differences in progression free (PFS) and overall survival (OS) according to miR expression were assessed using the Kaplan-Meier method and compared using the log rank test. Univariate and multivariate analyses using Cox proportional hazards method established the relationship between miR expression, HPV-status, clinical-pathological variables and survival. Results: miR-155 and miR-193b-3p were dysregulated in HPV-negative compared to HPV-positive OPSCC. MiR-193b-3p up-regulation was associated with worse PFS and OS in the training and validation cohorts and the TCGA cohort respectively. MiR-193b-3p prognostic effect was independent of HPV-status. Among HPV-positive patients, over-expression of miR-301b and down-modulation of miR-185b correlated with improved survival. Conclusion: Expression analysis for specific miRs in combination with tumor HPV-status and clinical-pathological variables may be useful in the prediction of clinical outcome for OPSCC patients.
2017-01-01 | GSE82064 | 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
Project description:OBJECTIVE: The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression. DESIGN: We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (>1?mg/dL) and platelet count (<100?000/mm3), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10?years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8?years). RESULTS: In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p<0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p<0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p<0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p<0.001) and all liver-related adverse events (HR=4.98, p<0.001). CONCLUSIONS: A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions. 145 liver tissue needle biopsy specimens from U.S. HCV cirrhosis cohort patients with histologically proven cirrhosis lacking evidence and a history of hepatic decompensation or HCC.
2014-08-22 | E-GEOD-54100 | biostudies-arrayexpress
Project description:OBJECTIVE: The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression. DESIGN: We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (>1 mg/dL) and platelet count (<100 000/mm3), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10 years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8 years). RESULTS: In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p<0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p<0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p<0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p<0.001) and all liver-related adverse events (HR=4.98, p<0.001). CONCLUSIONS: A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions. 90 liver tissue needle biopsy specimens from patients with histologically proven cirrhosis lacking evidence and a history of hepatic decompensation or HCC.
2014-08-22 | E-GEOD-54099 | biostudies-arrayexpress
Project description:OBJECTIVE: The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression. DESIGN: We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (>1 mg/dL) and platelet count (<100 000/mm3), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10 years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8 years). RESULTS: In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p<0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p<0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p<0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p<0.001) and all liver-related adverse events (HR=4.98, p<0.001). CONCLUSIONS: A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions.
2014-08-22 | GSE54101 | GEO
Project description:OBJECTIVE: The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression. DESIGN: We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (>1 mg/dL) and platelet count (<100 000/mm3), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10 years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8 years). RESULTS: In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p<0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p<0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p<0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p<0.001) and all liver-related adverse events (HR=4.98, p<0.001). CONCLUSIONS: A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions.
2014-08-22 | GSE54100 | GEO
Project description:OBJECTIVE: The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression. DESIGN: We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (>1 mg/dL) and platelet count (<100 000/mm3), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10 years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8 years). RESULTS: In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p<0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p<0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p<0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p<0.001) and all liver-related adverse events (HR=4.98, p<0.001). CONCLUSIONS: A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions.
2014-08-22 | GSE54099 | GEO
Project description:OBJECTIVE: The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression. DESIGN: We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (>1 mg/dL) and platelet count (<100 000/mm3), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10 years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8 years). RESULTS: In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p<0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p<0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p<0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p<0.001) and all liver-related adverse events (HR=4.98, p<0.001). CONCLUSIONS: A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions. Paired core needle liver biopsy specimens obtained with time interval ranging from 1 month to 7.5 years from three individuals, and liver tissues from right and left lobes of explanted liver with chronic HCV infection from one individual.
2014-08-22 | E-GEOD-54101 | biostudies-arrayexpress
Project description:We used machine-learning algorithms to identify a hypoxia-associated methylation signature in patients with HPV negative HNSCC in the TCGA-HNSCC cohort. This current submission forms the basis of the independent validation cohort used to test the Hypoxia-M classifier in our study.
2023-04-05 | E-MTAB-12431 | biostudies-arrayexpress