LINE-1 methylation as survival predictive factor in patients with stage III-IV oropharyngeal squamous cell carcinoma
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ABSTRACT:
PROVIDER: PRJEB55179 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR10031366_1.fastq.gz | Fastqsanger.gz | |||
| ERR10031366_2.fastq.gz | Fastqsanger.gz | |||
| ERR10031367_1.fastq.gz | Fastqsanger.gz | |||
| ERR10031367_2.fastq.gz | Fastqsanger.gz | |||
| ERR10031368_1.fastq.gz | Fastqsanger.gz |
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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: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.
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Project description:Background: The incidence of human papillomavirus (HPV) associated oropharyngeal carcinomas has increased rapidly over the last thirty years. These tumours behave as a distinct biological entity when compared to classical smoking- and alcohol-related disease. To gain more information regarding the pathway through pre-malignancy in HPV positive/HPV negative oropharyngeal carcinoma (OSCC), we investigated genomewide expression profiles in histopathologically confirmed tumour samples with site-matched normal epithelial controls. Methods: Twenty-four patients with primary oropharyngeal squamous cell carcinoma (4 with stage III and 20 with stage IV disease) were included in this prospective clinical trial (UKCRN11945). The tumour tissues were each assessed by a histopathologist with HPV status and typing by p16INK4A, consensus PGMY PCR, type-specific HPV16 DNA & RNA PCR and DNA sequencing. Fresh tissue samples were subjected to whole transcriptome analysis using the Illumina Bead Array (~47,000 transcripts) and the results validated with quantitative Real Time-PCR (qRT-PCR). In a separate cohort of twelve OSCC patients, laser capture micro-dissection of formalin fixed paraffin embedded (FFPE) tissue allowed RNA extraction from regions of in situ malignant change (with matched normal and invasive SCC samples). Results: The majority of OSCC patients (28/36) displayed evidence of high risk HPV positivity. Predictable fold changes of RNA expression in HPV-associated disease included multiple transcripts within the p53 oncogenic pathway (e.g. CDKN2A/CCND1). Other candidate transcripts found to have altered levels of expression in this study have not previously been established in HPV16 associated oropharyngeal cancer. These were involved in cell differentiation, proliferation and invasion and demonstrated considerable overlap with expression analysis data in other oncogenic pathways (SFRP1/CRCT1/DLG2/SYCP2/CRNN). SYCP2 showed the highest consistent fold change from baseline in both fresh frozen and FFPE tissue (qRT-PCR fresh frozen tissue [P<0.04]; FFPE tissue pre-invasive [P<0.01]; FFPE tissue invasive [P<0.01]), and aberrant expression of this meiosis-specific protein may contribute to genetic instability during HPV-associated cancer development. Conclusion: Investigation of differentially expressed genes in HPV-positive tumours may reveal unique pathways that can explain their different natural history and biological properties. The data from this study reveal SYCP2 (amongst others) as a potential biomarker in HPV positive oropharyngeal carcinoma, and if corroborated on a larger scale, may facilitate the development of a non-invasive screening tool. Twenty four samples (12 matched invasive oropharyngeal carcinoma and normal epithelial controls).
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2008-06-12 | E-GEOD-1993 | biostudies-arrayexpress