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Epigenetic modification of SALL1 as a novel biomarker for the prognosis of early stage head and neck cancer.

ABSTRACT: This study examined Sal-like protein (SALL)1 methylation profiles in head and neck squamous-cell carcinoma (HNSCC) patients at diagnosis and follow-up, and evaluated their prognostic significance and value as a biomarker. SALL1 expression was examined in a panel of cell lines by quantitative reverse transcription PCR (qRT-PCR). Promoter methylation was determined by quantitative methylation-specific polymerase chain reaction (qMSP) and was compared to the clinical characteristics of 205 samples. SALL1 promoter methylation was associated with transcriptional inhibition and was correlated with disease recurrence in 31.7% of cases, with an odds ratio of 1.694 (95% confidence interval: 1.093-2.626; P = 0.018) by multivariate Cox proportional hazard regression analysis. SALL1 promoter hypermethylation showed highly discriminatory receiver operator characteristic curve profiles that clearly distinguished HNSCC from adjacent normal mucosal tissue, and was correlated with reduced disease-free survival in early stage T1 and T2 patients (log-rank test, P < 0.001). SALL1 methylation was significantly correlated with the methylation status of both SALL3 and CDH1. This study suggests that CpG hypermethylation is a likely mechanism of SALL1 gene inactivation, supporting the hypothesis that SALL1 might play a role in HNSCC tumorigenesis and could serve as an important biomarker.

SUBMITTER: Misawa K

PROVIDER: S-EPMC5868161 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Epigenetic modification of SALL1 as a novel biomarker for the prognosis of early stage head and neck cancer.

Misawa Kiyoshi K Misawa Yuki Y Imai Atsushi A Mochizuki Daiki D Endo Shiori S Mima Masato M Ishikawa Ryuji R Kawasaki Hideya H Yamatodani Takashi T Kanazawa Takeharu T

Journal of Cancer 20180228 6

This study examined Sal-like protein (SALL)1 methylation profiles in head and neck squamous-cell carcinoma (HNSCC) patients at diagnosis and follow-up, and evaluated their prognostic significance and value as a biomarker. SALL1 expression was examined in a panel of cell lines by quantitative reverse transcription PCR (qRT-PCR). Promoter methylation was determined by quantitative methylation-specific polymerase chain reaction (qMSP) and was compared to the clinical characteri ...[more]

PMID: 29581773

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Project description:BackgroundChronic inflammation is a risk factor for head and neck squamous cell carcinoma (HNSCC) and other diseases. Prostanoid receptors are clearly involved in the development of many types of cancer. However, their role is not simple and is poorly understood in HNSCC.MethodsMethylation profiles of prostanoid receptor family genes were generated for tumour samples obtained from 274 patients with HNSCC, including 69 hypopharynx, 51 larynx, 79 oral cavity, and 75 oropharynx tumour samples, by quantitative methylation-specific PCR. Promoter methylation was then evaluated with respect to various clinical characteristics and patient survival.ResultsThe mean number of methylated genes per sample was 2.05 ± 2.59 (range 0 to 9). Promoters of PTGDR1, PTGDR2, PTGER1, PTGER2, PTGER3, PTGER4, PTGFR, PTGIR, and TBXA2R were methylated in 43.8%, 18.2%, 25.5%, 17.5%, 41.2%, 8.0%, 19.3%, 20.4%, and 11.3% of the samples, respectively. Methylation indices for prostanoid receptor family genes tended to be higher as the number of TET methylation events increased. Patients with 5-9 methylated genes had a significantly lower survival rate than that of patients with 0-4 methylated genes (log-rank test, P= 0.007). In multivariate analyses, PTGDR1 methylation was most highly correlated with recurrence in patients with hypopharyngeal cancer (P = 0.014). A similar correlation was observed for PTGER4 in patients with laryngeal cancer (P = 0.046). Methylation of the PTGIR and TBXA2R promoters was positively correlated with recurrence in oropharyngeal cancer (P = 0.028 and P = 0.006, respectively). Moreover, Patients with 5-9 methylated genes were extremely lower of 5hmC levels (P = 0.035) and was correlated with increasing expression of DNMT3A and DNMT3B (P < 0.05 and P < 0.05, respectively).ConclusionWe characterised the relationship between the methylation status of prostanoid receptor genes and recurrence in HNSCC. These results provide new perspectives for the development of molecular targeted treatment approaches.

Project description:The negative impact of tumor hypoxia on radiotherapeutic efficacy is well recognized. However, an easy to use, reliable imaging method for assessment of tumor oxygenation in routine clinical practice remains elusive. Photoacoustic imaging (PAI) is a relatively new imaging technique that utilizes a combination of light and ultrasound (US) to enable functional imaging of tumor hemodynamic characteristics in vivo. Several clinical trials are currently evaluating the utility of PAI in cancer detection for breast, thyroid, and prostate cancer. Here, we evaluated the potential of PAI for rapid, label-free, non-invasive quantification of tumor oxygenation as a biomarker of radiation response in head and neck cancer. Methods: Studies were performed human papilloma virus- positive (HPV+) and -negative (HPV-) patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma (HNSCC). PAI was utilized for longitudinal assessment of tumor hemodynamics (oxygenation saturation and hemoglobin concentration) before, during and after fractionated radiation therapy (fRT). Imaging datasets were correlated with histologic measures of vascularity (CD31), DNA damage (phosphorylated ?H2AX) and statistical modeling of tumor growth. Results: A differential response to fRT was observed between HPV+ and HPV- xenografts. Temporal changes in tumor hemodynamics (oxygen saturation and hemoglobin concentration) measured by PAI showed significant association with treatment outcomes. PAI-based changes in oxygen saturation were detected within days after initiation of fRT prior to detectable change in tumor volume, highlighting the potential of PAI to serve as an early biomarker of therapeutic efficacy. Consistent with PAI results, immunohistochemical staining of vascularity (CD31) and DNA damage (phosphorylated ?H2AX) revealed distinct patterns of response in HPV+ and HPV- xenografts. Conclusion: Collectively, our observations demonstrate the utility of PAI for temporal mapping of tumor hemodynamics and the value of PAI read-outs as surrogate measures of radiation response in HNSCC.

Project description:The PD-1 receptor and its ligands PD-L1 and PD-L2 are known to be significantly involved in T-cell regulation. Recent studies suggest that PD-L1 expression in malignant tumors contributes to an immunosuppressive microenvironment and disruption of antitumoral immune response. Drugs targeting this pathway are already tested in clinical trials against several tumor entities with promising results. However, until now comprehensive data with regard to PD-L1 and PD-L2 expression in head and neck squamous cell carcinoma (HNSCC) is still lacking.We assessed PD-L1 and PD-L2 expression via immunohistochemistry in two independent cohorts of 293 HNSCC patients.A significant subset of HNSCC showed high expression levels of PD-L1. Most remarkable, we detected a strong correlation between PD-L1 expression and overall survival time in both HNSCC cohorts. Further, in multivariate cox proportional hazard models, PD-L1 dominates as the strongest prognostic factor of patient's outcome in HNSCC, leaving even tumor stage and distant metastasis behind. Moreover, strong PD-L1 expression was associated with the presence of distant metastases in a subset of cases.In summary, while the significance of PD-L2 in HNSCC seems to minor, we show that PD-L1 expression is common in HNSCC and, more importantly, a both robust and strong prognostic biomarker. In this respect, our results provide hints on further application of therapies targeting the PD-1/PD-L1 pathway in HNSCC. Investigation of response and outcome of patients receiving anti-PD-1/PD-L1 containing therapies in correlation with PD-L1 expression analysis should be an important task for the future.In spite of improved treatment options and increasing knowledge of molecular alterations in HNSCC, the survival rate has not been dramatically changed in the past decades. Pies are missing in HNSCC. One promising candidate in cancer immune therapy is PD-L1. Drugs targeting PD-L1 or its receptor PD-1 are subject of several clinical studies in different cancer entities. However, comprehensive data about PD-L1 expression in HNSCC and therefore a rational basis for anti PD-L1/PD-1 therapy in HNSCC is lacking. Here, we provide wide-ranging data about PD-L1 expression in HNSCC of all major localizations. We observed a strong correlation between expression of PD-L1 and reduced overall survival time. Furthermore, high PD-L1 expression was identified as a strong prognostic factor of patient's outcome when verified together with recognized prognostic factors.

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Epigenetic modification of SALL1 as a novel biomarker for the prognosis of early stage head and neck cancer.

Publications

Epigenetic modification of <i>SALL1</i> as a novel biomarker for the prognosis of early stage head and neck cancer.

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