The REASON score: an epigenetic and clinicopathologic score to predict risk of poor survival in patients with early stage oral squamous cell carcinoma

Abstract

Background Oral squamous cell carcinoma (OSCC) is a capricious cancer with poor survival rates, even for early-stage patients. There is a pressing need to develop more precise risk assessment methods to appropriately tailor clinical treatment. Genome-wide association studies have not produced a viable biomarker. However, these studies are limited by using heterogeneous cohorts, not focusing on methylation although OSCC is a heavily epigenetically-regulated cancer, and not combining molecular data with clinicopathologic data for risk prediction. In this study we focused on early-stage (I/II) OSCC and created a risk score called the REASON score, which combines clinicopathologic characteristics with a 12-gene methylation signature, to predict the risk of 5-year mortality. Methods We combined data from an internal cohort (n = 515) and The Cancer Genome Atlas (TCGA) cohort (n = 58). We collected clinicopathologic data from both cohorts to derive the non-molecular portion of the REASON score. We then analyzed the TCGA cohort DNA methylation data to derive the molecular portion of the risk score. Results 5-year disease specific survival was 63% for the internal cohort and 86% for the TCGA cohort. The clinicopathologic features with the highest predictive ability among the two the cohorts were age, race, sex, tobacco use, alcohol use, histologic grade, stage, perineural invasion (PNI), lymphovascular invasion (LVI), and margin status. This panel of 10 non-molecular features predicted 5-year mortality risk with a concordance (c)-index = 0.67. Our molecular panel consisted of a 12-gene methylation signature (i.e., HORMAD2, MYLK, GPR133, SOX8, TRPA1, ABCA2, HGFAC, MCPH1, WDR86, CACNA1H, RNF216, CCNJL), which had the most significant differential methylation between patients who survived vs. died by 5 years. All 12 genes have already been linked to survival in other cancers. Of the genes, only SOX8 was previously associated with OSCC; our study was the first to link the remaining 11 genes to OSCC survival. The combined molecular and non-molecular panel formed the REASON score, which predicted risk of death with a c-index = 0.915. Conclusions The REASON score is a promising biomarker to predict risk of mortality in early-stage OSCC patients. Validation of the REASON score in a larger independent cohort is warranted.

Brush swab as a noninvasive surrogate for tissue biopsies in epigenomic profiling of oral cancer

“…As a result, none of these studies have produced a methylation biomarker with high prognostic performance. We recently used methylation signatures combined with clinicopathologic data to develop a risk score to predict 5-year mortality of early-stage (I/II) OSCC; the risk score accurately predicted mortality with a c-statistic = 0.915 [ 5 ]. The risk score, which we named the REASON score, leveraged the top 12 differentially methylated genes between early-stage OSCC patients who survived vs. died at 5 years after diagnosis.…”

“…The risk score, which we named the REASON score, leveraged the top 12 differentially methylated genes between early-stage OSCC patients who survived vs. died at 5 years after diagnosis. Of note, 11 of the 12 genes had not previously been investigated in OSCC, with our study being the first to correlate differential methylation of these 11 genes with outcomes in OSCC [ 5 ].…”

“…Currently, risk prediction to assign adjuvant treatment is entirely based on clinicopathologic information. Multiple retrospective and prospective studies have shown that these standard clinicopathologic factors have moderate accuracy with a concordance statistic (c-statistic) of 0.7 [ 4 , 5 ]. The key to improving survival in OSCC lies in developing more accurate risk prediction methods, particularly in early stage patients.…”

Risk Stratification in Oral Cancer: A Novel Approach

“…Patients in the low-risk group have localized (stage I/II) disease with 60%–80% 5-year OS ( 20 ). These patients were not advised of any adjuvant radiotherapy by the intra-institutional MDT.…”

Epigenome-wide gene–age interaction study reveals reversed effects of MORN1 DNA methylation on survival between young and elderly oral squamous cell carcinoma patients

“…DNA methylation is a reversible epigenetic modification without changing the DNA sequence ( 5 ). Nevertheless, its aberrant alterations play a decisive role in the occurrence and progression of various cancers ( 6 , 7 ), including OSCC ( 8 ). Emerging evidence has demonstrated that DNA methylation may potentially serve as a prognostic biomarker of OSCC and a target for improved therapy ( 9 , 10 ).…”