ABSTRACT
Oral
Americans
diagnosis,
early
like
used
clinical,
There
defined
features,
performance
methylation
retrospective
methylation
Epigenetic
personalized
with
construct
patients
squamous cell carcinoma (OSCC) is on the rise, increasing by two-thirds in 20 years. Each year 30,000
are diagnosed with OSCC, and 50% of these cases are early stage I/II. Despite the early stage at
these patients suffer from significant morbidity, and a 5-year mortality rate of 40%. Treatment for
stage OSCC is highly variable, ranging from just cancer resection, to the addition of adjuvant treatments
elective neck dissection (END), radiotherapy (RT), or chemoradiation (chemoRT). While stage is primarily
to assess risk and assign adjuvant treatment, its prognostic value is low. There is currently no reliable
histologic or molecular marker to determine individual risk in patients within the same cancer stage.
is a need to develop a r obust prognostic biomarker to guide treatment and improve survival. We recently
a mortality risk score for early stage OSCC patients, composed of methylation and clinicopathologic
using a discovery cohort and The Cancer Genome Atlas (TCGA) data, which has strong predictive
to identify patients at high risk of death in 5 years. In this application, we propose to validate this
biomarker in early stage OSCC patients with known 5-year survival from a multi-institutional
cohort of formalin-fixed, paraffin embedded (FFPE) tissues. We will combine our validated
(molecular) biomarker with clinicopathologic (non-molecular) markers to construct the high-Risk
And clinicopathologic Score for Oral caNcer ( REASON ) score. We hypothesize that this
score wil accurately predict the risk of 5-year cancer-specific mortality . The study will proceed
three aims. Firstly, we will perform an epigenome wide association study ( EWAS) using the EPIC array, to
and validate the REASON score with a retrospective cohort (cohort 1, n=400) of early stage OSCC
with known 5-year survival outcome, who underwent cancer resection only. Secondly,
l
we will apply
the REASON score to a separate retrospective cohort (cohort 2, n=400) of early stage OSCC patients who
underwent adjuvant treatments (i.e., END, RT, chemoRT) in addition to cancer resection. We will determine
whether these adjuvant treatments confer a survival advantage in high risk (high REASON score) patients over
cancer resection alone. We will also determine whether these adjuvant treatments could be spared in low risk
(low REASON score) patients.
in
certifiable
collect
signatures
prognostic
assembles
clinically
We will also perform technical validation of the methylation features discovered
the EWAS with MethylCap-Seq (MC-Seq), a robust, Clinical Laboratory Improvement Amendments (CLIA)
platform. Lastly, in an exploratory aim, we will prospectively enroll early stage OSCC patients and
noninvasive brush swabs and cancer tissues. We will determine the concordance of methylation
between paired brush swabs and cancer tissues in these patients using MC-Seq, and determine the
performance of the REASON score in this prospective cohort (cohort 3, n=200). This study
the largest cohort (n=1000) early stage OSCC patients to date, and is expected to produce a
robust mortality risk score.
