Project Grant R43CA257372

A DNA METHYLATION TEST FOR GUIDING LUNG CANCER SCREENING - LUNG CANCER KILLS 150,000 AMERICANS AND IS RESPONSIBLE FOR 150 BILLION DOLLARS OF ECONOMIC DAMAGE ANNUALLY. THE LARGEST RISK FACTOR FOR LUNG CANCER IS SMOKING. WHEN TOBACCO CONTROL EFFORTS FAIL, EARLY DETECTION AND TREATMENT OF LUNG CANCER OFFER THE BEST HOPE FOR SURVIVAL. THE NATIONAL LUNG SCREENING TRIAL (NLST) ENROLLED 53,454 SUBJECTS WHO REPORTED A CIGARETTE HISTORY OF AT LEAST 30 PACK YEARS AND SHOWED THAT LDCT SCREENING PREVENTED 3 LUNG CANCER DEATHS FOR EVERY 1,000 SCREENED SUBJECTS, A 16% RISK REDUCTION. HOWEVER, NEARLY 40% OF LDCT SUBJECTS HAD AN ABNORMAL SCAN WITH A FALSE DISCOVERY RATE OF 97%, PLACING MANY PATIENTS AT RISK FOR UNNECESSARY ADDITIONAL RADIATION EXPOSURE AND COMPLICATIONS FROM INVASIVE DIAGNOSTIC PROCEDURES. THE INCORPORATION OF DNA METHYLATION ASSESSMENTS MAY IMPROVE THE LDCT SCREENING PROCESS BY PROVIDING A BETTER ESTIMATE OF WHO MAY BENEFIT. IN BRIEF, THE CURRENT METHOD FOR EVALUATING WHETHER A PATIENT NEEDS LDCT, REFERRED TO AS THE PLCOM2012 MODE, USES THE OFTEN-UNRELIABLE VARIABLE OF SELF-REPORTED CIGARETTE CONSUMPTION. HOWEVER, BEHAVIORAL DIAGNOSTICS HAS DEVELOPED AN EPIGENETIC ASSAY THAT OBJECTIVELY DETERMINES SMOKING INTENSITY. USING A SIMILAR, YET LESS PRECISE QUANTITATIVE PCR ASSAY, BOJESEN AND COLLEAGUES STUDIED 2,576 LDCT SCREENING-ELIGIBLE SMOKERS IN THE COPENHAGEN CITY STUDY. THEY FOUND THAT DNA METHYLATION STATUS AT CG05575921 STRONGLY PREDICTED WHICH SMOKERS WOULD BENEFIT FROM LDCT SCREENING. INDEED, IN THEIR STUDY, THIS EPIGENETIC MARKER OF SMOKING OUTPERFORMED THE ENTIRE PLCOM2012 MODEL IN PREDICTING CANCER RISK AND SHOWED THAT OVER 20% OF THOSE WHO WOULD NORMALLY QUALIFY FOR LDCT SCREENING HAD NO PROSPECT OF BENEFITTING FROM SCREENING. IN THIS R43 PROPOSAL, WE WILL MEASURE CG05575921 METHYLATION IN 3200 SUBJECTS FROM THE NLST AND TEST WHETHER INCORPORATING CG05575921 METHYLATION STATUS INTO THE PLCOM2012 LUNG CANCER RISK MODEL IMPROVES PREDICTION. WE HYPOTHESIZE THAT DNA METHYLATION AT CG05575921 WILL PREDICT LUNG CANCER OCCURRENCE AND IDENTIFY A POPULATION OF SMOKERS WHO ARE UNLIKELY TO BENEFIT FROM LDCT SCREENING. THIS PROJECT WILL HAVE HIGH COMMERCIAL IMPACT BECAUSE IT MAY LEAD TO A MARKED DECREASE IN UNNECESSARY SCREENING. THE TEAM IS HIGHLY QUALIFIED. IT IS LED BY THE CEO OF BEHAVIORAL DIAGNOSTICS WHO INVENTED THE ASSAY AND THE COMPANY CONTROLS ALL NECESSARY IP. HE WILL BE ASSISTED BY DR. JEFF LONG, A BIOSTATISTICIAN WITH AN INTERNATIONAL REPUTATION FOR CONDUCTING BIOMARKER ANALYSES, AND A TEAM OF PULMONOLOGISTS, ETHICISTS AND OTHER SCIENTISTS. IT IS INNOVATIVE BECAUSE EPIGENETIC SCREENING IS RELATIVELY NEW TO CANCER SCREENING. IT IS FEASIBLE BECAUSE THE DNA AND CLINICAL INFORMATION HAS ALREADY BEEN COLLECTED. IF SUCCESSFUL, THE PATHWAY TO THE R44 EXTENSION, AND EVENTUALLY THE CLINIC, IS CLEAR-CUT BECAUSE THE ASSAY IS ALREADY MANUFACTURED UNDER GMP CONDITIONS, THE DIGITAL PCR PLATFORM IS ALREADY 510K APPROVED, WE HAVE COLLABORATORS HAVE EXPERIENCE WITH THE FDA SUBMISSION PROCESS, AND THE ECONOMICS DRIVING MARKET ADAPTION ARE ALREADY IN PLACE.