SPECIFIC AIMS Approximately 90% of lung cancer results from smoking. Low Dose Computerized Tomography (LDCT) of smokers can detect lung cancer earlier allowing more effective treatment. But determining which smokers should get LDCT screening is controversial and potentially harmful. Recently, the U.S Preventive Services Task Force (USPSTF) updated their opinion on screening to recommend annual LDCT screening for current or recent smokers between the ages of 50 and 80 who have smoked 20 pack years (PY) or more. In addition, they specifically called for the development of biomarker-based methods to predict who will benefit from screening. Precision Epigenetics may answer this call. In 2012, we showed that DNA methylation at cg05575921, a site in the aryl hydrocarbon receptor repressor (AHRR) gene, predicts smoking status. Since then, over 100 studies have replicated those findings. In 2018, we developed Smoke Signature©, a precise, reference free methylation sensitive digital PCR (MSdPCR) assay for this locus. In peer-reviewed publications, we have shown that the Receiver Operator Characteristic (ROC) area under the curve (AUC) for this assay is 0.984 for daily smokers, the amount of demethylation accurately predicts daily consumption and that the re-methylation response to smoking cessation can be used to monitor success of cessation therapy. Intriguingly, in 2017, Bojesen and colleagues showed that cg05575921 methylation also predicts those smokers likely to benefit from LDCT screening. Recently, we have now confirmed and extended these findings using a subset of DNA specimens from the National Lung Screening Trial (NLST). In particular for those NLST subjects who reported quitting smoking, our method significantly predicts lung cancer risk better than PY alone in a racial and gender-free manner. However, our method is based only the data from 3200 NLST subjects, all of whom smoked 30 PY or more. In this Phase II project, we propose to finish our assessments of the 4800 NLST subjects, all of whom have > 30 PY of consumption and LDCT data, then use DNA from 4800 subjects in x-ray only arm of the NLST and 4800 subjects from the PLCO collection to extend the range of our test down to 20 PY of cigarette consumption. We will then analyze the resulting data and develop a race and SES bias free Cox regression formula to predict risk for those between the ages of 50-80 years and >20 PY of smoking. The resulting laboratory developed test (LDT) will run on the 510K approved Bio-Rad QX-200 platform with reagents from companies that can comply with FDA standards. When implemented, the test will decrease healthcare costs and morbidity and mortality from unnecessary procedures. Eventually, we believe that this test will be essential for both prescreening counselling and treatment monitoring of all smokers.
Public Health Relevance Statement: Narrative The purpose of this application is to complete development of a DNA methylation test can help determine whether a smoker should undergo low dose CT screening for Lung Cancer and if this methylation test can help predict risk for cancer.
Project Terms: ages; Age; Algorithms; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Biopsy; Colon; Counseling; DNA; Deoxyribonucleic Acid; Educational Status; Educational Achievement; educational level; training achievement; training level; training status; Eligibility Determination; Eligibility; Protocol Screening; Genes; Recording of previous events; History; histories; Investments; Laboratories; Lung; Lung Respiratory System; pulmonary; Marketing; Methods; Methylation; Morbidity - disease rate; Morbidity; mortality; Persons; Patients; Peer Review; Production; Property Rights; Prostate; Prostate Gland; Prostatic Gland; Publications; Scientific Publication; Publishing; Race; Races; racial; racial background; racial origin; Reagent; Receiver Operating Characteristics; Receiver Operator Characteristics; Recommendation; Research; Risk; Running; Saliva; Smoke; Smoking; Testing; X-Ray Computed Tomography; CAT scan; CT X Ray; CT Xray; CT imaging; CT scan; Computed Tomography; Tomodensitometry; X-Ray CAT Scan; X-Ray Computerized Tomography; Xray CAT scan; Xray Computed Tomography; Xray computerized tomography; catscan; computed axial tomography; computer tomography; computerized axial tomography; computerized tomography; non-contrast CT; noncontrast CT; noncontrast computed tomography; Work; Roentgen Rays; X-Radiation; X-Ray Radiation; X-ray; Xray; Aryl Hydrocarbon Receptor; 2,3,7,8-Tetrachlorodibenzo-p-dioxin Receptors; AH Receptors; Dioxin Receptors; Nuclear Translocator; Polyaromatic Hydrocarbon Receptors; TCDD Receptors; Gender; cease smoking; quit smoking; stop smoking; smoking cessation; Health Costs; Healthcare Costs; Health Care Costs; Telemedicine; bases; base; improved; Ovarian; Site; Clinical; Phase; Malignant Tumor of the Lung; Pulmonary Cancer; Pulmonary malignant Neoplasm; lung cancer; Malignant neoplasm of lung; lung cancer early detection; lung cancer screening; Intellectual Property; tool; Smoker; Diagnostic; Specimen; Research Specimen; Malignant neoplasm of prostate; Malignant Tumor of the Prostate; Malignant prostatic tumor; Prostate CA; Prostate Cancer; Prostate malignancy; Prostatic Cancer; DNA Methylation; Area Under Curve; Unnecessary Procedures; Clinic; cancer risk; success; demethylation; Cigarette; Participant; Colon Carcinoma; Colon Cancer; cancer in the colon; Reporting; Radiation; response; Manufacturer; Malignant Ovarian Neoplasm; Malignant Ovarian Tumor; Malignant Tumor of the Ovary; Ovary Cancer; ovarian cancer; Malignant neoplasm of ovary; Dose; Data; Detection; International; Collection; Epigenetic Process; Epigenetic; Epigenetic Change; Epigenetic Mechanism; epigenetically; Smoking History; pack/year; Smoking Status; Update; Monitor; Development; developmental; Behavioral; aging effect; age effect; cost; digital; Consumption; innovate; innovative; innovation; commercialization; high risk; effective treatment; effective therapy; arm; screenings; screening; methylation testing; biomarker development; identification of biomarkers; marker identification; biomarker identification; Radiation exposure; low dose computerized tomography; low-dose CT; low dose computed tomography; Predicting Risk; forecasting risk; predict risk; predict risks; predicted risk; predicted risks; predicting risks; predictive risk; predicts risk; risk predictions; risk prediction; United States Preventative Services Task Force; U.S. Preventative Services Task Force; U.S. Preventative Task Force; U.S. Preventive Services Task Force; U.S. Preventive Task Force; US Preventative Services Task Force; US Preventative Task Force; US Preventive Health Services Task Force; US Preventive Services Task Force; US Preventive Task Force; USPSTF; United States Preventative Task Force; United States Preventive Services Task Force; United States Preventive Task Force
