Colorectal cancer (CRC) is often curable and preventable using current screening modalities. Unfortunately, screening compliance remains low, partly due to patient dissatisfaction with faecal/endoscopic testing. Recent guidelines advise CRC screening should begin with risk stratification. A blood-based test providing clinically actionable CRC risk information would likely improve screening compliance and enhance clinical decision making. We analyzed 196 gene expression profiles to select candidate CRC biomarkers. qRT-PCR was performed on 642 samples to develop a 7-gene biomarker panel using 112 CRC/120 controls (training set) and 202 CRC/208 controls (independent, blind test set). Panel performance characteristics and disease prevalence (0.7%) were then used to develop a scale assessing an individual's current risk of having CRC based on his/her gene signature. A 7-gene panel (ANXA3, CLEC4D, LMNB1, PRRG4, TNFAIP6, VNN1 and IL2RB) discriminated CRC in the training set (area under the receiver-operating-characteristic curve (ROC AUC), 0.80; accuracy, 73%; sensitivity, 82%; specificity 64%). The independent blind test set confirmed performance (ROC AUC, 0.80; accuracy, 71%; sensitivity, 72%; specificity, 70%). Individual gene profiles were compared against the population results and used to calculate the current relative risk for CRC. We have developed a 7-gene, blood-based biomarker panel that can stratify subjects according to their current relative risk across a broad range in an average-risk population. Across the continuous spectrum of risk as defined by the current relative risk scale, it is possible to identify clinically meaningful reference points that can assist patients and physicians in CRC screening decision making.Colorectal cancer (CRC), the third most frequently diagnosed cancer in men and women in the United States and the United Kingdom, carries an overall population lifetime risk of about 5%. 1,2 Despite being among the most preventable of neoplasms and surgically curable in early stages, cancer of the colon and rectum remains the second leading cause of cancer death in the western world. In the United States, $150,000 people will be diagnosed with CRC in 2008 and some 50,000 will die of their disease. 1 Each year in the United Kingdom, about 36,500 people receive a diagnosis of CRC and some 16,000 die of it. 2 Most CRC arises from precursor adenomatous polyps, developing over many years. 3 Stage at detection is critically related to patient survival. Localized cancers (tumor-nodemetastasis [TNM] Stages IÀII) have an excellent 5-year survival prognosis (93% and 83%); regional stage (TNM Stage III) patients have a 5-year survival rate about 60%; only 8% of patients with late stage (TNM Stage IV) disease will survive 5 years. 4 These features make CRC eminently suitable for a screening program, and health authorities have long promoted screening for CRC in average-risk adults, beginning at the age of 50 years. 1,5,6 Despite repeated recommendations and awareness campaigns, however, populations have...