A new DNA sequencing-based method could help noninvasively detect early stage cancers by analyzing fragments of genetic material circulating in the blood that originate from tumors. The findings may pave the way to more useful screening and management tools for patients with cancer. More than 14 million people globally are diagnosed with cancer every year, and most cases aren't detected until the disease has progressed to late stages with few treatment options. As such, early detection and clinical interventions for colorectal, ovarian, lung, and breast cancers might save as many as one million lives annually. Jillian Phallen and colleagues developed an ultrasensitive approach to identify molecular signatures of cancer from small pieces of genetic material released by cancer cells into the bloodstream called circulating tumor DNA (ctDNA). Plasma from 194 patients with colorectal, ovarian, lung, and breast cancers frequently contained ctDNA with mutations in one or more of 58 so-called cancer driver genes, unlike samples from 44 healthy individuals. Because ctDNA comprises a tiny fraction of the total DNA present in the blood (called cell-free DNA, or cfDNA), the scientists developed a new sample-preparation and computational analysis pipeline, which they dubbed TEC-Seq. By sequencing every molecule tens of thousands of times, the researchers picked out ctDNA and distinguished between cancer-associated alterations and normal variation in cfDNA with a false positive rate of fewer than one per three million DNA base pairs. On average, cancer patients had over four times more cfDNA in their blood overall as compared to healthy subjects, and increased levels correlated with more aggressive disease. The authors say analyzing a broader panel of driver genes may further boost the sensitivity and specificity of TEC-Seq.