Direct detection of early-stage cancers using circulating tumor DNA

Abstract

Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with stage I or II disease. Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients. In patients with resectable colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival. These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer.

Detection and localization of surgically resectable cancers with a multi-analyte blood test

“…New blood tests for cancer must have very high specificity; otherwise, too many healthy individuals will receive positive test results, leading to unnecessary follow-up procedures and anxiety. Blood tests that detect somatic mutations ( “ liquid biopsies ” ) offer the promise of exquisite specificity because they are based on driver gene mutations that are expected to be found only in abnormal clonal proliferations of cells, such as cancers (11–18). To date, the vast majority of cancer patients evaluated with mutation-based liquid biopsies have advanced-stage disease.…”

Possible application of circulating free tumor DNA in non-small cell lung cancer patients

“…Furthermore, platelet RNA biomarker signatures can be altered in the presence of cancer and can be used for cancer detection (64,65). Other investigators have also shown that detection of cancer at early stages is feasible using cfDNA (66). Several research and development efforts regarding liquid biopsy diagnostics exist throughout Europe and the US, but they lack an integration of concepts, including, discovery, development, standardization, clinical validation and implementation.…”

Molecular genetic testing methodologies in hematopoietic diseases: current and future methods

“…Currently, there is much ongoing study and promise for cfDNA in lymphomas, plasma cell neoplasms, and even in leukemias. The concentration of cfDNA, or this circulating tumor DNA (ctDNA) in the case of cancer patients, is typically several fold higher (10‐200 ng/mL) compared to a healthy controls (1‐20 ng/mL) . Though cfRNAs are yet to gain as much prominence as cfDNAs, they are found to play an important role in certain cancers such as prostate cancers .…”