Sequencing Approach to Detect Genomic Alterations

This unprecedented combination of breadth and depth, dubbed “high-intensity” sequencing, yields about 100 times more data than other sequencing approaches.

Molecular biologists at the Memorial Sloan Kettering Cancer Center (MSK, New York, NY, USA) collected blood from 124 evaluable patients with metastatic breast, non-small cell lung, or prostate cancer. To confirm that the high-intensity sequencing approach was detecting DNA shed by the tumor, the team then compared the alterations identified in the cfDNA with those identified in each person’s tumor tissue by MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), a powerful 410-gene diagnostic test. This test was developed at MSK and provides detailed genomic information about a person’s cancer and is used to analyze tumors from most people with advanced cancer treated at MSK. To date, more than 10,000 tumors have been sequenced using MSK-IMPACT, and this data is made available to the larger scientific community via a database developed at MSK called cBioPortal.

The investigators detected 864 clonal and subclonal genomic alterations in tissue samples across the three tumor types, and 627 (73%) of these alterations were found in the blood. Clonal alterations were significantly more likely to be detected in the cfDNA than subclonal alterations. In 89% of the study’s patients, at least one of the alterations identified in the tumor tissue was also found in the blood, 97% for those with metastatic breast cancer, 85% for those with non-small cell lung cancer, and 84% for those with metastatic prostate cancer. Most actionable mutations detected in tissue were also detected previously in the blood (76%).

Pedram Razavi, MD, PhD, a medical oncologist and lead investigator, said, “Prior studies in this field has primarily focused on using knowledge from tumor tissue sequencing to choose which specific changes to test for in cell-free DNA or to cover small portions of genome suitable for detection of actionable alterations. But at the earliest stages of cancer, a doctor would not necessarily know which alterations to look for. Our findings demonstrate that a high-intensity sequencing approach allows us to detect, with high confidence, changes in cfDNA across a large part of the genome without information from tumor tissue.” The study was presented at the American Society of Clinical Oncology (ASCO) Annual Meeting on June 3, 2017, held in Chicago, IL, USA.

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Memorial Sloan Kettering Cancer Center