Clonal Hematopoiesis Complicates Clinical Genomic Profiling of Solid Tumors

Tuesday, June 5, 2018

Bottom Line:

This study demonstrates how clonal hematopoiesis (CH)–derived mutations could lead to erroneous reporting and treatment recommendations when tumor-only sequencing is employed. If data about the blood are not part of test results, mutations present in the blood may be misread as mutations in the tumor, which can potentially affect the therapies patients receive. Sequencing matched blood alongside tumor samples can be used to distinguish frequent CH somatic mutations from those in the solid tumor cells and therefore more accurately guide precision therapy.

What:

Data presented at the annual meeting of the American Society of Clinical Oncology by Ahmet Zehir, PhD, Director of Clinical Bioinformatics at Memorial Sloan Kettering Cancer Center (MSK). The data were simultaneously published in JAMA Oncology on June 5.

Author Comment:

“As the application of next-generation sequencing technologies continues to expand in clinical settings, it is important to identify sources of potential discrepancies and misleading results. This work shows that you also need to analyze a blood sample if you want to be 100 percent confident in choosing the right therapy,” explained Dr. Zehir. “While these findings add another layer of complexity to precision medicine, our hope is that these data will compel doctors to be more aware of this issue when interpreting tumor-sequencing results, as this is a phenomenon that could affect up to 5 percent of people with advanced cancer.”

Background:

CH explains why cancer mutations may be present in a person’s blood, even in those who don’t have blood cancer. This phenomenon occurs when hematopoietic stem cells — the cells that give rise to all types of blood cells — form a subpopulation of cells that is genetically distinct from the rest of the bloodstream.

MSK-IMPACT™ is MSK’s next-generation sequencing test that looks for mutations in 468 cancer-causing genes in people’s tumors. Unlike some sequencing tests, MSK-IMPACT analyzes a blood sample from each individual in addition to the tumor sample. When tumors are sequenced without matched blood, CH alterations may be misattributed as tumor-derived somatic events. As a subset of CH-derived alterations involve actionable cancer genes, failure to recognize such mutations as blood-derived may lead to erroneous treatment recommendations. While a few reports have showed that CH-derived mutations can contaminate solid tumor sequencing results, a comprehensive analysis has not been reported before.

Methods and Findings:

MSK researchers set out to identify and quantify CH-related mutations in patients with solid tumors using matched tumor-blood sequencing and to establish the proportion that would be misattributed to the tumor from unmatched analysis.

A retrospective analysis of samples was conducted from 17,469 people with solid tumors who underwent prospective clinical sequencing of DNA isolated from tumor tissue and matched peripheral blood using the MSK-IMPACT™ assay between January 2014 and August 2017. The researchers identified the presence of CH-related mutations in each patient’s blood leukocytes and quantified the fraction of DNA molecules harboring the mutation in the corresponding matched tumor sample.

A total of 7,608 CH-associated mutations were identified in the blood of 4,628 patients (26.5 percent). Fourteen percent of CH-associated mutations were also detectable in the matched tumor above established thresholds for somatic mutations. Overall, 5 percent of the patients would have had at least one CH-associated mutation incorrectly identified as tumor-derived in the absence of matched blood sequencing.

These results demonstrate the perils of tumor-only sequencing platforms. If data about the blood are not part of test results, mutations present in the blood may be misread as mutations in the tumor, which can potentially affect the therapies given to patients. In addition, misinterpreting the results could also alter the outcomes of clinical trials for new drugs, if patients are assigned to a trial for a drug targeting a mutation their tumor doesn’t have.