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JAMA Oncol. 2018 Nov 1;4(11):1589-1593. doi: 10.1001/jamaoncol.2018.2297.

Prevalence of Clonal Hematopoiesis Mutations in Tumor-Only Clinical Genomic Profiling of Solid Tumors.

Author information

1
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
3
now with Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill.
4
Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York.
5
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York.

Abstract

Importance:

Although clonal hematopoiesis (CH) is well described in aging healthy populations, few studies have addressed the practical clinical implications of these alterations in solid-tumor sequencing.

Objective:

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 based on tumor-only sequencing (unmatched analysis).

Design, Setting, and Participants:

Retrospective analysis of samples from 17 469 patients with solid cancers 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.

Main Outcomes and Measures:

We 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.

Results:

The mean age of the 17 469 patients with cancer at sample collection was 59.2 years (range, 0.3-98.9 years); 53.6% were female. We identified 7608 CH-associated mutations in the blood of 4628 (26.5%) patients. A total of 1075 (14.1%) CH-associated mutations were also detectable in the matched tumor above established thresholds for calling somatic mutations. Overall, 912 (5.2%) patients would have had at least 1 CH-associated mutation erroneously called as tumor derived in the absence of matched blood sequencing. A total of 1061 (98.7%) of these mutations were absent from population scale databases of germline polymorphisms and therefore would have been challenging to filter informatically. Annotating variants with OncoKB classified 534 (49.7%) as oncogenic or likely oncogenic.

Conclusions and Relevance:

This study demonstrates how CH-derived mutations could lead to erroneous reporting and treatment recommendations when tumor-only sequencing is used.

PMID:
29872864
PMCID:
PMC6224316
[Available on 2019-06-05]
DOI:
10.1001/jamaoncol.2018.2297

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