To what extent can clonal hematopoiesis (CH) lead to misclassification of blood-derived somatic mutations as tumor-derived somatic mutations in clinical next-generation sequencing performed in the absence of a matched blood control?
In this gene-sequencing study including a cohort of 17 469 patients with advanced cancer, paired next-generation sequencing results show that 5% of the patients would have at least 1 CH-associated mutation misattributed as tumor derived in the absence of matched blood sequencing.
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; sequencing matched blood can be used to distinguish frequent CH somatic mutations from those in the solid-tumor cells and perhaps lead to more accurate precision therapy.
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.
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.
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.
Ptashkin RN, Mandelker DL, Coombs CC, et al. Prevalence of Clonal Hematopoiesis Mutations in Tumor-Only Clinical Genomic Profiling of Solid Tumors. JAMA Oncol. 2018;4(11):1589–1593. doi:10.1001/jamaoncol.2018.2297
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