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

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.

SUBMITTER: Ptashkin RN

PROVIDER: S-EPMC6224316 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceUse of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain.ObjectiveTo determine which patients derived the greatest degree of clinical benefit from NGS profiling.Design, setting, and participantsPatients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020.Main outcomes and measuresPatients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer.ResultsDuring the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses.Conclusions and relevanceThe high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.

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

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