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Molecular Pathology Abstracts

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Editors: Donna E. Hansel, MD, PhD, chief, Division of Anatomic Pathology, and professor, Department of Pathology, University of California, San Diego; James Solomon, MD, PhD, resident, Department of Pathology, UCSD; Charmi Patel, MD, molecular genetic pathology fellow, Department of Pathology, UCSD; and Sounak Gupta, MBBS, PhD, molecular pathology fellow, Memorial Sloan Kettering Cancer Center, New York.


Prevalence of clonal hematopoiesis mutations in tumor-only clinical genomic profiling of solid tumors

August 2018—Challenges to implementing next-generation sequencing-based comprehensive molecular profiling of solid tumors include reliably separating germline variants from somatic variants. This is an important consideration, particularly when a “tumor-only” profiling approach is used. Bioinformatic strategies in this setting involve filtering out germline variants based on annotated population frequencies in public datasets, such as 1000 Genomes, ExAC, and gnomAD, while reporting mutations occurring at cancer-associated hotspots. This study involves next-generation sequencing (NGS)-based profiling of solid tumors from more than 17,000 patients using a paired normal (blood) specimen to filter out germline variants. The results provide valuable insight into the potential pitfalls of molecular profiling using a tumor-only approach. This is highlighted by the documentation of clonal hematopoiesis events in the authors’ institutional clinical sequencing cohort. Clonal hematopoiesis refers to clonal expansion of hematopoietic progenitor cells that have shared molecular alterations; these events are not uncommon in patients with solid tumors. Therefore, the presence of these alterations within tumor-infiltrating lymphocytes might lead to misattributing clonal hematopoiesis alterations as somatic variants in the solid tumor. These misattributions can have significant clinical consequences, particularly for actionable alterations that can be seen in solid tumors and hematologic malignancies. Specific examples documented by the authors include IDH2 p.R140Q alterations, as well as a KRAS p.G12R alteration in a patient with colorectal carcinoma, both of which would alter targeted therapy strategies. Conversely, the authors highlighted scenarios in which the use of a matched normal (blood) sample could lead to misattributing a variant as a germline alteration. For instance, a BRCA2 truncating alteration was detected in a solid tumor and a blood specimen of a patient with melanoma, suggesting a germline alteration. In this case, the sequencing of multiple normal specimens (saliva, buccal swab, non-neoplastic colon tissue) helped correctly attribute this alteration to clonal hematopoiesis. In summary, the authors noted that in the absence of matched normal (blood) sequencing, more than five percent of patients within their clinical sequencing cohort would have had at least one clonal hematopoiesis-related alteration erroneously attributed to the solid tumor. Furthermore, more than 95 percent of the clonal hematopoiesis variants likely would not be filtered out bioinformatically using a tumor-only profiling strategy as they were not present in common public databases.

Ptashkin RN, Mandelker DL, Coombs CC, et al. Prevalence of clonal hematopoiesis mutations in tumor-only clinical genomic profiling of solid tumors [published online June 5, 2018]. JAMA Oncol. doi:10.1001/jamaoncol.2018.2297.

Correspondence: Dr. Ahmet Zehir at zehira@mskcc.org

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