Chemotherapy-associated clonal hematopoiesis mutations should be taken seriously in plasma cell-free DNA KRAS/NRAS/BRAF genotyping for metastatic colorectal cancer |
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| Institution: | 1. Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, PR China;2. Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, PR China;3. Department of Laboratory Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, 668 Jin Hu Road, Xiamen 361015, PR China;4. Department of Laboratory Medicine, Wusong Branch, Zhongshan Hospital, Fudan University, 101 Tong Tai North Road, Shanghai 200940, PR China;1. DynaLIFE Medical Labs and University of Alberta Department of Laboratory Medicine and Pathology, Edmonton, AB, Canada;2. St Michael’s Hospital and University of Toronto Department of Medicine, Toronto, ON, Canada;3. Sunnybrook Hospital and University of Toronto Department of Laboratory Medicine and Pathobiology, Toronto, ON, Canada;4. St Michael’s Hospital and University of Toronto Department of Laboratory Medicine and Pathobiology, Toronto, ON, Canada;1. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA;2. New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA;3. Department of Emergency Medicine, Weill Cornell Medicine, New York, NY, USA;4. Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA;5. Departments of Laboratory Medicine and Pathology, Hennepin Healthcare/Hennepin County Medical Center and University of Minnesota, Minneapolis, MN, USA;1. Clinical Laboratory, Hospital Universitari de Sant Joan d’Alacant, Sant Joan d’Alacant, Spain;2. Department of Clinical Medicine, Universidad Miguel Hernández, Elche, Spain;3. Department of Biochemistry and Molecular Pathology, Universidad Miguel Hernandez, Elche, Spain;4. CIBER en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain;5. Department of Radiology, University of Missouri, Columbia, MO, USA;1. Clinical Laboratory, Biochemistry Department, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Sabadell, Spain;2. Paediatrics Department, Parc Taulí Hospital Universitari, Sabadell, Spain |
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| Abstract: | BackgroundGenotyping of plasma cell-free DNA (cfDNA) is an increasingly important method to assess the tumor mutation status in colorectal cancer (CRC) patients. Clonal hematopoiesis (CH) releases non-tumor somatic mutations into blood, causing false positive results in cfDNA-based tumor genotyping. It is still not clear if CH should be examined in all CRC patients undergoing cfDNA analysis.MethodsWe analyzed cfDNA KRAS, NRAS and BRAF genotypes in 236 metastatic CRC patients, who had matched tissue genotyping results, by next-generation sequencing using plasma cfDNA. The cfDNA-only mutations with allele frequencies (AFs) < 5% were highly suspicious for being CH-derived mutations. The origins of cfDNA mutations were confirmed by droplet digital polymerase chain reaction (ddPCR) using paired peripheral blood cells (PBCs) and CH-derived mutations were finally determined. One patient with a CH-derived mutation was followed up and the subpopulation of blood cells, in which CH was present, was investigated.ResultsThree CH-derived mutations, KRAS Q61H, KRAS G12D and KRAS G12V, were identified in the patient cohort. All three patients harboring corresponding CH-derived mutations had a prior chemotherapy history. The CH-derived KRAS G12V mutation in a patient was found only present in lymphocytes and persisting under treatment. For all cfDNA mutations, the CH-derived ones were clustered in the patients with < 5% mutation AF and prior chemotherapy.ConclusionThe prevalence of CH in CRC patients was limited, and prior chemotherapy was a contributing factor of CH. It is recommended for patients with < 5% mutation AF and prior chemotherapy to have genotyping analysis of their PBCs following plasma cfDNA genotyping. |
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| Keywords: | Metastatic colorectal cancer Plasma cell-free DNA Clonal hematopoiesis Next-generation sequencing Droplet digital PCR |
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