Clonal hematopoiesis mutations in plasma cfDNA RAS/BRAF genotyping of metastatic colorectal cancer.

• DOI: 10.1200/jco.2019.37.15_suppl.e15083
• Publication Date: 2019-05-27T16:06:12Z
• Authors: Beili Wang; Fei Huang; Minna Shen; Shengchao Wu; Qian Yu; Huiqin Jiang; Yiyi Yu; Yihui Yang; Ying Zhao; Yiwen Zhou; Baishen Pan; Tianshu Liu; Wei Guo
• Keywords: 03 medical and health sciences; 0302 clinical medicine; 3. Good health

e15083 Background: Clonal hematopoiesis (CH) leads to blood-derived somatic mutations in KRAS, NRAS and BRAF. Our aim is to identify the prevalence of CH-derived mutations in these three genes in metastatic colorectal cancer (mCRC) patients and reveal the practical clinical implication of these mutations on plasma genotyping. Methods: We analyzed KRAS, NRAS and BRAF genotypes in plasma and matched tumor tissues of 236 mCRC patients through next-generation sequencing (NGS) and polymerase chain reaction. Suspected CH mutations were defined as those only detected in plasma with variant allelic frequencies (AFs) of <5% and were confirmed by paired peripheral blood cells (PBCs) using droplet digital PCR (ddPCR). The hemopoietic lineage harboring a CH-derived mutation was analyzed through flow cytometry. Results: We identified suspected CH mutations in twenty patients (8.4%, 20/236). Three of these patients (1.27%, 3/236) had a CH-derived KRAS mutation, which was confirmed present in paired PBCs. Two of them had a KRAS G12X and the third had a KRAS Q61H. We did not detect CH-derived NRAS or BRAF mutations in our cohort. All three patients harboring a CH-derived mutation previously received chemotherapy treatment. In a selected CH-derived KRAS G12X case, the mutation was enriched in lymphocytes and persisted in plasma cell-free DNA (cfDNA) over the course of 4 months of therapy. Conclusions: In summary, we confirmed the existence of CH-derived KRAS mutations in a small proportion of mCRC patients. This should be noted to prevent misclassification as tumor somatic mutations when performing cfDNA sequencing in the absence of genotyping matched PBCs.