626PClonal hematopoiesis mutations in plasma cfDNA RAS/BRAF genotyping of metastatic colorectal cancer

Abstract 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 cell-free DNA (cfDNA) genotyping. Methods We analyzed KRAS, NRAS and BRAF genotypes in plasma and matched tumor tissues of 236 mCRC patients through next-generation sequencing (NGS). Suspected CH mutations were defined as those only present in plasma with variant allelic frequencies (AFs) 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. Two of them had a KRAS G12X and the third had a KRAS Q61H. We did not detect CH-derived NRAS or BRAF mutations. Patients harboring a CH-derived mutation previously received chemotherapy treatment. In one CH-derived KRAS G12X case, the mutation was enriched in lymphocytes and persisted in cfDNA over the course of 4 months of therapy. Conclusions 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. Legal entity responsible for the study The authors. Funding The National Natural Science Foundation of China (81572064, 81772263, 81772511, 81602038), the Key Developing Disciplines of Shanghai Municipal Commission of Health and Family Planning (2015ZB0201), the Projects from the Shanghai Science and Technology Commission (16411952100), the Projects from Zhongshan Hospital, Fudan University (2018ZSLC05). Disclosure All authors have declared no conflicts of interest.