Synapse - Same-cell co-occurrence of RAS hotspot and BRAF V600E mutations in treatment-naive colorectal cancer

Same-cell co-occurrence of RAS hotspot and BRAF V600E mutations in treatment-naive colorectal cancer Journal Article

Authors:	Gularte-Mérida, R.; Smith, S.; Bowman, A. S.; da Cruz Paula, A.; Chatila, W.; Bielski, C. M.; Vyas, M.; Borsu, L.; Zehir, A.; Martelotto, L. G.; Shia, J.; Yaeger, R.; Fang, F.; Gardner, R.; Luo, R.; Schatz, M. C.; Shen, R.; Weigelt, B.; Sánchez-Vega, F.; Reis-Filho, J. S.; Hechtman, J. F.
Article Title:	Same-cell co-occurrence of RAS hotspot and BRAF V600E mutations in treatment-naive colorectal cancer
Abstract:	PURPOSE Mitogen-activated protein kinase pathway–activating mutations occur in the majority of colorectal cancer (CRC) cases and show mutual exclusivity. We identified 47 epidermal growth factor receptor/BRAF inhibitor-naive CRC patients with dual RAS hotspot/BRAF V600E mutations (CRC-DD) from a cohort of 4,561 CRC patients with clinical next-generation sequencing results. We aimed to define the molecular phenotypes of the CRC-DD and to test if the dual RAS hotspot/BRAF V600E mutations coexist within the same cell. MATERIALS AND METHODS We developed a single-cell genotyping method with a mutation detection rate of 96.3% and a genotype prediction accuracy of 92.1%. Mutations in the CRC-DD cohort were analyzed for clonality, allelic imbalance, copy number, and overall survival. RESULTS Application of single-cell genotyping to four CRC-DD revealed the co-occurrence of both mutations in the following percentages of cells per case: NRAS G13D/KRAS G12C, 95%; KRAS G12D/NRAS G12V, 48%; BRAF V600E/KRAS G12D, 44%; and KRAS G12D/NRAS G13V, 14%, respectively. Allelic imbalance favoring the oncogenic allele was less frequent in CRC-DD (24 of 76, 31.5%, somatic mutations) compared with a curated cohort of CRC with a single-driver mutation (CRC-SD; 119 of 232 mutations, 51.3%; P = .013). Microsatellite instability–high status was enriched in CRC-DD compared with CRC-SD (23% v 11.4%, P = .028). Of the seven CRC-DD cases with multiregional sequencing, five retained both driver mutations throughout all sequenced tumor sites. Both CRC-DD cases with discordant multiregional sequencing were microsatellite instability–high. CONCLUSION Our findings indicate that dual-driver mutations occur in a rare subset of CRC, often within the same tumor cells and across multiple tumor sites. Their presence and a lower rate of allelic imbalance may be related to dose-dependent signaling within the mitogen-activated protein kinase pathway. © 2022 by American Society of Clinical Oncology
Journal Title:	JCO Precision Oncology
Volume:	6
ISSN:	2473-4284
Publisher:	American Society of Clinical Oncology
Date Published:	2022-03-02
Start Page:	e2100365
Language:	English
DOI:	10.1200/po.21.00365
PROVIDER:	scopus
PMCID:	PMC8906458
PUBMED:	35235413
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85127605439&doi=10.1200%2fPO.21.00365&partnerID=40&md5=dbdf27bb1e6b7dd64384fd789c20e258
Notes:	Article -- Export Date: 2 May 2022 -- Source: Scopus