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Article: Same-Cell Co-Occurrence of RAS Hotspot and BRAF V600E Mutations in Treatment-Naive Colorectal Cancer

TitleSame-Cell Co-Occurrence of RAS Hotspot and BRAF V600E Mutations in Treatment-Naive Colorectal Cancer
Authors
Issue Date2022
Citation
JCO Precis Oncol, 2022, v. 6, p. e2100365 How to Cite?
AbstractPURPOSE: 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.
Persistent Identifierhttp://hdl.handle.net/10722/315050
ISSN
2023 Impact Factor: 5.3
2023 SCImago Journal Rankings: 2.249
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorGularte-Merida, R-
dc.contributor.authorSmith, S-
dc.contributor.authorBowman, AS-
dc.contributor.authorda Cruz Paula, A-
dc.contributor.authorChatila, W-
dc.contributor.authorBielski, CM-
dc.contributor.authorVyas, M-
dc.contributor.authorBorsu, L-
dc.contributor.authorZehir, A-
dc.contributor.authorMartelotto, LG-
dc.contributor.authorShia, J-
dc.contributor.authorYaeger, R-
dc.contributor.authorFang, F-
dc.contributor.authorGardner, R-
dc.contributor.authorLuo, R-
dc.contributor.authorSchatz, MC-
dc.contributor.authorShen, R-
dc.contributor.authorWeigelt, B-
dc.contributor.authorSanchez-Vega, F-
dc.contributor.authorReis-Filho, JS-
dc.contributor.authorHechtman, JF-
dc.date.accessioned2022-08-05T09:39:18Z-
dc.date.available2022-08-05T09:39:18Z-
dc.date.issued2022-
dc.identifier.citationJCO Precis Oncol, 2022, v. 6, p. e2100365-
dc.identifier.issn2473-4284-
dc.identifier.urihttp://hdl.handle.net/10722/315050-
dc.description.abstractPURPOSE: 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.-
dc.languageeng-
dc.relation.ispartofJCO Precis Oncol-
dc.titleSame-Cell Co-Occurrence of RAS Hotspot and BRAF V600E Mutations in Treatment-Naive Colorectal Cancer-
dc.typeArticle-
dc.identifier.emailLuo, R: rbluo@cs.hku.hk-
dc.identifier.authorityLuo, R=rp02360-
dc.identifier.doi10.1200/PO.21.00365-
dc.identifier.hkuros335144-
dc.identifier.volume6-
dc.identifier.spagee2100365-
dc.identifier.epagee2100365-
dc.identifier.isiWOS:000771048900010-

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