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Case Reports
. 2022 Apr 7:12:863639.
doi: 10.3389/fonc.2022.863639. eCollection 2022.

Concurrent RAS and RAS/BRAF V600E Variants in Colorectal Cancer: More Frequent Than Expected? A Case Report

Veronica Zelli  1   2 , Alessandro Parisi  3   4 , Leonardo Patruno  1   4 , Katia Cannita  5 , Corrado Ficorella  1   4 , Carla Luzi  1   2 , Chiara Compagnoni  1 , Francesca Zazzeroni  1 , Edoardo Alesse  1 , Alessandra Tessitore  1   2
Affiliations
Case Reports

Concurrent RAS and RAS/BRAF V600E Variants in Colorectal Cancer: More Frequent Than Expected? A Case Report

Veronica Zelli et al. Front Oncol. .

Abstract

The assessment of RAS and BRAF mutational status is one of the main steps in the diagnostic and therapeutic algorithm of metastatic colorectal cancer (mCRC). Multiple mutations in the BRAF and RAS pathway are described as a rare event, with concurrent variants in KRAS and BRAF genes observed in approximately 0.05% of mCRC cases. Here, we report data from a case series affected by high-risk stage III and stage IV CRC and tested for RAS and BRAF mutation, treated at our Medical Oncology Unit. The analysis of KRAS, NRAS (codons 12, 13, 59, 61, 117, 146), and BRAF (codon 600) hotspot variants was performed in 161 CRC tumors from August 2018 to September 2021 and revealed three (1.8%) patients showing mutations in both KRAS and BRAF (V600E), including two cases with earlier CRC and one with metastatic disease. We also identified one patient (0.6%) with a mutation in both KRAS and NRAS genes and another one (0.6%) with a double KRAS mutation. Notably, the latter was characterized by aggressive behavior and poor clinical outcome. The mutational status, pathological features, and clinical history of these five CRC cases are described. Overall, this study case series adds evidence to the limited available literature concerning both the epidemiological and clinical aspects of CRC cases characterized by the presence of concurrent RAS/BRAF variants. Future multicentric studies will be required to increase the sample size and provide additional value to results observed so far in order to improve clinical management of this subgroup of CRC patients.

Keywords: case report; clinical–pathological features; colorectal cancer; concurrent RAS/BRAF variants; mutation frequency.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Case 2, KRAS/BRAF genotyping: (A) qRT-PCR results using EasyPGX® KRAS kit showing the KRAS G12V/D/A (c.35G>H) variant in tumor DNA. The assay detects but not distinguishes the c. 35G>T (G12V), c. 35G>A (G12D) and c. 35G>C (G12A) mutations. Each assay contains primers and fluorescent probes allowing the simultaneous detection of target (FAM) and endogenous control gene (HEX). Threshold fluorescence for FAM (blue line) and HEX (green line) are shown. The assay clearly shows the presence of the variant, based on fluorescence signals quality and cutoff parameters. (B) Electropherogram from direct sequencing confirming the presence of KRAS c.35G>T (G12V) mutation in tumor DNA. (C) qRT-PCR results using EasyPGX® BRAF kit showing the BRAF c. 1799T>A or c. 1799_1800TG>AA (indistinguishable) (V600E) mutation in tumor DNA. The mutation was undetectable by Sanger sequencing, (E) but it was still detected by qRT-PCR, respecting all quality and cutoff parameters, when tumor DNA was used at 1:10 dilution (D).
Figure 2
Figure 2
Case 5, KRAS genotyping. (A) qRT-PCR results using EasyPGX® KRAS kit showing the double KRAS variant in tumor DNA. The assay KRAS G12V/D/A detects but not distinguishes the c. 35G>T (G12V ), c. 35G>A (G12D) and c. 35G>C (G12A) mutations. The assay KRAS A146X detects but not distinguishes the c. 436G>A (A146T), c. 436G>C (A146P) and c. 437C>T (A146V) variants. Each assay contains primers and fluorescent probes allowing the simultaneous detection of target (FAM) and endogenous control gene (HEX). Threshold fluorescence for FAM (blue line) and HEX (green line) are shown. The assays clearly show the presence of the variants, based on fluorescence signals quality and cutoff parameters. (B) Electropherogram from direct sequencing confirming KRAS variants c.35G>C (G12A) and c.437C>T (A146V).
Figure 3
Figure 3
Computed tomography (CT) scan evaluation in patient 5 before (A) and after (B) 3 months of systemic treatment, showing rapid disease progression to the liver.
See this image and copyright information in PMC

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