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      The clinical and genomic distinctions of Class1/2/3 BRAF-mutant colorectal cancer and differential prognoses

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          Abstract

          BRAF mutations are the oncogenic drivers in colorectal cancer and V600 mutations (Class1), which lead to RAS-independent active monomers, are the most common mutation types. BRAF non-V600 mutants can be further classified as RAS-independent active dimers (Class2) and RAS-dependent impaired kinase (Class3). We retrospectively reviewed the mutational profiles of 328 treatment-naïve colorectal tumors with BRAF mutations detected using capture-based hybrid next-generation sequencing targeting 400 + cancer-related genes. The clinical and genetic distinctions of patients harboring Class1/2/3 BRAF mutations were investigated, which revealed that tumors with Class1 BRAF mutations showed more unique genomic profiles than those with Class2/3 mutations. Also, by using an external dataset from cBioPortal, we demonstrated that patients with Class3 BRAF mutations had the best survival outcomes compared to the other two subgroups. These findings promoted the development of anti-BRAF strategies by distinguishing BRAF mutant subgroups. 

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          The online version contains supplementary material available at 10.1186/s40364-022-00443-8.

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          Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer

          Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1134 CRCs. We identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1 , increasing oncogenic WNT pathway alterations to 96% of CRCs. Right-sided primary site in microsatellite stable mCRC was associated with shorter survival, older age at diagnosis, increased mutations, and enrichment of oncogenic alterations in KRAS , BRAF , PIK3CA , AKT1 , RNF43 , and SMAD4 compared to left-sided primaries. Left-sided tumors frequently had no identifiable genetic alteration in mitogenic signaling, but exhibited higher mitogenic ligand expression. Our results suggest different pathways to tumorigenesis in right- and left-sided microsatellite stable CRC that may underlie clinical differences.
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            Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS

            Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants—those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS–GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.
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              Targeting Alterations in the RAF–MEK Pathway

              The MAPK pathway is one of the most commonly mutated oncogenic pathways in cancer. While RAS mutations are the most frequent MAPK alterations, less frequent alterations in downstream components of the pathway, including the RAF and MEK genes, offer promising therapeutic opportunities. In addition to BRAF V600 mutations, for which several approved therapeutic regimens exist, other alterations in RAF and MEK genes may provide more rare, but tractable, targets. However, recent studies have illustrated the complexity of MAPK signaling and highlighted that distinct alterations in these genes may have strikingly different properties. Understanding the unique functional characteristics of specific RAF and MEK alterations, reviewed herein, will be critical for developing effective therapeutic approaches for these targets.
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                Author and article information

                Contributors
                guanxin@hrbmu.edu.cn
                tongyulin@hotmail.com
                Journal
                Biomark Res
                Biomark Res
                Biomarker Research
                BioMed Central (London )
                2050-7771
                25 January 2023
                25 January 2023
                2023
                : 11
                : 11
                Affiliations
                [1 ]GRID grid.54549.39, ISNI 0000 0004 0369 4060, Department of Medical Oncology, Sichuan Cancer Center, School of Medicine, , Sichuan Cancer Hospital and Institute, University of Electronic Science and Technology of China, ; No. 55, Section 4, South Renmin Road, Sichuan 610041 Chengdu, China
                [2 ]GRID grid.190737.b, ISNI 0000 0001 0154 0904, Department of Gastrointestinal Cancer Center, , Chongqing University Cancer Hospital, ; 400030 Chongqing, China
                [3 ]GRID grid.488525.6, Department of Medical Oncology, , The Sixth Affiliated Hospital of Sun Yat-sen University, ; 510655 Guangzhou, China
                [4 ]Geneseeq Research Institute, Nanjing Geneseeq Technology Inc, 210000 Nanjing, China
                [5 ]GRID grid.488530.2, ISNI 0000 0004 1803 6191, Department of Medical Oncology, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, , Sun Yat-sen University Cancer Center, ; 510060 Guangzhou, China
                [6 ]GRID grid.54549.39, ISNI 0000 0004 0369 4060, Department of Pathology, Sichuan Cancer Center, School of Medicine, , Sichuan Cancer Hospital and Institute, University of Electronic Science and Technology of China, ; 610041 Chengdu, China
                [7 ]GRID grid.452859.7, ISNI 0000 0004 6006 3273, Department of Medical Oncology, , The Fifth Affiliated Hospital of Sun Yat-sen University, ; 519000 Zhuhai, China
                [8 ]GRID grid.412615.5, ISNI 0000 0004 1803 6239, Department of Medical Oncology, , The First Affiliated Hospital of Sun Yat-sen University, ; 510080 Guangzhou, China
                [9 ]GRID grid.412651.5, ISNI 0000 0004 1808 3502, Department of Radiation Oncology, , Harbin Medical University Cancer Hospital, ; 150 Haping Road, Nangang District, 150040 Harbin, Heilongjiang China
                [10 ]GRID grid.414008.9, ISNI 0000 0004 1799 4638, Department of Medical Oncology, , The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, ; 450008 Zhengzhou, China
                [11 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Thoracic Medical Oncology, , Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, ; 283 Tongzipo Road, Yuelu District, 410013 Changsha, China
                [12 ]GRID grid.410560.6, ISNI 0000 0004 1760 3078, Department of Medical Oncology, Cancer Center, , Affiliated Hospital of Guangdong Medical University, ; 524023 Zhanjiang, China
                [13 ]GRID grid.256607.0, ISNI 0000 0004 1798 2653, Department of Medical Oncology, , Guangxi Medical University Cancer Hospital, ; 530021 Nanning, China
                [14 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, School of Public Health, , Nanjing Medical University, ; 211166 Nanjing, China
                Article
                443
                10.1186/s40364-022-00443-8
                9875443
                36694231
                fd57e8c5-adb2-48f0-8430-c890b9919b4d
                © The Author(s) 2023

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 10 August 2022
                : 15 December 2022
                Funding
                Funded by: Program of Science and Technology of Sichuan Province
                Award ID: 2021YFQ0037
                Funded by: Science Foundation of the Postdoctoral Department of Heilongjiang Province
                Award ID: LBH-Q21118
                Funded by: Haiyan Research Funding of the Harbin Medical University Cancer Hospital
                Award ID: JJZD2021-03
                Categories
                Correspondence
                Custom metadata
                © The Author(s) 2023

                braf,colorectal cancer,next-generation sequencing,prognosis

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