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Impact of BRAF-V600E mutation on immunologic characteristics of the tumor microenvironment (TME) and associated genomic alterations in patients with microsatellite instability-high (MSI-H) or mismatch-repair–deficient (dMMR) colorectal cancer (CRC)
Background
The BRAF V600E mutation is associated with the hypermethylator phenotype CIMP, which can also lead to the MSI-H phenotype. BRAF V600E mutation and MSI-H/dMMR status seem to be biologically intertwined; however, the impact of coexisting BRAFV 600E mutations on the TME and immunometabolomic features of MSI-H/dMMR CRC tumors is not well characterized.
Methods
A retrospective review of deidentified records of patients with MSI-H/dMMR CRC tumors was conducted using next-generation sequencing data (Tempus |xT assay: DNA-seq of 595-648 genes at 500x coverage, and full transcriptome RNA-seq). Several immune markers of tumor immunogenicity in BRAF wild-type (BRAFwt ) vs. V600E-mutated (BRAFV 600E ) tumors were assessed, including tumor mutational burden (TMB), neoantigen tumor burden (NTB, ScanNeo), PD-L1 expression, immune infiltration, and canonical immuno-metabolomic pathways (82 geneset signatures).
Results
A total of 459 MSI-H/dMMR CRC tumors were analyzed, of which 123 (27%) tumors harbored BRAF V600E mutations, and 336 (73%) were BRAF wt. MSI-H/dMMR BRAF V600E tumors were more frequently identified in females (69% vs. 55%; P= 0.01), non-Hispanic or non-Latino (100% vs. 73%; P =0.001), and older patients (median age: 76 yrs vs. 62 yrs; P BRAF WT, BRAF V600E tumors exhibited significantly higher TMB (Median: 49 mut/MB vs. 36 mut/MB; P 10 mut/MB; 100% vs. 95%; P = 0.008); however, no significant differences were observed with tumor NTB, immune score, or T cell infiltration (CD4 or CD8). NK cell infiltration was higher in the BRAF V600E cohort (BRAF WT tumors, BRAF V600E tumors harbored a greater frequency of mutations in MSH6 (42% vs. 20%), B2M (33% vs. 16%), BRCA2 (31% vs. 12%), ATM (23% vs. 12%), and TP53 (30% vs. 19%) but a lower frequency of MSH2 (3.3% vs. 11%), all P BRAF V600E tumors: glycerophospholipid, galactose, cyclin-dependent cell signaling; Nucleotide, and TH1 inflammation. Five pathways were downregulated (Wnt, Notch, TH17 inflammation, amino sugar, and cancer stem cell signaling).
Conclusions
MSI-H/dMMR BRAF V600E CRCs undergo broad metabolic reprogramming (e.g., glycerophospholipidgalactose, nucleotide). A rise in lipid metabolism, particularly with NK inflammation, suggests that BRAF V600E-mutated tumors may be associated with a non-classical immune component. BRAF V600E and BRAF wt CRCs exhibited similar NTB and T cell infiltration, suggesting that both are likely to benefit from immune checkpoint inhibitors.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosures
S. Kopetz: Advisory / Consultancy: Roche, Redx Pharma, Jacobio, Merck, Navire Pharma, Holy Stone, Biocartis, Natera, Karyopharm Therapeutics, Repare Therapeutics, Genentech, Lilly, AstraZeneca/MedImmune, EMD Serono, Daiichi Sankyo, Amal Therapeutics, Boehringer Ingelheim, Bayer Health, Lutris, Pfizer, Amgen, Pierre Fabre, Symphogen, Novartis, Boston Biomedical, Ipsen, HalioDx, Inivata, GSK, Jazz pharmaceuticals Iylon, Xilis, AbbVie, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier, Carina Biotechnology, Bicara Therpeutics, Endeavor BioMedicines, Numab Pharma, Johnson & Johnson/Janssen, Genomic Health, Fro; Research grant / Funding (self): Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/ Roche, EMD Serono, MedImmune, Novartis, Amgen, Lilly, Daiichi Sankyo; Shareholder / Stockholder / Stock options: MolecularMatch, Frontier Medicines, Lutris, Iylon. S. El-Refai: Full / Part-time employment: TEMPUS LABS. J. Tabernero: Honoraria (self): educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER).; Advisory / Consultancy: scientific consultancy role for Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Sotio Biotech, Taiho, Tessa Therapeutics and TheraMyc. T. George: Advisory / Consultancy: Tempus, Pfizer. E. Van Cutsem: Advisory / Consultancy: AbbVie, Array, Astellas, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Helsinn, Incyte, Ipsen, Janssen Research, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Pierre Fabre, Roche, Seattle Genetics, Servier, Sirtex, Terumo, Taiho, TRIGR, Zymeworks ; Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier . T. André: Honoraria (self): Amgen, Astra-Zeneca, Bristol-Myers Squibb, Gritstone Oncology, GlaxoSmithKline, Haliodx, Kaleido Biosciences, Merck & Co., Inc., Pierre Fabre, Sanofi, Servier et , Merck & Co., Inc, Servier; Advisory / Consultancy: Astellas Pharma, BMS, Gritstone Oncology,Transgène, Roche/Ventana, Seagen, Merck & Co., Inc, Sevier; Research grant / Funding (institution): BMS, Seagen, GSK; Travel / Accommodation / Expenses: BMS, Merck & Co., Inc. M. Overman: Advisory / Consultancy: AbbVie and Takeda Pharmaceuticals (Japan), AgilVax and Merck Sharp & Dohme Corp, Acrotech Biopharma and Novartis Pharmaceuticals corp. All other authors have declared no conflicts of interest.
