Landscape of BRAF mutation classes in intrahepatic cholangiocarcinoma.
Authors: Tang Tin-Yun , Danner De Armas Anaemy , Ross Jeffrey S. , Pavlick Dean C. , Sharaf Radwa , Kaplan Benjamin G , Sokol Ethan , Rodon Ahnert Jordi , Javle Milind M. 
Published: January 2023

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Background: Genomic alterations (GA) in BRAF are categorized as Class I, II, or III mutations (muts) and are oncogenic drivers in intrahepatic cholangiocarcinoma (iCCA). Class I muts, such as BRAF V600, directly increase monomeric kinase activity at high levels to drive oncogenic ERK signaling. In comparison, BRAF Class II muts require homodimerization to increase kinase activity to an intermediate level and Class III muts have low kinase activity or are kinase-dead. There is emerging evidence that BRAF mut iCCA as a group are unique from BRAF wildtype (wt) iCCA and furthermore that BRAF Class II and III muts as a group are distinct from BRAF Class I muts. Methods: 8,069 iCCA underwent comprehensive genomic profiling (CGP) using an FDA-approved clinical-grade hybrid capture-based system to determine all classes of GA, MSI status and TMB. PD-L1 expression was measured using the Dako 22C3 TPS system (0% = negative, 1-49% low positive and > 50% = high positive). Genomic ancestry analysis was performed using patient SNPs. Cohorts compared with false discovery rate corrected using Bonferroni adjustment. Results: 7701 (95.4%) of iCCA were BRAF WT and 368 (4.6%) were BRAF mut with 186 (50.5%) Class I, 77 (20.9%) Class II and 105 (28.5%) Class III. BRAF muts (all classes) compared to BRAF wt have higher proportions of East Asians (7.0% v 4.7%, p=.04,) and GA in CDKN2A (45% v 30%, p<.001), CDKN2B (38% v 21%, p<.001), MTAP loss (28% v 15%, p<.001) and PD-L1 low positive (34% v 24%, p=.03); BRAF muts vs BRAF wt have lower proportions of African patients (3.0% v 7.9%, p<.001), GA in BAP1 (10% v 14%, p=.03), ERBB2 (2.4% v 5.0%, p=.03), FGFR2 (1.1% v 12%, p<.001), IDH2 (1.9% v 4.1%, p=.03), KRAS (4.9% v 21%, p<.001), MDM2 (1.4% v 4.4%, p=.002), MYC (2.4% v 4.7%, p=.04), NF1 (0.8%, 2.8%, p=.02), PBRM1 (5.7% v 11%, p<.001), TP53 (25% v 34%, p<.001), and gLOH-high (11% v 20%, p=.002). BRAF Class II+III muts versus BRAF Class I muts have higher mean age (66 v 59, p<.001), GA/tumor (5.1 v 4.2, p=.002), proportion of East Asians (10% v 3.7%, p=.01), GA in ARID1A (32% v 8.6%, p<.001), BAP1 (16% v 4.8%, p<.001), IDH1 (19% v 2.7%, p<.001), IDH2 (3.8% v 0%, p=.007), KRAS (8.2% v 1.6%, p=.003), MDM2 (2.7% v 0%, p=.03), PBRM1 (9.3% v 2.2%, p=.003), SMAD4 (14% v 1.6%, p<.001), TP53 (31% v 19%, p=.009), Mean TMB (3.6 v 2.1, P=.03), and TMB≥10 (6.0% v 1.6%, p=.03); BRAF Class II+III muts versus BRAF class I muts have lower proportion of Europeans (73% v 84%, p=.01), GA in CKN2A (34% v 56%, p<.001), CDKN2B (25% v 49%, p<.001), MTAP loss (20% v 37%, p=.003), and TERT (0.6% v 15%, p<.001). There were no differences across in COSMIC trinucleotide signatures across BRAF mut versus BRAF wt and BRAF II+III versus BRAF I. Conclusions: CGP reveals significant differences in patient characteristics and GA between BRAF mut and BRAF wt iCCA. Additional differences emerge when BRAF II+III are compared to BRAF I. These differences should be accounted for in the clinical trials setting with iCCA BRAF mut patients.