Background: BRAF mutations are classified into four molecularly distinct groups, and Class 1 (V600) mutant tumors are treated with targeted therapies. Effective treatment has not been established for Class 2/3 or BRAF Fusions. We investigated whether BRAF mutation class differed according to clinical, genomic, and transcriptomic variables in cancer patients. Methods: Using the AACR GENIE (v.12) cancer database, the distribution of BRAF mutation class in adult cancer patients was analyzed according to sex, age, primary race, and tumor type. Genomic alteration data and transcriptomic analysis was performed using The Cancer Genome Atlas. Results: BRAF mutations were identified in 9515 (6.2%) samples among 153,834, with melanoma (31%), CRC (20.7%), and NSCLC (13.9%) being the most frequent cancer types. Class 1 harbored co-mutations outside of the MAPK pathway (TERT, RFN43) vs. Class 2/3 mutations (RAS, NF1). Across all tumor types, Class 2/3 were enriched for alterations in genes involved in UV response and WNT/β-catenin. Pathway analysis revealed enrichment of WNT/β-catenin and Hedgehog signaling in non-V600 mutated CRC. Males had a higher proportion of Class 3 mutations vs. females (17.4% vs. 12.3% q = 0.003). Non-V600 mutations were generally more common in older patients (aged 60+) vs. younger (38% vs. 15%p< 0.0001), except in CRC (15% vs. 30% q = 0.0001). Black race was associated with non-V600 BRAF alterations (OR: 1.58;p< 0.0001). Conclusions: Class 2/3 BRAFs are more present in Black male patients with co-mutations outside of the MAPK pathway, likely requiring additional oncogenic input for tumorigenesis. Improving access to NGS and trial enrollment will help the development of targeted therapies for non-V600 BRAF mutations.
背景：BRAF突变被分为四个分子特征不同的类别，其中1类（V600）突变肿瘤可采用靶向治疗。针对2/3类突变或BRAF融合突变目前尚未建立有效治疗方案。本研究旨在探讨癌症患者中BRAF突变类别是否随临床特征、基因组及转录组学变量存在差异。方法：基于美国癌症研究协会GENIE（v.12）癌症数据库，按性别、年龄、主要种族和肿瘤类型分析成年癌症患者BRAF突变类别的分布特征。利用癌症基因组图谱数据库进行基因组变异数据分析和转录组学研究。结果：在153,834例样本中共发现9515例（6.2%）BRAF突变，其中黑色素瘤（31%）、结直肠癌（20.7%）和非小细胞肺癌（13.9%）为最常见肿瘤类型。与2/3类突变（RAS、NF1）相比，1类突变更多伴随MAPK通路外共突变（TERT、RFN43）。在所有肿瘤类型中，2/3类突变富集于紫外线应答和WNT/β-catenin通路相关基因变异。通路分析显示非V600突变结直肠癌中WNT/β-catenin和Hedgehog信号通路显著富集。男性患者中3类突变比例高于女性（17.4% vs. 12.3%，q = 0.003）。除结直肠癌外（15% vs. 30%，q = 0.0001），非V600突变在老年患者（60岁以上）中普遍更常见（38% vs. 15%，p < 0.0001）。黑人种族与非V600 BRAF变异显著相关（OR: 1.58; p < 0.0001）。结论：2/3类BRAF突变更多见于伴有MAPK通路外共突变的黑人男性患者，其肿瘤发生可能需要额外的致癌信号输入。提高二代测序技术的可及性并加强临床试验入组，将有助于推动针对非V600 BRAF突变的靶向治疗研发。
The Clinical, Genomic, and Transcriptomic Landscape of BRAF Mutant Cancers
肿瘤(癌症)患者之家