BRAF mutations are relatively common in many cancers, particularly melanoma, colorectal cancer, and thyroid cancer and to a lesser extent in lung cancer. These mutations can be targeted by BRAF and MEK inhibitors, which exhibit good clinical activity. There are conflicting reports of the various relative rates of BRAF Class I mutations (V600 locus), defined as those that exhibit extremely strong kinase activity by stimulating monomeric activation of BRAF, Class II, define as non-V600 mutations that activate BRAF to signal as a RAS-independent dimer, and Class III mutations, defined as “kinase-dead” with low kinase activity as compared to wild type BRAF. Prospective studies have largely focused on patients with tumors harboring Class I BRAF mutations (limited to the V600 locus) where response rates up to 70% with BRAF plus MEK inhibition have been demonstrated. We report on the relative prevalence of various types of BRAF mutations across human cancers in a cohort of 114,662 patients that received comprehensive genomic profiling using next-generation sequencing. Of these patients, 4517 (3.9%) a pathogenic or presumed pathogenic BRAF mutation (3.9%). Of these, 1271 were seen in melanoma, representing 39.7% of all melanomas sequenced, representing the highest rate in all tumors. Class I (V600) mutations were seen overall in 2841 patients (62.1% of BRAF mutations, 2.4% of total cancers). Class II mutations were seen in 746 tumors (16.5% of BRAF mutant, 0.7% of total), and Class III mutations were seen in 801 tumors (17.7% of BRAF, 0.7% of total). Knowledge of the relative prevalence of these types of mutations can aid in the development of agents that might better address non-V600 mutations in cancer.

Impact statement

These data represent the largest aggregation of BRAF mutations within a single clinical database to our knowledge. The relative proportions of both BRAF V600 mutations and non-V600 mutations are informative in all cancers and by malignancy, and can serve as a definitive gold-standard for BRAF mutation cancer incidence by malignancy. The rate of BRAF mutation in human cancer in a real-world large database is lower than previously reported likely representing testing more broadly across tumor types. The relative percentages of Class II and Class III BRAF mutations are higher than previously reported, representing almost 35% of BRAF mutations in cancer. These findings provide support for the development of effective treatments for non-V600 BRAF mutations in cancer.

中文翻译：

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大型基因组数据库中 114,662 名癌症患者中 I-III 类 BRAF 突变的流行率

BRAF 突变在许多癌症中相对常见，特别是黑色素瘤、结直肠癌和甲状腺癌，在肺癌中的程度较低。这些突变可以被 BRAF 和 MEK 抑制剂靶向，它们表现出良好的临床活性。关于 BRAF I 类突变（V600 基因座）的各种相对率的报告存在相互矛盾的报告，该突变定义为通过刺激 BRAF 的单体激活表现出极强激酶活性的那些，II 类定义为激活 BRAF 以发出信号的非 V600 突变RAS 非依赖性二聚体和 III 类突变，定义为“激酶死亡”，与野生型 BRAF 相比具有低激酶活性。前瞻性研究主要集中在具有 I 类 BRAF 突变（仅限于 V600 基因座）的肿瘤患者，其中 BRAF 加 MEK 抑制的反应率高达 70%。我们报告了使用下一代测序进行全面基因组分析的 114,662 名患者队列中各种类型的 BRAF 突变在人类癌症中的相对流行率。在这些患者中，4517 名 (3.9%) 具有致病性或推测的致病性 BRAF 突变 (3.9%)。其中，1271 例见于黑色素瘤，占所有测序黑色素瘤的 39.7%，在所有肿瘤中比例最高。在 2841 名患者中总共观察到 I 类 (V600) 突变（BRAF 突变的 62.1%，总癌症的 2.4%）。在 746 个肿瘤中观察到 II 类突变（BRAF 突变体的 16.5%，总数的 0.7%），在 801 个肿瘤中观察到 III 类突变（BRAF 的 17.7%，总数的 0.7%）。了解这些类型突变的相对流行率有助于开发可能更好地解决癌症中非 V600 突变的药物。

影响陈述

据我们所知，这些数据代表了单个临床数据库中最大的 BRAF 突变聚合。BRAF V600 突变和非 V600 突变的相对比例在所有癌症和恶性肿瘤中都能提供信息，并且可以作为 BRAF 突变癌症发病率的明确金标准。在真实世界的大型数据库中，人类癌症的 BRAF 突变率低于先前报告的可能代表更广泛的肿瘤类型测试。II 类和 III 类 BRAF 突变的相对百分比高于先前报道的，几乎占癌症 BRAF 突变的 35%。这些发现为开发针对癌症中非 V600 BRAF 突变的有效治疗方法提供了支持。