Background: Malignant pleural mesothelioma (MPM) is a highly lethal disease comprising a heterogeneous group of tumors with challenging to predict biological behavior. The diagnosis is complex, and the histologic classification includes 2 major subtypes of MPM: epithelioid (∼60% of cases) and sarcomatous (∼20%). Its identification depends upon pathological investigation supported by clinical and radiological evidence and more recently ancillary molecular testing. Treatment options are currently limited, with no known targeted therapies available. Objectives: To elucidate the mutation profile of driver tumor suppressor and oncogenic genes in a cohort of Brazilian patients. Methods: We sequenced 16 driver genes in a series of 43 Brazilian malignant mesothelioma (MM) patients from 3 distinct Brazilian centers. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue blocks, and the TERT promoter region was amplified by PCR followed by direct capillary sequencing. The Illumina TruSight Tumor 15 was used to evaluate 250 amplicons from 15 genes associated with solid tumors (AKT1, GNA11, NRAS, BRAF, GNAQ, PDGFRA, EGFR, KIT, PIK3CA, ERBB2, KRAS, RET, FOXL2, MET,and TP53). Library preparation with the TruSight Tumor 15 was performed before sequencing at the MiSeq platform. Data analysis was performed using Sophia DDM software. Results: Out of 43 MPM patients, 38 (88.4%) were epithelioid subtype and 5 (11.6%) were sarcomatoid histotype. Asbestos exposure was present in 15 (39.5%) patients with epithelioid MPM and 3 (60%) patients with sarcomatoid MPM. We found a TERT promoter mutation in 11.6% of MM, and the c.-146C>T mutation was the most common event. The next-generation sequencing was successful in 33 cases. A total of 18 samples showed at least 1 pathogenic, with a median of 1.8 variants, ranging from 1 to 6. The most mutated genes were TP53 and ERBB2 with 7 variants each, followed by NRAS BRAF, PI3KCA, EGFR and PDGFRA with 2 variants each. KIT, AKT1, and FOXL2 genes exhibited 1 variant each. Interestingly, 2 variants observed in the PDGFRA gene are classic imatinib-sensitive therapy. Conclusions: We concluded that Brazilian MPM harbor mutation in classic tumor suppressor and oncogenic genes, which might help in the guidance of personalized treatment of MPM.

中文翻译：

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巴西恶性胸膜间皮瘤中驱动肿瘤抑制基因和致癌基因的突变分析

背景：恶性胸膜间皮瘤 (MPM) 是一种高度致命的疾病，包括一组异质性的肿瘤，难以预测生物学行为。诊断很复杂，组织学分类包括 MPM 的 2 个主要亚型：上皮样（~60% 的病例）和肉瘤（~20%）。它的识别取决于由临床和放射学证据以及最近的辅助分子检测支持的病理学调查。目前治疗选择有限，没有已知的靶向疗法可用。目的：阐明一组巴西患者中驱动肿瘤抑制基因和致癌基因的突变谱。方法：我们对来自 3 个不同巴西中心的 43 名巴西恶性间皮瘤 (MM) 患者的 16 个驱动基因进行了测序。从福尔马林固定石蜡包埋的肿瘤组织块中提取基因组DNA，通过PCR扩增TERT启动子区域，然后直接毛细管测序。Illumina TruSight Tumor 15 用于评估来自与实体瘤相关的 15 个基因（AKT1、GNA11、NRAS、BRAF、GNAQ、PDGFRA、EGFR、KIT、PIK3CA、ERBB2、KRAS、RET、FOXL2、MET 和 TP53）的 250 个扩增子. 在 MiSeq 平台上测序之前，使用 TruSight Tumor 15 进行文库制备。使用 Sophia DDM 软件进行数据分析。结果：在 43 名 MPM 患者中，38 名 (88.4%) 为上皮样亚型，5 名 (11.6%) 为肉瘤样组织型。15 名 (39.5%) 上皮样 MPM 患者和 3 名 (60%) 肉瘤样 MPM 患者存在石棉暴露。我们在 11.6% 的 MM 中发现了 TERT 启动子突变，c.-146C> T突变是最常见的事件。二代测序成功33例。总共18个样本显示至少1个致病性，中位数为1.8个变异，范围从1到6个。突变最多的基因是TP53和ERBB2，各有7个变异，其次是NRAS BRAF、PI3KCA、EGFR和PDGFRA，有2个变异每个。KIT、AKT1 和 FOXL2 基因各有 1 个变异。有趣的是，在 PDGFRA 基因中观察到的 2 个变异是经典的伊马替尼敏感疗法。结论：我们得出结论，巴西 MPM 存在经典抑癌基因和致癌基因的突变，这可能有助于指导 MPM 的个性化治疗。突变最多的基因是 TP53 和 ERBB2，各有 7 个变体，其次是 NRAS BRAF、PI3KCA、EGFR 和 PDGFRA，各有 2 个变体。KIT、AKT1 和 FOXL2 基因各有 1 个变异。有趣的是，在 PDGFRA 基因中观察到的 2 个变异是经典的伊马替尼敏感疗法。结论：我们得出结论，巴西 MPM 存在经典抑癌基因和致癌基因的突变，这可能有助于指导 MPM 的个性化治疗。突变最多的基因是 TP53 和 ERBB2，各有 7 个变体，其次是 NRAS BRAF、PI3KCA、EGFR 和 PDGFRA，各有 2 个变体。KIT、AKT1 和 FOXL2 基因各有 1 个变异。有趣的是，在 PDGFRA 基因中观察到的 2 个变异是经典的伊马替尼敏感疗法。结论：我们得出结论，巴西 MPM 存在经典抑癌基因和致癌基因的突变，这可能有助于指导 MPM 的个性化治疗。