Objectives

Primary pulmonary salivary gland-type tumors (PSGTs) mainly comprise of mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC), which are rare and molecularly poorly understood. This study aimed to profile the molecular alterations of PSGTs via targeted next-generation sequencing (NGS).

Material and methods

Immunohistochemistry was used to screen PSGTs in 32 patients and MAML2 and MYB rearrangements were detected using fluorescence in situ hybridization. 1021-Genepanel of targeted NGS was conducted to profile genomic mutations in all the PSGT patients.

Results

Among the 32 patients, 25 had MEC and 7 had ACC. MAML2 and MYB rearrangements were detected in 80.0% (20/25) of the MEC and 71.4% (5/7) of the ACC patients. Among the MEC patients, 10 (40.0%) had ≥1 mutation, and 6 of them had 11 isolated mutations with abundance >5%, namely NFE2L2, MYOD1, INPP4B, CCND2, SNTG1, HSPD1, TGFBR1, RBM10, NOTCH4, ASXL1, and PTPRD mutations. The remaining 4 patients had 9 mutations with abundance <5%, namely KMT2A, PDCD11, FLT1, BRCA2, APC, SLX4, FOXP1, FGFR1, and HRAS mutations. All the ACC patients had mutations, which were enriched in 5 pathways including the PI3K and NOTCH pathways, chromatin and cytoskeleton remodeling, and DNA damage. These results explain PSGTs harbor distinct driver features of MAML2 or MYB rearrangement, accompanied with wide mutational diversity with very low rate of somatic mutation. Several important pathways, including the NOTCH and PI3K pathways, and chromatin remodeling could be targeted to improve the survival in patients with ACC.

中文翻译：

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通过靶向二代测序研究原发性肺唾液腺型肿瘤的突变图谱

目标

原发性肺唾液腺型肿瘤 (PSGT) 主要包括粘液表皮样癌 (MEC) 和腺样囊性癌 (ACC)，它们很少见且分子水平知之甚少。本研究旨在通过靶向下一代测序 (NGS) 分析 PSGT 的分子变化。

材料与方法

免疫组织化学用于筛选 32 名患者的 PSGT，并使用荧光原位杂交检测 MAML2 和 MYB 重排。进行了靶向 NGS 的 1021-Genepanel 以分析所有 PSGT 患者的基因组突变。

结果

在 32 名患者中，25 名患有 MEC，7 名患有 ACC。在 80.0% (20/25) 的 MEC 和 71.4% (5/7) 的 ACC 患者中检测到 MAML2 和 MYB 重排。MEC患者中，10例（40.0%）有≥1个突变，其中6例有11个孤立突变，丰度>5%，即NFE2L2、MYOD1、INPP4B、CCND2、SNTG1、HSPD1、TGFBR1、RBM10、NOTCH4、ASXL1、和 PTPRD 突变。其余4例患者有9个丰度<5%的突变，即KMT2A、PDCD11、FLT1、BRCA2、APC、SLX4、FOXP1、FGFR1和HRAS突变。所有 ACC 患者均有突变，富含 PI3K 和 NOTCH 通路、染色质和细胞骨架重塑、DNA 损伤等 5 条通路。这些结果解释了 PSGT 具有明显的 MAML2 或 MYB 重排驱动特征，伴随着广泛的突变多样性和非常低的体细胞突变率。