Mutational landscape of primary pulmonary salivary gland-type tumors through targeted next-generation sequencing

Abstract

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.

Keywords: MAML2 and MYB rearrangements; Molecular alterations; Primary pulmonary salivary gland-type tumors.