Genomic and Transcriptomic Analysis of Salivary Adenoid Cystic Carcinomas Defines Molecular Subtypes

= 723) to obtain the genome and transcriptome profile, including copy number variation (CNV) type, gene fusion, and transcriptional expression. We found that CNV and gene fusion patterns differed among the 3 pathological subtypes and correlated with clinical outcome. We also found a mutually exclusive relationship between MYBL1::NFIB fusion and 6q-loss, and they displayed distinct different transcriptional profiles. We discovered that molecular markers 6q-loss and 14q-loss were strongly associated with poor prognosis in ACC. Patients with 6q-loss or 14q-loss had a higher risk of tumor metastasis and recurrence, whereas MYB::NFIB and MYBL1::NFIB fusions showed no adverse prognostic impact. Based on these findings, we propose a new CNV-based molecular classification that stratifies patients into the subgroups of 6q-loss, 14q-loss, and others. The molecular classification method increased the prognostic accuracy from 74.49% (the pathological method) to now 82.65%, especially in cribriform patients (increased from 64% to 80%). Fluorescence in situ hybridization-based detection of 6q-loss and 14q-loss by probe ESR1-6q25 and FOS-14q24 provided a rapid and clinically feasible validation in ACC prognostic assessment. Further multicohort and multifactor analysis demonstrated the robustness and independence of the prognostic value in overall survival and metastasis-free survival of the molecular classification method.