Prognostic and histogenetic roles of gene alteration and the expression of key potentially actionable targets in salivary duct carcinomas

Abstract

The molecular characteristics of therapeutically-relevant targets and their clinicopathological implications in salivary duct carcinomas (SDCs) are poorly understood. We investigated the gene alterations and the immunoexpression of crucial oncogenic molecules in 151 SDCs. The mutation rates that were identified, in order of frequency, were as follows: <i>TP53</i>, 68%; <i>PIK3CA</i>, 18%; <i>H-RAS</i>, 16%; <i>BRAF</i>, 4%; and <i>AKT1</i>, 1.5%. <i>PIK3CA/H-RAS/BRAF</i> mutations were more common in <i>de novo</i> SDC than in SDC ex-pleomorphic adenoma. Furthermore, these mutations were mutually exclusive for HER2 overexpression/amplification. <i>TP53</i> mutations were frequently detected in cases with the aberrant p53 expression, and <i>TP53</i> missense and truncating mutations were associated with p53-extreme positivity and negativity, respectively. DISH analysis revealed no cases of <i>EGFR</i> amplification. The rates of PI3K, p-Akt, and p-mTOR positivity were 34%, 22%, and 66%, respectively; PTEN loss was observed in 47% of the cases. These expressions were correlated according to the signaling axis. Cases with PI3K negativity and PTEN loss appeared to show a lower expression of androgen receptor. In the multivariate analysis, patients with SDC harboring <i>TP53</i> truncating mutations showed shorter progression-free survival. Conversely, p-Akt positivity was associated with a favorable outcome. This study might provide information that leads to advances in personized therapy for SDC.