PRKD1 Mutations Characterize Salivary Gland Polymorphous Low-Grade Adenocarcinoma

Polymorphous low-grade adenocarcinoma (PLGA) is a relatively indolent malignant salivary tumor that metastasizes to the lymph nodes in approximately 29% of patients but rarely metastasizes to distant sites. PLGAs are histologically heterogeneous and thus are difficult to distinguish from more aggressive salivary gland cancer subtypes. To identify characteristic molecular features of salivary gland PLGA that may aid in diagnosis, Weinreb, Piscuoglio, Martelotto, Waggott, and colleagues performed whole-transcriptome and whole-exome sequencing of 3 PLGAs and whole-exome sequencing of an additional 3 tumors and identified a protein kinase D1 (PRKD1) mutation resulting in an E710D amino acid substitution in 5 of 6 samples. Screening of an additional 53 salivary gland PLGAs revealed that this hotspot mutation occurred in 43 of 59 (73%) PLGAs overall. Although PRKD1 was found to be mutated in 2% of samples in published cancer genome datasets, none of the tumors had the E710D hotspot mutation, suggesting that this might be a distinguishing feature of PLGA. Indeed, in an analysis of 311 benign and malignant salivary gland tumors, this PRKD1 mutation was found only in PLGAs. The E710D mutation, which lies within the catalytic loop of the PRKD1 kinase domain, led to significantly increased kinase activity compared with wild-type PRKD1 in an in vitro kinase assay, suggesting that this mutation activates PRKD1. Interestingly, forced expression of the E710D mutant promoted proliferation and altered the glandular architecture of epithelial cells in vitro, further suggesting that this mutation confers a growth advantage to cells, but expression of the mutant protein reduced cellular migration. Consistent with these findings, the presence of the PRKD1 hotspot mutation was significantly associated with metastasis-free survival. Collectively, these findings indicate that PRKD1 mutations may have diagnostic and prognostic utility and distinguish indolent PLGA from more aggressive salivary gland tumors.

Weinreb I, Piscuoglio S, Martelotto LG, Waggott D, Ng CK, Perez-Ordonez B, et al. Hotspot activating PRKD1 somatic mutations in polymorphous low-grade adenocarcinomas of the salivary glands. Nat Genet 2014 Sep 21 [Epub ahead of print].

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