Chromosome Translocations, Gene Fusions, and Their Molecular Consequences in Pleomorphic Salivary Gland Adenomas

Abstract

Salivary gland tumors are a heterogeneous group of tumors originating from the major and minor salivary glands. The pleomorphic adenoma (PA), which is the most common subtype, is a benign lesion showing a remarkable morphologic diversity and that, upon recurrence or malignant transformation, can cause significant clinical problems. Cytogenetic studies of >500 PAs have revealed a complex and recurrent pattern of chromosome rearrangements. In this review, we discuss the specificity and frequency of these rearrangements and their molecular/clinical consequences. The genomic hallmark of PA is translocations with breakpoints in 8q12 and 12q13-15 resulting in gene fusions involving the transcription factor genes PLAG1 and HMGA2. Until recently, the association between these two oncogenic drivers was obscure. Studies of the Silver–Russel syndrome, a growth retardation condition infrequently caused by mutations in IGF2/HMGA2/PLAG1, have provided new clues to the understanding of the molecular pathogenesis of PA. These studies have demonstrated that HMGA2 is an upstream regulator of PLAG1 and that HMGA2 regulates the expression of IGF2 via PLAG1. This provides a novel explanation for the 8q12/12q13-15 aberrations in PA and identifies IGF2 as a major oncogenic driver and therapeutic target in PA. These studies have important diagnostic and therapeutic implications for patients with PA.

Molecular testing in salivary gland cytopathology: A practical overview in conjunction with the Milan system

“…Indeed, PLAG1 and HMGA2 gene fusions along with a variety of different partner genes are the classic molecular alterations in PAs. 25 However, PLAG1 gene fusions have also been described in 40% of MEs 26 and in 38% of myoepithelial carcinomas (MECAs), 27 Among these gene fusions, TGFBR3::PLAG1 seems to be significantly associated with both MECAs and atypical myoepithelial loid cells may at times be interconnected. 32 Recently, the efficiency of FNA samples in distinguishing between benign basaloid salivary gland neoplasms from more aggressive salivary gland tumours has improved thanks to the emergence of new diagnostic biomarkers.…”

“…Indeed, PLAG1 and HMGA2 gene fusions along with a variety of different partner genes are the classic molecular alterations in PAs 25 . However, PLAG1 gene fusions have also been described in 40% of MEs 26 and in 38% of myoepithelial carcinomas (MECAs), 27 Among these gene fusions, TGFBR3::PLAG1 seems to be significantly associated with both MECAs and atypical myoepithelial neoplasms 28,29 .…”

Don't SUMP it! Utility of PLAG1 immunocytochemistry in basaloid SUMP subcategory

“…Given that a significant proportion of PAs harbor recurrent rearrangements involving the pleomorphic adenoma gene 1 (PLAG1) on 8q12, immunohistochemistry (IHC) for PLAG1 can be performed in challenging cases to help with the differential diagnosis. 9,10 Results from prior studies assessing the utility of PLAG1 IHC in surgical excision (SE) specimens and cell block (CB) preparations of salivary gland neoplasms have shown positivity in 55%-100% of PAs. 9,[11][12][13] Nevertheless, CBs may be paucicellular or unavailable for FNAC samples, making an alternative testing option highly valuable.…”

“…Although conventional PAs are generally straightforward to diagnose, cellular PAs with scant chondromyxoid matrix may present a diagnostic challenge. Given that a significant proportion of PAs harbor recurrent rearrangements involving the pleomorphic adenoma gene 1 ( PLAG1 ) on 8q12, immunohistochemistry (IHC) for PLAG1 can be performed in challenging cases to help with the differential diagnosis 9,10 . Results from prior studies assessing the utility of PLAG1 IHC in surgical excision (SE) specimens and cell block (CB) preparations of salivary gland neoplasms have shown positivity in 55%–100% of PAs 9,11–13 .…”

FGFR1/2/3‐rearranged carcinoma of the head and neck: expanded histological spectrum crossing path with high‐risk HPV in the sinonasal tract

“…2 Oncogenic FGFR rearrangements are rare and mainly represented by FGFR3::TACC3 fusions in approximately 3% of SCC. In addition, FGFR1::PLAG1 fusions were detected in pleomorphic adenoma (PA) and carcinomas ex PA, [2][3][4][5][6] being particularly enriched in myoepithelial carcinomas ex PA. 4,7 However, these tumours are generally considered PLAG1-instead of FGFR1-driven, given that the latter's kinase domain is typically absent in the fusion transcript. 4 Interestingly, several reports of SCC have concurrently harboured human papillomavirus (HPV) and FGFR3::TACC3 fusions.…”