Multi-dimensional genomic analysis of myoepithelial carcinoma identifies prevalent oncogenic gene fusions

Abstract

Myoepithelial carcinoma (MECA) is an aggressive salivary gland cancer with largely unknown genetic features. Here we comprehensively analyze molecular alterations in 40 MECAs using integrated genomic analyses. We identify a low mutational load, and high prevalence (70%) of oncogenic gene fusions. Most fusions involve the PLAG1 oncogene, which is associated with PLAG1 overexpression. We find FGFR1-PLAG1 in seven (18%) cases, and the novel TGFBR3-PLAG1 fusion in six (15%) cases. TGFBR3-PLAG1 promotes a tumorigenic phenotype in vitro, and is absent in 723 other salivary gland tumors. Other novel PLAG1 fusions include ND4-PLAG1; a fusion between mitochondrial and nuclear DNA. We also identify higher number of copy number alterations as a risk factor for recurrence, independent of tumor stage at diagnosis. Our findings indicate that MECA is a fusion-driven disease, nominate TGFBR3-PLAG1 as a hallmark of MECA, and provide a framework for future diagnostic and therapeutic research in this lethal cancer.

The key radiologic and cytomorphologic features of oncocytic and oncocytoid lesions of the salivary gland

“…A number of molecular alterations have been identified in MyoEpCs. As might be expected, those arising as ex‐PA will frequently harbor translocations involving PLAG1 and HMGA2 . Moreover, oncogenic somatic mutations have been identified in roughly 70% of lesions, regardless of whether they arose de novo or ex ‐PA.…”

“…Cases occur over a wide age distribution with a mean age at diagnosis in the late 40s to early 50s . There is no gender predilection …”

“…Moreover, oncogenic somatic mutations have been identified in roughly 70% of lesions, regardless of whether they arose de novo or ex ‐PA. A clinically aggressive subset of MyoEpCs demonstrates a predominance of clear cells and may demonstrate a t(12;22) translocation involving EWSR1‐ATF1, which has also been identified in clear cell carcinomas …”

“…Finally, FISH can be performed to detect the characteristic CCC‐defining EWSR1‐ATF1 fusion . As noted, however, a variant of MyoEpC with a dominant clear cell population has been described which demonstrates the same gene rearrangements …”

Recurrent rearrangements of the PLAG1 and HMGA2 genes in lacrimal gland pleomorphic adenoma and carcinoma ex pleomorphic adenoma

“…) FGFR1 (8p11.23)*(Persson et al 2008) TCEA1 (8q11.23)*(Asp et al 2006) CHCHD7 (8q12.1)*(Asp et al 2006) GEM (8q22.1)*(Dalin et al 2017) ACTA2 (10q23.31)(Dalin et al 2017) ND4 (mitochondrial gene)(Dalin et al 2017) HMGA2 (12q.14)FHIT (3p14.2)(Geurts et al 1997) NFIB(9p23-p22.3) (Geurts et al 1998) WIF1 (12q14.3)* (Persson et al 2009b) Intergenic regions on chromosome 3, 6, and 12* (Dalin et al 2017) * Gene located in close proximity to PLAG1 or HMGA2, rendering fusion undetectable with break-apart fluorescence in situ hybridization. Pleomorphic adenoma (PA) and carcinoma ex pleomorphic adenoma (ca-ex-PA) of the lacrimal gland.…”