Molecular diversity of embryonic-type neuroectodermal tumors arising from testicular germ cell tumors.

Abstract

Embryonic-type neuroectodermal tumors (ENTs) arising from testicular germ cell tumors (GCTs) is a relatively common type of somatic transformation in GCTs with poor prognosis and limited therapeutic options, particularly when patients develop disease recurrence or metastasis. Knowledge of key events driving this transformation is limited to the paucity of comprehensive genomic data. We performed a retrospective database search in a CLIA- and CAP-certified laboratory for testicular GCT-derived ENTs that had previously undergone NGS-based comprehensive genomic profiling during the course of clinical care. Clinicopathological and genomic data were centrally re-reviewed. Here we report the molecular features of 10 ENTs of testicular GCT origin. All tumors harbored gain of chromosome 12p, often with KRAS, CCND2 and KMD5A co-amplification, supporting a germ cell origin. The tumors were microsatellite stable and exhibited low tumor mutational burden. Three tumors (30%) exhibited MYCN or MYC amplification with co-occurring inactivation of the p53 pathway via either TP53 mutations or MDM2 amplification in two tumors. Three additional tumors (30%) had activation of the PI3K pathway via PIK3CA and PIK3CG mutations or PIK3C2B amplification; one tumor with co-occurring CDK4 amplification. Gene rearrangements were detected in three tumors (30%), with novel BRD4-MAU2 and BCOR-CLIP2 fusions as well as an internal truncating ATRX rearrangement, respectively. In summary, ENTs arising from GCTs are molecularly heterogeneous; however, a large fraction of testicular ENTs could be stratified by two distinct sets of genetic alterations, including MYCN/MYC amplification with concurrent suppression of the p53 pathway, and activation of the PI3K pathway with co-occurring CDK4 amplification. Moreover, the novel gene fusions identified in a subset of testicular GCT-derived ENTs overlap with molecularly defined tumors of embryonic-type neuroectodermal features in the central nervous system, indicating the potential common driving events for tumorigenesis from different anatomic sites.