Genomic profiling identifies GPC5 amplification in association with sarcomatous transformation in a subset of uterine carcinosarcomas

Abstract

Uterine carcinosarcoma, also known as Malignant Mixed Müllerian Tumour, is a high‐grade biphasic neoplasm composed of sarcomatous elements thought to originate via transdifferentiation from high‐grade endometrial carcinoma. To identify molecular factors contributing to the histogenesis of this tumour, we analyzed DNA extracted from matched carcinoma and sarcoma components from 12 cases of carcinosarcoma by a molecular inversion probe microarray to assess genomic copy number alterations (CNAs) and allelic imbalances. Widespread CNAs were identified in tumours with serous histology in the carcinoma component (9/12), while the remaining three cases with endometrioid carcinoma were near‐diploid. Quantification of the extent of genomic aberrations revealed a significant increase in sarcoma relative to carcinoma in tumours with well‐delineated histologic components. Focal amplification of 13q31.3 was identified in 6/12 profiled tumours, of which four harboured the aberration exclusively in the sarcoma component. This result was verified by fluorescence in situ hybridization against GPC5, the only gene situated within the minimal region of amplification. In a validation cohort composed of 97 carcinosarcomas and other uterine sarcomas, amplification of GPC5 (GPC5/CEP13 ratio ≥ 2.2) was identified in 11/97 (11.3%) cases (9/64 carcinosarcoma, 1/3 rhabdomyosarcoma, 1/21 leiomyosarcoma, 0/8 adenosarcoma, 0/1 undifferentiated endometrial sarcoma) and an additional 4 (2.8%) cases had low level gains (GPC5/CEP13 ratio ≥1.5 but <2.2). The functional relevance of Glypican‐5, the gene product of GPC5, in regulating differentiation and lineage commitment was demonstrated in an endometrial carcinoma cell line in vitro. In conclusion, we identified GPC5 amplification as a molecular event mediating epithelial‐mesenchymal transdifferentiation in a subset of uterine carcinosarcomas.

Molecular profiling of the biphasic components of hepatic carcinosarcoma by the use of targeted next‐generation sequencing

“…There has been a plethora of evidence showing that the carcinomatous element of uterine carcinosarcomas is the ‘driving force’, and that the sarcomatous component is derived from the carcinoma . One of the representative studies was published by Chui et al ., who not only demonstrated more copy number alterations in the sarcoma component than in the corresponding carcinoma component, but also provided good evidence that gene amplification can mediate epithelial–mesenchymal transition. In our study, two patients (cases 1 and 8) were identified with more copy number alterations in the sarcoma component, and the MET amplification seen only in their sarcomatous element might contribute to the pathogenesis of sarcoma by creating an expanded premalignant progenitor cell population and further allowing the occurrence of transforming events in this population, e.g.…”

Molecular Basis of Tumor Heterogeneity in Endometrial Carcinosarcoma

“…Likewise, in a cultured cell model, overexpression of URI1 induced ATM (ATM Serine/Threonine Kinase) expression and resistance to cisplatin [60]. Recurring GPC5 (Glypican 5) gain/amplification has been detected in a subset of ECS, mostly in the sarcoma component, and the authors linked the involvement of GPC5 with sarcomatous transformation [61].…”

A 4‐gene panel predicting the survival of patients with glioblastoma

“…Sano F et al 30 suggested that RTN1 might be involved in the proliferation of GBM cells. Chui et al 31 demonstrated that the amplification GPC5 (glypican 5) was associated with sarcomatous transformation of uterine carcinosarcomas. Wang et al 32 suggested that GPC5 expression was related with the proliferation of gastric cancer cells.…”