J Pathol Clin Res 2018 Jan 24;4(1):69-78. Epub 2018 Jan 24.
Department of PathologyUniversity Health Network, University of TorontoTorontoCanada.
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 hybridization against , the only gene situated within the minimal region of amplification. In a validation cohort composed of 97 carcinosarcomas and other uterine sarcomas, amplification of (/ 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 ( ratio ≥1.5 but <2.2). The functional relevance of Glypican-5, the gene product of , in regulating differentiation and lineage commitment was demonstrated in an endometrial carcinoma cell line . In conclusion, we identified amplification as a molecular event mediating epithelial-mesenchymal transdifferentiation in a subset of uterine carcinosarcomas.