Genomic profiling of dedifferentiated endometrial carcinomas arising in the background of high‐grade carcinoma: a targeted next‐generation sequencing study

Abstract

AimsOur understanding of dedifferentiated endometrial carcinoma (DEC), a rare and aggressive malignancy, mainly reflects undifferentiated carcinomas (UC) arising in the setting of low‐grade endometrial cancer (DEC‐LG). However, cases of UC arising in the setting of high‐grade EC (DEC‐HG) have been noted in the literature. Our knowledge of the genomics of DEC‐HG is limited. To characterise the molecular landscape of DEC‐HC, targeted genomic sequencing and immunohistochemical analysis was carried out on seven DEC‐HG and four DEC‐LG.Methods and resultsDEC‐HG and DEC‐LG, including undifferentiated and differentiated components, both showed a similar frequency and spectrum of mutations. ARID1A mutations were identified in 6/7 (86%) DEC‐HG and 4/4 (100%) DEC‐LG, while SMARCA4 mutations were present in 4/7 (57%) DEC‐HG and in 1/4 (25%) DEC‐LG. Concurrent SMARCA4/BRG1 protein loss by immunohistochemistry was observed in 3/4 and 1/1 SMARCA4 mutated DEC‐HG and DEC‐LG, respectively. Neither genomic alterations nor protein loss in SMARCB1/INI1 were observed in any of our cases. TP53 mutations were detected in 4/7 (57%) DEC‐HG and in 2/4 (50%) DEC‐LG, while mutation‐pattern p53 immunohistochemistry expression was observed in 2/7 (29%) DEC‐HG and none of the DEC‐LG. MLH1 mutations were observed in 1/7 (14%) DEC‐HG and 1/4 (25%) DEC‐LG. MSH2 and MSH6 mutations were each detected in 1/7 (14%) DEC‐HG, but neither was associated with corresponding loss of protein expression.ConclusionThe findings support expanding the definition of DEC to include DEC‐HG, a previously under‐recognised phenomenon with genomic similarities to DEC‐LG.