Clinical outcome of 23 patients with mixed endometrioid and serous endometrial carcinomas (mixed EEC-SC) was compared to that of pure endometrioid (EEC) and pure serous (SC) carcinomas. Hotspot mutation frequencies in KRAS, PIK3CA, PTEN, and TP53 and microsatellite instability (MSI) status were determined in mixed EEC-SC, as well as in their EEC and SC microdissected components separately, and alterations were compared to frequencies in pure EEC and SC. Relapse-free (RFS) and overall survival (OS) differed significantly between mixed EEC-SC and pure EEC and SC, revealing that outcome of mixed EEC-SCs was intermediate to that of pure EEC and pure SC. PTEN mutations were absent in pure SC, but occurred in 20 % of pure EEC, and 13 % of mixed EEC-SC. In contrast, TP53 mutations were more frequent in pure SC (17 %) and mixed EEC-SC (22 %) than in pure EEC (2 %). Mutations in mixed EEC-SC were shared by the two microdissected components in 30 %, whereas in 35 %, some mutations were component-specific. Mutation analysis confirms similarities between the EEC and SC components of mixed EEC-SC with pure EEC and pure SC, respectively. However, PTEN and KRAS mutations were more frequent in the SC component of mixed EEC-SC than in pure SC, while TP53 mutations were more frequent in the EEC component of mixed EEC-SC than in pure EEC. Presence of different clonal mutation pattern between EEC and SC components of mixed EEC-SC raises the possibility of divergent tumor heterogeneity or biclonal origin in some cases.
Endometrial cancer Mixed endometrial carcinomas Mutation analysis Clinical outcome
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This work was supported by the Verelst Uterine Cancer Fund Leuven (VBL) and by a research grant of FWO Flanders (G.0827.13). This work is a result of collaboration within ENITEC (European Network for Individualised Treatment in Endometrial Cancer) as part of ESGO (European Society of Gynecological Oncology). L.C. is a postdoctoral fellow of FWO Flanders and F.A. is senior researcher for FWO Flanders.
Conflict of interest
The authors declare that they have no conflict of interest.
Supplementary Table 1Detailed overview of all detected mutations in separate components of mixed EEC-SC. When a mutation is detected, this is indicated with 1, wild-type is indicated with 0. Colors are used to differentiate between mutations that are present in both components (green), mutations only in EEC component (yellow) and mutations only in SC component (orange). (DOC 108 kb) (DOC 56 kb)
Supplementary Table 2Overview of MSI status of the separate components of the mixed EEC-SC. MSI status was determined using the 59-marker panel recently established by Zhao et al. (under revision). (DOC 56 kb)
Yeramian A, Moreno-Bueno G, Dolcet X, Catasus L, Abal M, Colas E et al (2013) Endometrial carcinoma: molecular alterations involved in tumor development and progression. Oncogene 32:403–413CrossRefPubMedGoogle Scholar
Quddus MR, Sung CJ, Zhang C, Lawrence WD (2010) Minor serous and clear cell components adversely affect prognosis in “mixed-type” endometrial carcinomas: a clinicopathologic study of 36 stage-I cases. Reprod Sci 17:673–678CrossRefPubMedGoogle Scholar
Roelofsen T, van Ham MA, Wiersma van Tilburg JM, Zomer SF, Bol M, Massuger LF et al (2012) Pure compared with mixed serous endometrial carcinoma: two different entities? Obstet Gynecol 120:1371–1381PubMedGoogle Scholar
McConechy MK, Ding J, Cheang MC, Wiegand KC, Senz J, Tone AA et al (2012) Use of mutation profiles to refine the classification of endometrial carcinomas. J Pathol 228:20–30PubMedCentralPubMedGoogle Scholar
Kurman RJ, Carcangiu ML, Herrington CS, Young RH (2014) WHO classification of tumors of the female reproductive organs. WHO classification of tumors. IARC press, LyonGoogle Scholar
Garcia-Dios DA, Lambrechts D, Coenegrachts L, Vandenput I, Capoen A, Webb PM et al (2013) High-throughput interrogation of PIK3CA, PTEN, KRAS, FBXW7 and TP53 mutations in primary endometrial carcinoma. Gynecol Oncol 128:327–334CrossRefPubMedGoogle Scholar
Lax SF, Kendall B, Tashiro H, Slebos RJ, Hedrick L (2000) The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways. Cancer 88:814–824CrossRefPubMedGoogle Scholar
Zhang L, Liu Y, Hao S, Woda BA, Lu D (2011) IMP2 expression distinguishes endometrioid from serous endometrial adenocarcinomas. Am J Surg Pathol 35:868–872CrossRefPubMedGoogle Scholar
Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D et al (2011) COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 39:D945–D950CrossRefPubMedCentralPubMedGoogle Scholar
Catasus L, Gallardo A, Cuatrecasas M, Prat J (2009) Concomitant PI3K-AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis. Mod Pathol 22:522–529CrossRefPubMedGoogle Scholar
Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H et al (2013) Integrated genomic characterization of endometrial carcinoma. Nature 497:67–73Google Scholar