CHAPTER 4 92 DISCUSSION The primary aim of this study was to identify and compare the molecular and IHC background of pure and mixed uterine CCC in association with clinical outcome. Interestingly, all TCGA subgroups were observed within this cohort, in line with previous findings showing that uterine CCCs are molecularly heterogeneous 19. Only one mixed uterine CCC with a POLE mutation was found with an excellent outcome. In pure uterine CCCs, no POLE mutations were found, in line with a previous study by Hoang et al 19. DeLair et al, however, comprehensively sequenced a cohort of 32 pure CCCs and did find two patients with pathogenic POLE mutations 18. Interestingly, in our study, mixed uterine CCCs were found to be MSI frequently, whereas pure uterine CCCs were mainly microsatellite stable. DeLair et al found MMRd in 19%, whereas Hoang et al found MSI in none of the evaluated tumors. The secondary aim was to evaluate whether histological classification, molecular and IHC features affect clinical outcome. In Kaplan-Meier analysis, outcome was correlated to histology, molecular subgroups and L1CAM status. In multivariable Cox regression analysis, molecular status was correlated to OS and DSS, whereas histology was not. These results may suggest that differences in outcome between pure and mixed uterine CCCs may rather be explained by distinct molecular background. TP53 mutations were found more often in pure uterine CCC, which could be contributive to their dismal prognosis 19, 27. POLE mutations and MSI, associated with improved outcome, were on the other hand observed in mixed uterine CCCs more frequently. Previously, it was shown by Köbel et al. that mixed uterine CCCs harbor a superior prognosis compared to pure uterine CCCs 20. Also in serous ECs it is known that mixed serous ECs harbor a superior prognosis compared to pure serous ECs 12. In this previous study however it was not investigated whether differences in prognosis could be explained by molecular signatures. The oncogenesis of mixed tumors has not been fully elucidated. In ten patients with mixed uterine CCCs, we sequenced both histological components separately and found that eight tumors harbored at least one shared mutation in both components. Also, in nine tumors ‘non-shared’ mutations were found, most frequently ARID1A mutations. Most ‘non-shared’ mutations were found in patients with POLE mutated or MSI tumors. A previous study has shown that both components in mixed CCCs harbored shared mutations, but also showed significant molecular heterogeneity and non-shared mutations. 28 These data are indicative that both components may evolve from a single clone but diverge along the way by obtaining new and unique mutations. POLE mutated and MSI tumors are considered as ultra/hypermutated tumors due to the acquirement of an extremely high burden of secondary mutations due to
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