Abstract
BackgroundThe newly developed Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) has consistently been shown to be prognostically significant in endometrial carcinomas (EC). Recently, we and others have demonstrated L1 cell-adhesion molecule (L1CAM) to be a significant indicator of high-risk disease in EC. In the current study, it was our aim to determine the prognostic significance of aberrant L1CAM expression in ProMisE subgroups in a large, single centre, population-based EC cohort.MethodsProMisE (POLE; MMR-D; p53 wt/NSMP; p53 abn) classification results from a cohort of 452 EC were available for analysis. L1CAM expression was studied by immunohistochemistry on whole slides. Correlations between clinicopathological data and survival were calculated.ResultsExpression of L1CAM was most frequent in p53 abnormal tumours (80%). L1CAM status was predictive of worse outcome among tumours with no specific molecular profile (p53 wt/NSMP) (p < 0.0001). Among p53 wt/NSMP EC, L1CAM remained a significant prognosticator for disease-specific survival after multivariate analysis (p = 0.035).ConclusionL1CAM status was able to significantly stratify risk among tumours of the large p53 wt/NSMP ProMisE subgroup of EC. Furthermore, our study confirms a highly significant correlation between mutation-type p53 immunostaining and abnormal L1CAM expression in EC.
Highlights
The newly developed Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) has consistently been shown to be prognostically significant in endometrial carcinomas (EC)
Tumours were evaluated for 4 prognostic subgroups: Polymerase epsilon exonuclease domain mutations (POLE) detected through sequencing, mismatch repair deficiency (MMR-D) evaluated using IHC for the absence of MSH6 or PMS2, and TP53 mutation evaluated using IHC for p53, revealing p53 wild-type (p53 wt/ NSMP) and p53 abnormal (p53 abn) subgroups
In order to guide surgery and/or adjuvant treatment there is still a need to further refine molecular risk stratification. This is most important for intermediate-risk groups of MMR-D and p53 wt/NSMP tumours, which constitute a large percentage of cases (64–79%).[11,12,15]
Summary
The newly developed Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) has consistently been shown to be prognostically significant in endometrial carcinomas (EC). An important step has been the genomic characterisation of EC by The Cancer Genome Atlas (TCGA) group and others, defining four prognostically distinct molecular subgroups.[9,10] In order to simplify the methodologies and to lower cost involved in identifying these molecular subgroups, research teams have recently described surrogate markers that can be studied more .[11,12,13,14,15] Talhouk et al have developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), demonstrating an easy pragmatic classification system for ECs.[11,12,15] The four prognostic ProMisE subgroups are as follows: DNA Polymerase epsilon exonuclease domain mutation (POLE), mismatch repair deficiency (MMR-D), p53 wild-type (p53 wt) and p53 abnormal (p53 abn).[11] Tumours within the p53 wt group, which do not harbour mutations of neither POLE, mismatch repair genes nor abnormal p53, are referred to as tumours with “No Specific Molecular Profile, NSMP”.16
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