Prognostic significance of L1CAM expression and its association with mutant p53 expression in high-risk endometrial cancer

Abstract

Studies in early-stage, predominantly low- and intermediate-risk endometrial cancer have demonstrated that L1 cell adhesion molecule (L1CAM) overexpression identifies patients at increased risk of recurrence, yet its prognostic significance in high-risk endometrial cancer is unclear. To evaluate this, its frequency, and the relationship of L1CAM with the established endometrial cancer biomarker p53, we analyzed the expression of both markers by immunohistochemistry in a pilot series of 116 endometrial cancers (86 endometrioid, 30 non-endometrioid subtype) with high-risk features (such as high tumor grade and deep myometrial invasion) and correlated results with clinical outcome. We used The Cancer Genome Atlas (TCGA) endometrial cancer series to validate our findings. Using the previously reported cutoff of 10% positive staining, 51/116 (44%) tumors were classified as L1CAM-positive, with no significant association between L1CAM positivity and the rate of distant metastasis (P=0.195). However, increasing the threshold for L1CAM positivity to 50% resulted in a reduction of the frequency of L1CAM-positive tumors to 24% (28/116), and a significant association with the rate of distant metastasis (P=0.018). L1CAM expression was strongly associated with mutant p53 in the high-risk and TCGA series (P<0.001), although a substantial fraction (36% of endometrioid, 10% of non-endometrioid morphology) of p53-mutant endometrial cancers displayed <10% L1CAM positivity. Moreover, 30% of p53-wild-type non-endometrioid endometrial cancers demonstrated diffuse L1CAM staining, suggesting p53-independent mechanisms of L1CAM overexpression. In conclusion, the previously proposed threshold for L1CAM positivity of >10% does not predict prognosis in high-risk endometrial cancer, whereas an alternative threshold (>50%) does. L1CAM expression is strongly, but not universally, associated with mutant p53, and may be strong enough for clinical implementation as prognostic marker in combination with p53. The high frequency of L1CAM expression in high-risk endometrial cancers suggests that it may also be a promising therapeutic target in this tumor subset.

High Expression of Ubiquitin C-terminal Hydrolase L1 Is Associated With Poor Prognosis in Endometrial Cancer Patients

“…Recently, several studies have been performed using the Cancer Genome Atlas Research network. 32,33 A large-scale retrospective study of approximately 1200 cases showed that L1 cell adhesion molecule is a strong prognostic factor for endometrial cancer. 33 Deubiquitinating enzymes have been reported to be involved in differentiation and proliferation in several cancer tissues.…”

Added Value of Estrogen Receptor, Progesterone Receptor, and L1 Cell Adhesion Molecule Expression to Histology-Based Endometrial Carcinoma Recurrence Prediction Models: An ENITEC Collaboration Study

“…14,16 One study has shown that expression of L1CAM and p53 are strongly, but not universally associated, and both markers are therefore valuable prognostic markers. 17 A study including ER, PR, and L1CAM has not yet been conducted, and their added value to the currently used prognostic models and to each other is not yet known. The aim of this study therefore is to analyze the relationship between these 3 markers and to analyze the combined value of ER, PR, and L1CAM in predicting recurrent disease.…”

Prognostic significance of L1 cell adhesion molecule in cancer patients: A systematic review and meta-analysis

“…A total of 11 studies [7, 13, 16, 21, 26, 29, 30, 37, 38, 40, 42] estimated the prognostic value of L1CAM expression on PFS/RFS. Consistent with the above results, significantly shorter PFS/RFS was observed in cancer patients expressing high levels of L1CAM (pooled HR=2.07, 95%CI 1.41-3.05, p<0.001) (Figure 3B).…”