FBXW7, L1CAM, and TGM2 in endometrial cancer.

Abstract

FBXW7 is frequently somatically mutated in grade 3 endometrioid endometrial cancers and serous endometrial cancers, high-risk cancers associated with a poor prognosis. Urick et al1 used clustered regularly interspaced short palindromic repeats (CRISPR)–edited cell lines to identify the proteomic and phosphoproteomic effects of FBXW7 mutations in 3 high-risk endometrial cancers, including altered protein levels of L1CAM and TGM2. They found decreased levels of L1CAM and TGM2 proteins after the reversion of endogenous FBXW7 mutations in 2 cell lines derived from grade 2 endometrioid endometrial cancers. This result is important because L1CAM and TGM2 are druggable proteins that could represent new therapeutic targets. To further investigate the relationship of FBXW7, L1CAM, and TGM2 with endometrial cancer, we consulted The Cancer Genome Atlas (TCGA). We used cBioPortal for Cancer Genomics to analyze data in TCGA. We used the University of California Santa Cruz Xena Browser to analyze gene expression. For differential gene expression analysis, the 2018 version of the gene ontology molecular function was used. We analyzed data from 522 patients in the Genomic Data Commons (GDC) TCGA endometroid cancer data set. The mean age was 64 ± 11 years. Grade 3 tumors were most common. Mutations in FBX7, L1CAM, and TGM2 tended to significantly co-occur. Cancer gene alterations usually do not occur at random. Alterations of certain cancer genes tend to co-occur, and this indicates that they may work in tandem to drive tumor formation and development.2 This may be the case with the co-occurring alterations of FBXW7, L1CAM, and TGM2. FBXW7 mutations affected gene expression of L1CAM but were unrelated to TGM2 gene expression. L1CAM gene expression was significantly related to survival. Patients with lower L1CAM gene expression had better survival (P = .00000032 [log-rank test]). FBXW7 mutations were unrelated to survival (P = .11 [log-rank test]). TGM2 gene expression was unrelated to FBXW7 mutations. TGM2 gene expression was unrelated to survival for all tumor grades (P = .5 [log-rank test]) or grade 3 alone (P = .4 [log-rank test]). Urick et al1 reported that phosphorylated proteins exhibited significantly different levels (P < .05) in CRISPR-edited FBXW7-mutant HEC-50B cells in comparison with matched FBXW7-nonmutant parental cells. A differential gene expression analysis of the GDC TCGA endometroid cancer data set demonstrated phosphorylated proteins at significantly different levels in grade 2 cancers versus grade 3 cancers, with significant downregulation in grade 2. The expression of phosphorylated proteins (eg, p-MAPK) is increased in actively proliferating tissues such as normal proliferative-phase endometrium and endometrial carcinoma. In endometrial carcinoma, the MAPK signaling pathway appears to play a major role in tumor cell proliferation and survival.3 Urick et al noted the effect of phosphorylated proteins in their cell lines, and we documented the effect of phosphorylation in the GDC TCGA endometroid cancer data set. We agree with Urick et al1 that L1CAM is a promising druggable target in endometrial carcinoma. However, the lack of a relationship of TGM2 expression with FBXW7 mutations and endometrial cancer survival suggests that TGM2 might not be of as much value as a druggable target in comparison with L1CAM. Further investigations are warranted. The 2 authors contributed equally to this article. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this letter was also supported by the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD018522 and S10OD026880. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors made no disclosures.