title: 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.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Inge C
authors.initials: IC
authors.lastname: Van Gool
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Stelloo
authors.affiliation: Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Remi A
authors.initials: RA
authors.lastname: Nout
authors.affiliation: Department of Gynecology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: Institute of Cancer Sciences, University of Manchester, St Marys Hospital, Manchester, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Edmondson
authors.affiliation: Molecular and Population Genetics Laboratory, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Oxford Cancer Centre, Churchill Hospital, Oxford, UK.
authors.forename: David N
authors.identifier: http://orcid.org/0000-0002-4617-962X
authors.initials: DN
authors.lastname: Church
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Princess Margaret Hospital/University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: MacKay
authors.affiliation: Department of Medicine, Gynecology Unit, Gustave Roussy, Villejuif, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Leary
authors.affiliation: Department of Clinical Oncology, Barts Health NHS Trust, London, UK.
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Powell
authors.affiliation: Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Mileshkin
authors.affiliation: Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Carien L
authors.initials: CL
authors.lastname: Creutzberg
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Vincent T H B M
authors.initials: VT
authors.lastname: Smit
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tjalling
authors.initials: T
authors.lastname: Bosse
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics*; D018269:Carcinoma, Endometrioid / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000556:secondary / Q000628:therapy; D004252:DNA Mutational Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D016889:Endometrial Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D039842:Neural Cell Adhesion Molecule L1 / Q000032:analysis*; D010641:Phenotype; D010865:Pilot Projects; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D039842:Neural Cell Adhesion Molecule L1; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53