title: Tumor heterogeneity at protein level as an independent prognostic factor in endometrial cancer.
abstract: Intratumor heterogeneity implies heterogeneous protein function, facilitating tumor adaptation which results in therapeutic failure. We hypothesized that tumor heterogeneity at protein level may influence the course of the disease. As a single biopsy might not represent the full biologic complexity of the tumor, we have analyzed immunohistochemically four different cores obtained from each primary tumor within the cohort of 364 patients with endometrial cancer (EC). The following proteins were examined: estrogen receptor 1 (ESR1), progesterone receptor, epidermal growth factor receptor, v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, receptor tyrosine-protein kinase erbB-3, v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4, phosphatidylinositol-4,5-bisphosphate 3-kinase, phosphorylated v-akt murine thymoma viral oncogene homolog 1, v-myc avian myelocytomatosis viral oncogene homolog, DNA topoisomerase II alpha 170 kDa (TOP2A), cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53, RAD21 homolog, S. pombe, and runt-related transcription factor 1. Particularly strong correlation was found between TOP2A and CDKN2A heterogeneity and higher stage of the disease (P = .0002 and P = .0003, respectively). Most correlations with clinicopathologic data were observed for ESR1 heterogeneity that correlated with non-endometrioid carcinomas (P=.02), higher stage (P=.005), grade (P=.01), and the presence of metastases (P = .01). Thirty-nine (11.0%) patients were classified as "globally heterogeneous". Cumulative tumor heterogeneity strongly correlated with the presence of metastases, higher stage, and higher grade of the disease (all P b .05). It also carried negative prognostic value (P=.0008). We show that the degree of heterogeneity in EC might serve as a clinically valid molecular marker.
authors.affiliation: Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, 80-211 Gdańsk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Supernat
authors.affiliation: Department of Gynaecology, Gynaecological Oncology and Gynaecological Endocrinology, Medical University of Gdańsk, 80-402 Gdańsk, Poland.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Lapińska-Szumczyk
authors.affiliation: Department of Pathomorphology, Medical University of Gdańsk, 80-214 Gdańsk, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Majewska
authors.affiliation: Department of Pathology and Neuropathology, Medical University of Gdańsk, 80-211 Gdańsk, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Gulczyński
authors.affiliation: Department of Pathomorphology, Medical University of Gdańsk, 80-214 Gdańsk, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Biernat
authors.affiliation: Department of Gynaecology, Gynaecological Oncology and Gynaecological Endocrinology, Medical University of Gdańsk, 80-402 Gdańsk, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Wydra
authors.affiliation: Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, 80-211 Gdańsk, Poland. Electronic address: azaczek@gumed.edu.pl.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Zaczek