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      Cyclin D1 expression predicts postoperative distant metastasis and survival in resectable esophageal squamous cell carcinoma

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          Abstract

          Purpose

          We aim to identify esophageal squamous cell carcinoma patients with increased risk of postoperative metastases.

          Results

          A high level of cyclin D1 expression, together with poor tumor cell differentiation and advanced tumor stages, increased risk of postoperative metastasis and decreased distant metastasis-free survival in ESCC in both cohorts. A high level of cyclin D1 expression also decreased overall survival in the training cohort ( p < 0.01) but not in the validation cohort ( p = 0.415). However, when the two cohorts of patients were pooled to obtain a larger case number, a high level of cyclin D1 expression was again demonstrated as an independent predictor that decreased overall survival ( p < 0.01).

          Methods

          We used data from two institutions to establish training ( n = 319) and validation ( n = 164) cohorts. Tissue microarrays were generated for immunohistochemical evaluation. The correlation among cyclin D1 expression, clinicopathologic variables, postoperative distant metastases, overall survival, and distant metastasis-free survival were analyzed. Multivariate analyses were used to test the independent factors impacting postoperative distant metastases and survival. The outcomes generated from the training cohort were then tested using the validation cohort and pooled dataset.

          Conclusions

          High level of cyclin D1 expression increased distant metastasis, decreased overall survival and distant metastasis-free survival in resectable ESCC. Using a combination of cyclin D1 expression, tumor cell differentiation grade, and tumor stages, identifying patients with increased risk of postoperative metastases becomes possible.

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          Most cited references24

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          Genetic landscape of esophageal squamous cell carcinoma.

          Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers. We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2; 19%), KMT2C (MLL3; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1, FAT2, FAT3 or FAT4 (27%) or AJUBA (JUB; 7%) and NOTCH1, NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.
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            Worldwide esophageal cancer collaboration.

            The aim of this study is to report assemblage of a large multi-institutional international database of esophageal cancer patients, patient and tumor characteristics, and survival of patients undergoing esophagectomy alone and its correlates. Forty-eight institutions were approached and agreed to participate in a worldwide esophageal cancer collaboration (WECC), and 13 (Asia, 2; Europe, 2; North America, 9) submitted data as of July 1, 2007. These were used to construct a de-identified database of 7884 esophageal cancer patients who underwent esophagectomy. Four thousand six hundred and twenty-seven esophagectomy patients had no induction or adjuvant therapy. Mean age was 62 +/- 11 years, 77% were men, and 33% were Asian. Mean tumor length was 3.3 +/- 2.5 cm, and esophageal location was upper in 4.1%, middle in 27%, and lower in 69%. Histopathologic cell type was adenocarcinoma in 60% and squamous cell in 40%. Histologic grade was G1 in 32%, G2 in 33%, G3 in 35%, and G4 in 0.18%. pT classification was pTis in 7.3%, pT1 in 23%, pT2 in 16%, pT3 in 51%, and pT4 in 3.3%. pN classification was pN0 in 56% and pN1 in 44%. The number of lymph nodes positive for cancer was 1 in 12%, 2 in 8%, 3 in 5%, and >3 in 18%. Resection was R0 in 87%, R1 in 11%, and R2 in 3%. Overall survival was 78, 42, and 31% at 1, 5, and 10 years, respectively. Unlike single-institution studies, in this worldwide collaboration, survival progressively decreases and is distinctively stratified by all variables except region of the world. A worldwide esophageal cancer database has been assembled that overcomes problems of rarity of this cancer. It reveals that survival progressively (monotonically) decreased and was distinctively stratified by all variables except region of the world. Thus, it forms the basis for data-driven esophageal cancer staging. More centers are needed and encouraged to join WECC.
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              D-type cyclins.

              C Sherr (1995)
              D-type cyclins couple extracellular signals to the biochemical machinery that governs progression through G1 phase of the mammalian cell division cycle. Induced by growth factor stimulation, D-type cyclins assemble with cyclin-dependent kinases CDK4 and CDK6 to form holoenzymes that facilitate exit from G1 by phosphorylating key substrates, including the retinoblastoma protein. Activation of the holoenzymes is antagonized by polypeptide inhibitors of CDK activity, which are induced by antiproliferative signals. Once cells pass a late G1 restriction point, cyclin-D-dependent kinases are unnecessary for completion of the cell cycle, implying that their primary role is to sense the cell's readiness to replicate DNA and to enforce the commitment to enter S phase.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                24 May 2016
                28 April 2016
                : 7
                : 21
                : 31088-31096
                Affiliations
                1 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou City, Guangdong Province, China
                2 Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou City, Guangdong Province, China
                3 Guangdong Esophageal Cancer Institute, Guangzhou City, Guangdong Province, China
                4 Department of Thoracic Surgery, Linzhou Esophageal Cancer Hospital, Yaocun Town, Linzhou City, Henan Province, China
                5 Institute of Medical Statistics and Epidemiology, Sun Yat-sen University Medical College, Guangzhou City, Guangdong Province, China
                6 Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou City, Guangdong Province, China
                Author notes
                Correspondence to: Hao-Xian Yang, yanghx@ 123456sysucc.org.cn
                Article
                9078
                10.18632/oncotarget.9078
                5058741
                27145270
                560f85bf-59d4-4cbd-a7be-f114f1700056
                Copyright: © 2016 Hou et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 February 2016
                : 11 April 2016
                Categories
                Research Paper

                Oncology & Radiotherapy
                esophageal neoplasm,esophageal squamous cell carcinoma,cyclin d1,surgery,metastasis

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