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For Peer Review Carcinogenesis Genome-wide DNA methylation profile of early-onset endometrial cancer: Its correlation with genetic aberrations and comparison with late-onset endometrial cancer Journal: Carcinogenesis ManuscriptFor ID CARCIN-2018-00453.R2 Peer Review Manuscript Type: Original Manuscript Date Submitted by the 28-Jan-2019 Author: Complete List of Authors: Makabe, Takeshi; Keio University School of Medicine Graduate School of Medicine, Pathology; Keio University School of Medicine Graduate School of Medicine, Obstetrics and Gynecology Arai, Eri; Keio University School of Medicine, Department of Pathology; National Cancer Center Reserach Institute, Division of Molecular Pathology Hirano, Takuro; Keio University School of Medicine Graduate School of Medicine, Pathology; Keio University School of Medicine Graduate School of Medicine, Obstetricus and Gynecology Ito, Nanako; Keio University School of Medicine, Department of Pathology Fukamachi, Yukihiro; Mitsui Knowledge Industry Co Ltd, Bioscience Takahashi, Yoriko; Mitsui Knowledge Industry Co., Ltd., Bioscience Department, Business Development Division Hirasawa, Akira; Keio University School of Medicine Graduate School of Medicine, Obstetrics and Gynecology Yamagami, Wataru; Keio University School of Medicine Graduate School of Medicine, Obstetrics and Gynecology Susumu, Nobuyuki; International University of Health and Welfare School of Medicine, Obstetrics and Gynecology Aoki, Daisuke; Keio Gijuku Daigaku Igakubu Daigakuin Igaku Kenkyuka, Department of Obstetrics and Gynecology Kanai, Yae; Keio University School of Medicine, Department of Pathology; National Cancer Center Research Institute, Division of Molecular Pathology DNA methylation, Infinium array, endometrioid endometrial cancer, Keywords: early-onset, fertility preservation Page 1 of 37 Carcinogenesis 1 Makabe et al. 1 2 3 4 5 6 Genome-wide DNA methylation profile of early-onset endometrial cancer: Its 7 8 correlation with genetic aberrations and comparison with late-onset endometrial 9 10 11 cancer 12 13 14 15 16 Takeshi Makabe,1,2 Eri Arai,1* Takuro Hirano,1,2 Nanako Ito,1 Yukihiro Fukamachi,3 17 18 Yoriko Takahashi,3 Akira Hirasawa,2 Wataru Yamagami,2 Nobuyuki Susumu,2,4 Daisuke 19 20 2 1 21 Aoki, Yae Kanai For Peer Review 22 23 24 25 26 1Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan, 27 28 2Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo 29 30 3 31 160-8582, Japan, Bioscience Department, Mitsui Knowledge Industry Co., Ltd., Tokyo, 32 33 105-6215, Japan, 4Department of Obstetrics and Gynecology, International University of 34 35 Health and Welfare School of Medicine, Chiba 286-8686, Japan 36 37 38 39 40 * 41 To whom correspondence should be addressed: Department of Pathology, Keio 42 43 University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. 44 45 Tel: 81-3-3353-1211; Fax: 81-3-3353-3290; E-mail: [email protected]. 46 47 48 49 50 51 Running head: DNA methylation profile of endometrial cancer 52 53 54 55 56 Abbreviations: CNA, copy number alteration; CTNNB1-M, tissue samples of early- 57 58 59 60 Carcinogenesis Page 2 of 37 1 Makabe et al. 2 2 3 4 5 6 onset endometrioid endometrial cancer with somatic mutation of the CTNNB1 gene; 7 8 CTNNB1-W, tissue samples of early-onset endometrioid endometrial cancer without 9 10 11 somatic mutation of the CTNNB1 gene; EE, early-onset endometrioid endometrial cancer 12 13 tissue; FGFR2-M, tissue samples of late-onset endometrioid endometrial cancer with 14 15 somatic mutation of the FGFR2 gene; FGFR2-W, tissue samples of late-onset 16 17 endometrioid endometrial cancer without somatic mutation of the FGFR2 gene; GO, gene 18 19 20 ontology; MPA, medroxyprogesterone acetate; LE, late-onset endometrioid endometrial 21 For Peer Review 22 cancer tissue; PCA, principal component analysis; ROC, receiver operating 23 24 characteristic; TSS, transcription start site. 25 26 27 28 29 30 Topic: DNA methylation, Infinium array, endometrioid endometrial cancer, early-onset, 31 32 fertility preservation. 33 34 35 36 37 Issue Section: ORIGINAL MANUSCRIPT 38 39 40 41 42 43 248 words of abstract, 4,363 words of text, one table, 5 figures and 48 references. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 3 of 37 Carcinogenesis 1 Makabe et al. 3 2 3 4 5 6 Abstract 7 8 9 The present study was performed to clarify the significance of DNA methylation 10 11 alterations during endometrial carcinogenesis. Genome-wide DNA methylation analysis 12 13 and targeted sequencing of tumor-related genes were performed using the Infinium 14 15 16 MethylationEPIC BeadChip and the Ion AmpliSeq Cancer HotSpot Panel v2, 17 18 respectively, for 31 samples of normal control endometrial tissue from patients without 19 20 endometrial cancer and 81 samples of endometrial cancer tissue. Principal component 21 For Peer Review 22 analysis revealed that tumor samples had a DNA methylation profile distinct from that of 23 24 25 control samples. Gene ontology enrichment analysis revealed significant differences of 26 27 DNA methylation at 1,034 CpG sites between early-onset endometrioid endometrial 28 29 cancer (EE) (patients aged <40 years) and late-onset cancer (LE), which were 30 31 accumulated among “transcriptional factors”. Mutations of the CTNNB1 gene or DNA 32 33 34 methylation alterations of genes participating in Wnt signaling were frequent in EEs, 35 36 whereas genetic and epigenetic alterations of FGF signaling genes were observed in LEs. 37 38 Unsupervised hierarchical clustering grouped EE samples into Clusters EA (n=22) and 39 40 EB (n=12). Clinicopathologically less aggressive tumors tended to be accumulated in 41 42 43 Cluster EB, and DNA methylation levels of 18 genes including HOXA9, HOXD10 and 44 45 SOX11 were associated with differences in such aggressiveness between the two clusters. 46 47 We identified eleven marker CpG sites that discriminated EB samples from EA samples 48 49 with 100% sensitivity and specificity. These data indicate that genetically and 50 51 52 epigenetically different pathways may participate in the development of EEs and LEs, 53 54 and that DNA methylation profiling may help predict tumors that are less aggressive and 55 56 amenable to fertility preservation treatment. 57 58 59 60 Carcinogenesis Page 4 of 37 1 Makabe et al. 4 2 3 4 5 6 Summary 7 8 9 Genome-wide analysis using 112 samples of endometrial tissue has revealed that 10 11 genetically and epigenetically different pathways may participate in early- and late-onset 12 13 endometrial carcinogenesis. DNA methylation profiling may predict tumors that are less 14 15 16 aggressive and amenable to fertility preservation treatment. 17 18 19 20 21 For Peer Review 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 5 of 37 Carcinogenesis 1 Makabe et al. 5 2 3 4 5 6 Introduction 7 8 9 Endometrial cancer is one of the most common gynecological malignancies in the 10 11 developed countries, with about 320,000 new cases diagnosed annually worldwide (1). 12 13 Although it is typically a disease of post-menopausal women, approximately 2-14% of 14 15 16 cases occur in women aged 40 years or less (2-4), and in fact recently endometrial cancer 17 18 in younger patients has shown a marked increase (4). The standard treatment for 19 20 endometrial cancer is hysterectomy and bilateral salpingo-oophorectomy 21 For Peer Review 22 with or without lymph node dissection, but for younger patients fertility-sparing treatment 23 24 25 that avoids surgical menopause needs to be considered. Currently, conservative treatment 26 27 with hormones such as medroxyprogesterone acetate (MPA) is used for early-stage early- 28 29 onset endometrial cancer without myometrial invasion or extrauterine spread (5). 30 31 However, we have reported previously that the recurrence rate after MPA therapy is 32 33 34 63.2%, and the resulting pregnancy rate lower than would be desired (6). In order to 35 36 improve the outcome of medical treatment for patients with endometrial cancer, there is 37 38 a need to clarify the molecular basis of endometrial carcinogenesis, especially in young 39 40 patients. 41 42 43 It is well known that not only genomic but also epigenomic alterations participate 44 45 in carcinogenesis in various human organs (7,8). DNA methylation alterations are one of 46 47 48 the most important epigenomic changes resulting in chromosomal instability and aberrant 49 50 expression of tumor-related genes (9-11). We and other groups have shown that DNA 51 52 methylation alterations are frequently associated with tumor aggressiveness and poorer 53 54 patient outcome, and can be employed clinically as prognostic markers in cancers of 55 56 57 various organs (12-17). Recently single-CpG resolution genome-wide DNA methylation 58 59 60 Carcinogenesis Page 6 of 37 1 Makabe et al. 6 2 3 4 5 6 screening using the Infinium assay has been introduced for analysis of human tissue 7 8 specimens. However, none of previous studies of endometrial cancer based on the 9 10 11 Infinium assay (18-22), including the study by The Cancer Genome Atlas (TCGA) (23), 12 13 focused on early-onset endometrial cancer. 14 15 16 In the present study, to further clarify the significance of DNA methylation 17 18 alterations during endometrial carcinogenesis and their correlation with genetic 19 20 abnormalities, we performed genome-wide DNA methylation (methylome) analysis 21 For Peer Review 22 using the high-density EPIC BeadChip on 31 samples of normal control endometrial 23 24 25 tissue from patients without endometrial cancer and 81 samples of endometrial cancer 26 27 tissue including 35 samples of early-onset endometrial cancer.
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