Two Distinct Tumorigenic Processes in Endometrial Endometrioid Adenocarcinoma
2019; Elsevier BV; Volume: 190; Issue: 1 Linguagem: Inglês
10.1016/j.ajpath.2019.09.022
ISSN1525-2191
AutoresYuko Sugiyama, Osamu Gotoh, Nobuyuki Fukui, Norio Tanaka, Katsuhiko Hasumi, Yutaka Takazawa, Tetsuo Noda, Seiichi Mori,
Tópico(s)RNA Research and Splicing
ResumoEndometrial endometrioid adenocarcinoma (EEA) is conventionally considered to be a single pathologic entity that develops through a hyperplasia-carcinoma sequence under the influence of estrogen. Previously, another EEA subtype was described and proposed to arise directly from normal endometrium. These conventional and de novo subtypes are designated groups 1 and 2, respectively. To identify the molecular mechanisms of these distinct tumorigenic processes, we conducted comprehensive integrated analyses of genomic data with hormonal status for group 1 paired carcinoma and hyperplasia and group 2 carcinoma samples. Although group 1 carcinomas mostly exhibited genomically stable characteristics and the activation of estrogen signaling, group 2 EEAs showed enriched hypermutator and CpG island methylator phenotypes. Pairwise comparisons of hyperplasia and carcinoma, along with time-course analyses of the hyperplasia-carcinoma sequence, revealed the acquisition of driver mutations in the evolutionary process of hyperplasia but not in the transition from hyperplasia to carcinoma. The current study confirms the existence of two different histopathologic programs during EEA development that harbor distinct molecular bases and demonstrates the biological relevance of these differential tumorigenic processes. Endometrial endometrioid adenocarcinoma (EEA) is conventionally considered to be a single pathologic entity that develops through a hyperplasia-carcinoma sequence under the influence of estrogen. Previously, another EEA subtype was described and proposed to arise directly from normal endometrium. These conventional and de novo subtypes are designated groups 1 and 2, respectively. To identify the molecular mechanisms of these distinct tumorigenic processes, we conducted comprehensive integrated analyses of genomic data with hormonal status for group 1 paired carcinoma and hyperplasia and group 2 carcinoma samples. Although group 1 carcinomas mostly exhibited genomically stable characteristics and the activation of estrogen signaling, group 2 EEAs showed enriched hypermutator and CpG island methylator phenotypes. Pairwise comparisons of hyperplasia and carcinoma, along with time-course analyses of the hyperplasia-carcinoma sequence, revealed the acquisition of driver mutations in the evolutionary process of hyperplasia but not in the transition from hyperplasia to carcinoma. The current study confirms the existence of two different histopathologic programs during EEA development that harbor distinct molecular bases and demonstrates the biological relevance of these differential tumorigenic processes. Endometrial cancer is the most common gynecologic malignancy in industrialized countries, with the incidence increasing globally. In the widely accepted dualistic model, endometrial cancer is divided into two clinical/epidemiological entities: type 1 cancers, which occur in young and obese patients, are associated with excess estrogen, a favorable prognosis, and endometrioid histology, and are often accompanied by and/or following endometrial hyperplasia (EH); versus type 2 cancers, which represent tumors that arise in older and nonobese patients, are related to poor prognosis and nonendometrioid histotypes, and are typically of serous histology, without associated hyperplastic lesions.1Bokhman J.V. Two pathogenetic types of endometrial carcinoma.Gynecol Oncol. 1983; 15: 10-17Abstract Full Text PDF PubMed Scopus (1821) Google Scholar, 2Deligdisch L. Cohen C.J. 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Bokhman redux: endometrial cancer "types" in the 21st century.Gynecol Oncol. 2017; 144: 243-249Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Endometrial endometrioid adenocarcinoma (EEA) has been conventionally thought to develop from EH as a precursor lesion through a process called hyperplasia-carcinoma sequence. Although signs of hyperestrogenism—as exemplified by the presence of EH and delayed menopause—are typical features of patients with EEA,3Amant F. Moerman P. Neven P. Timmerman D. Van Limbergen E. Vergote I. Endometrial cancer.Lancet. 2005; 366: 491-505Abstract Full Text Full Text PDF PubMed Scopus (1274) Google Scholar, 4Setiawan V.W. Yang H.P. Pike M.C. McCann S.E. Yu H. Xiang Y.B. et al.Type I and II endometrial cancers: have they different risk factors?.J Clin Oncol. 2013; 31: 2607-2618Crossref PubMed Scopus (515) Google Scholar, 5Murali R. Soslow R.A. Weigelt B. 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Although patients with group 2 EEA are less likely to have hyperestrogenic phenotypes—similar to that seen with type 2 endometrial cancer8Sivridis E. Fox H. Buckley C.H. Endometrial carcinoma: two or three entities?.Int J Gynecol Cancer. 1998; 8: 183-188Crossref Scopus (39) Google Scholar,10Koul A. Willen R. Bendahl P.O. Nilbert M. Borg A. Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis.Cancer. 2002; 94: 2369-2379Crossref PubMed Scopus (96) Google Scholar, 11Geels Y.P. Pijnenborg J.M. van den Berg-van Erp S.H. Bulten J. Visscher D.W. Dowdy S.C. Massuger L.F. Endometrioid endometrial carcinoma with atrophic endometrium and poor prognosis.Obstet Gynecol. 2012; 120: 1124-1131Crossref PubMed Scopus (18) Google Scholar, 12Hasumi K. Sugiyama Y. Sakamoto K. Akiyama F. Small endometrial carcinoma 10 mm or less in diameter: clinicopathologic and histogenetic study of 131 cases for early detection and treatment.Cancer Med. 2013; 2: 872-880Crossref PubMed Scopus (3) Google Scholar—the biological and clinicopathologic properties and tumorigenic processes of group 2 EEAs are largely unknown. Similarly, despite previous endeavors to understand the molecular mechanisms involved in the development of conventional group 1 EEA,3Amant F. Moerman P. Neven P. Timmerman D. Van Limbergen E. Vergote I. Endometrial cancer.Lancet. 2005; 366: 491-505Abstract Full Text Full Text PDF PubMed Scopus (1274) Google Scholar, 4Setiawan V.W. Yang H.P. Pike M.C. McCann S.E. Yu H. Xiang Y.B. et al.Type I and II endometrial cancers: have they different risk factors?.J Clin Oncol. 2013; 31: 2607-2618Crossref PubMed Scopus (515) Google Scholar, 5Murali R. Soslow R.A. Weigelt B. Classification of endometrial carcinoma: more than two types.Lancet Oncol. 2014; 15: e268-e278Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar,13Kandoth C. Schultz N. Cherniack A.D. Akbani R. Liu Y. Shen H. Robertson A.G. Pashtan I. Shen R. Benz C.C. Yau C. Laird P.W. Ding L. Zhang W. Mills G.B. Kucherlapati R. Mardis E.R. Levine D.A. Cancer Genome Atlas Research NetworkIntegrated genomic characterization of endometrial carcinoma.Nature. 2013; 497: 67-73Crossref PubMed Scopus (3017) Google Scholar the processes involved in the transitions from normal endometrium to EH and from EH to EEA remain unclear. Numerous previous studies have identified recurrent somatic mutations in well-described cancer genes, including PTEN, PIK3CA, ARID1A, CTNNB1, and KRAS, which can drive EEA tumorigenesis.5Murali R. Soslow R.A. Weigelt B. Classification of endometrial carcinoma: more than two types.Lancet Oncol. 2014; 15: e268-e278Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar Several reports using next-generation sequencing technology have confirmed the significance of these driver alterations in EEA.13Kandoth C. Schultz N. Cherniack A.D. Akbani R. Liu Y. Shen H. Robertson A.G. Pashtan I. Shen R. Benz C.C. Yau C. Laird P.W. Ding L. Zhang W. Mills G.B. Kucherlapati R. Mardis E.R. Levine D.A. Cancer Genome Atlas Research NetworkIntegrated genomic characterization of endometrial carcinoma.Nature. 2013; 497: 67-73Crossref PubMed Scopus (3017) Google Scholar, 14Gibson W.J. Hoivik E.A. Halle M.K. Taylor-Weiner A. Cherniack A.D. Berg A. Holst F. Zack T.I. Werner H.M. Staby K.M. Rosenberg M. Stefansson I.M. Kusonmano K. Chevalier A. Mauland K.K. Trovik J. Krakstad C. Giannakis M. Hodis E. Woie K. Bjorge L. Vintermyr O.K. Wala J.A. Lawrence M.S. Getz G. Carter S.L. Beroukhim R. Salvesen H.B. 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Such genomic information would help to gain an understanding of the biological underpinnings of group 1 EEA tumorigenesis and to determine possible treatment strategies for EH. Profiling the pattern of somatic genomic aberrations by The Cancer Genome Atlas (TCGA) identified four molecular subtypes in endometrial cancer: polymerase ε-mutated (POLE), microsatellite instability (MSI), copy number high (CNH), and copy number low (CNL) subtypes.13Kandoth C. Schultz N. Cherniack A.D. Akbani R. Liu Y. Shen H. Robertson A.G. Pashtan I. Shen R. Benz C.C. Yau C. Laird P.W. Ding L. Zhang W. Mills G.B. Kucherlapati R. Mardis E.R. Levine D.A. Cancer Genome Atlas Research NetworkIntegrated genomic characterization of endometrial carcinoma.Nature. 2013; 497: 67-73Crossref PubMed Scopus (3017) Google Scholar These molecular subtypes were shown to be tightly linked with histotype (endometrioid or serous), histologic grade (1/2 or 3), patient prognosis, and other clinicopathologic characteristics.13Kandoth C. Schultz N. Cherniack A.D. Akbani R. Liu Y. Shen H. Robertson A.G. Pashtan I. Shen R. Benz C.C. Yau C. Laird P.W. Ding L. Zhang W. Mills G.B. Kucherlapati R. Mardis E.R. Levine D.A. Cancer Genome Atlas Research NetworkIntegrated genomic characterization of endometrial carcinoma.Nature. 2013; 497: 67-73Crossref PubMed Scopus (3017) Google Scholar,28Stelloo E. Bosse T. Nout R.A. MacKay H.J. Church D.N. Nijman H.W. Leary A. Edmondson R.J. Powell M.E. Crosbie E.J. Kitchener H.C. Mileshkin L. Pollock P.M. Smit V.T. Creutzberg C.L. 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A clinically applicable molecular-based classification for endometrial cancers.Br J Cancer. 2015; 113: 299-310Crossref PubMed Scopus (425) Google Scholar Because genomic aberrations are derived from various forms of DNA repair or proofreading deficiencies, each tumor belonging to the POLE, MSI, or CNH subtype—exhibiting a hypermutator phenotype—often has a causative defect in a corresponding DNA repair/proofreading system. POLE tumors are characterized by a substantial number of single-nucleotide variants (SNVs) due to mutations in the exonuclease domain of the gene coding for DNA polymerase ε (POLE), which leads to defective proofreading in DNA synthesis. Tumors with the MSI subtype exhibit a high proportion of insertions/deletions (indels) caused by MLH1 gene silencing, with hypermethylation of the promoter or germline/somatic inactivation of DNA mismatch repair genes, such as MSH2, MSH6, and PMS2. Elevated copy number (CN) abnormality is a predominant characteristic of the CNH subtype, which coincides frequently with mutated TP53 and less frequently with germline/somatic mutations and epigenetic changes in the genes of the homologous recombination repair pathway components, including BRCA1 and BRCA2.13Kandoth C. Schultz N. Cherniack A.D. Akbani R. Liu Y. Shen H. Robertson A.G. Pashtan I. Shen R. Benz C.C. Yau C. Laird P.W. Ding L. Zhang W. Mills G.B. Kucherlapati R. Mardis E.R. Levine D.A. Cancer Genome Atlas Research NetworkIntegrated genomic characterization of endometrial carcinoma.Nature. 2013; 497: 67-73Crossref PubMed Scopus (3017) Google Scholar,30Hansen J.M. Baggerly K.A. Wang Y. Wu S. Previs R.A. Zand B. Dalton H.J. Hu W. Coleman R.L. Sood A.K. Homologous recombination deficiency in endometrioid uterine cancer: an unrecognized phenomenon.Gynecol Oncol. 2015; 137: 21Abstract Full Text Full Text PDF Google Scholar,31Lee Y.C. Milne R.L. Lheureux S. Friedlander M. 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DNA repair, genome stability and cancer: a historical perspective.Nat Rev Cancer. 2016; 16: 35-42Crossref PubMed Scopus (436) Google Scholar it would be informative to be able to relate this molecular subtyping scheme with such histologic tumorigenic subgroups. The aims of this study are twofold: first, to identify the clinical and biological differences between group 1 and 2 tumorigenic processes; and, second, to detail the stepwise emergence of driver events in the hyperplasia-carcinoma sequence during group 1 EEA development. Herein, we address these questions by analyzing genomic and epigenomic data with hormonal status derived from synchronous pairs of group 1 hyperplasia and carcinoma, together with time-course sequential sampling, and group 2 carcinoma samples. The current study highlights a differential mutational burden for the tumorigenic programs associated with groups 1 and 2 and the acquisition of driver mutations in the evolutionary process of hyperplasia but not in the transition from EH to EEA. Ethical approval was obtained from internal review boards of the Japanese Foundation for Cancer Research. Recruited patients provided written informed consent. Pathologic diagnosis and classification of endometrial carcinoma were performed on the basis of the World Health Organization Classification of Tumors 200335Tavassoli F.A. Devilee P. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. IARC Press, Lyon, France2003Google Scholar by three independent gynecologic pathologists (Y.S., K.H., and Y.T.). Staging was performed according to the 2008 modified International Federation of Gynecology and Obstetrics system.36Creasman W. Revised FIGO staging for carcinoma of the endometrium.Int J Gynaecol Obstet. 2009; 105: 109Crossref PubMed Scopus (501) Google Scholar Pathologic definition of endometrial hyperplasia (EH) was as previously described.37Kurman R.J. Blaustein's Pathology of the Female Genital Tract. Springer, London2002Google Scholar Differential diagnosis for hyperplasia and carcinoma was performed according to the criteria of Silverberg and Kurman.38Silverberg S.G. Kurman R.J. Tumors of the Uterine Corpus and Gestational Trophoblastic Disease. Armed Forces Institute of Pathology, Washington, DC1992Google Scholar Tumorigenic subtypes of endometrioid carcinoma were rigorously evaluated by the presence or absence of EH adjacent to the carcinoma in the entire endometrium of the uterus after hysterectomy, as previously described.12Hasumi K. Sugiyama Y. Sakamoto K. Akiyama F. Small endometrial carcinoma 10 mm or less in diameter: clinicopathologic and histogenetic study of 131 cases for early detection and treatment.Cancer Med. 2013; 2: 872-880Crossref PubMed Scopus (3) Google Scholar Because carcinoma can grow into and over adjacent hyperplasia, smaller EEAs (<15 mm along the major axis) were selected to minimize misclassifications. Although each of the 35 group 1 tissues contained EH without atypia, 22 also included atypia lesions. Atypical hyperplasia was removed with laser-capture microdissection, and all genomic assays for hyperplasia samples were performed only using EH without atypia. Patient clinical characteristics were obtained through medical records. Patients had not received chemotherapy or radiation therapy before surgical treatment. Four patients (three in group 1; one in group 2) were treated with oral progestin. Surgical EEA specimens were dissected and processed for histopathologic or immunohistochemical examinations (formalin fixed) as well as exome, methylome, and t
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