Molecular Profiles of Mixed Endometrial Carcinoma

Supplemental Digital Content is available in the text. Mixed endometrial carcinomas are defined as a combination of 2 or more distinct histologic subtypes, one of which must be a type II tumor comprising at least 5% of the tumor volume. The oncogenesis of these tumors remains unclear, particularly in light of the increasingly appreciated morphologic overlap among subtypes, as well as evolving molecular data. We evaluated 8 cases of mixed endometrial carcinoma, including 4 endometrioid (EC)/serous (SC), 1 SC/clear cell (CC), and 3 EC/CC cases, to study the underlying molecular features and oncogenic mechanisms at play. Each component was analyzed by a targeted next-generation sequencing assay. All tumors shared mutations in both components. In 6 cases, one component showed additional mutations. Two EC/SC cases showed shared mutations and mutations unique to each component. When present, unique mutations were typically seen in the SC component, including variants in POLE and TP53, as well as potentially targetable genes DDR2, MAP2K1, and CCNE1. In EC/SC tumors, ERBB2 abnormalities were seen in 2 cases. EC/CC cases showed FGFR2 activating mutations in the EC component only. No fusion drivers were identified. Our data suggest that the majority of these tumors begin as a single clone and diverge along 2 pathways: (1) tumor progression, with one component showing additional mutations, and (2) tumor divergence, in which tumor components have both shared mutations and mutations unique to each component. In addition, the findings suggest a component of morphologic mimicry in these tumors. Our findings are clinically relevant since targetable mutations may be present in only one component of mixed tumors.

[1]  M. Köbel,et al.  Targeted Molecular and Immunohistochemical Analyses of Endometrial Clear Cell Carcinoma Show that POLE Mutations and DNA Mismatch Repair Protein Deficiencies Are Uncommon , 2019, The American journal of surgical pathology.

[2]  C. Gilks,et al.  Issues in the Differential Diagnosis of Uterine Low-grade Endometrioid Carcinoma, Including Mixed Endometrial Carcinomas: Recommendations from the International Society of Gynecological Pathologists , 2018, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[3]  A. Talhouk,et al.  Molecular Subtype Not Immune Response Drives Outcomes in Endometrial Carcinoma , 2018, Clinical Cancer Research.

[4]  A. Naiki‐Ito,et al.  MET amplification in endometrial cancers with clear‐cell carcinoma components , 2018, Pathology international.

[5]  A. Talhouk,et al.  Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[6]  R. Soslow,et al.  Molecular insights into the classification of high-grade endometrial carcinoma. , 2017, Pathology.

[7]  E. Pirog,et al.  Despite Diagnostic Morphology, Many Mixed Endometrial Carcinomas Show Unexpected Immunohistochemical Staining Patterns , 2017, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[8]  Donavan T. Cheng,et al.  The genetic landscape of endometrial clear cell carcinomas , 2017, The Journal of pathology.

[9]  J. Prat,et al.  Undifferentiated and Dedifferentiated Endometrial Carcinomas With POLE Exonuclease Domain Mutations Have a Favorable Prognosis , 2017, The American journal of surgical pathology.

[10]  P. Pollock,et al.  FGFR2 mutations are associated with poor outcomes in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study. , 2017, Gynecologic oncology.

[11]  A. Talhouk,et al.  Confirmation of ProMisE: A simple, genomics‐based clinical classifier for endometrial cancer , 2017, Cancer.

[12]  A. Talhouk,et al.  Interobserver Agreement in Endometrial Carcinoma Histotype Diagnosis Varies Depending on The Cancer Genome Atlas (TCGA)-based Molecular Subgroup , 2017, The American journal of surgical pathology.

[13]  A. Talhouk,et al.  New classification of endometrial cancers: the development and potential applications of genomic-based classification in research and clinical care , 2016, Gynecologic Oncology Research and Practice.

[14]  X. Matías-Guiu,et al.  Molecular genetic heterogeneity in undifferentiated endometrial carcinomas , 2016, Modern Pathology.

[15]  J. Prat,et al.  Mixed and Ambiguous Endometrial Carcinomas: A Heterogenous Group of Tumors With Different Clinicopathologic and Molecular Genetic Features , 2016, The American journal of surgical pathology.

[16]  Jorge S Reis-Filho,et al.  TP53 Mutational Spectrum in Endometrioid and Serous Endometrial Cancers , 2016, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[17]  M. Köbel,et al.  Molecular Analysis of Mixed Endometrial Carcinomas Shows Clonality in Most Cases , 2015, The American journal of surgical pathology.

[18]  M. Köbel,et al.  Endometrial Carcinomas With Clear Cells: A Study of a Heterogeneous Group of Tumors Including Interobserver Variability, Mutation Analysis, and Immunohistochemistry With HNF-1&bgr; , 2015, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[19]  A. Talhouk,et al.  A clinically applicable molecular-based classification for endometrial cancers , 2015, British Journal of Cancer.

[20]  M. Squires,et al.  Second-line dovitinib (TKI258) in patients with FGFR2-mutated or FGFR2-non-mutated advanced or metastatic endometrial cancer: a non-randomised, open-label, two-group, two-stage, phase 2 study. , 2015, The Lancet. Oncology.

[21]  P. Klenerman,et al.  POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer , 2015, Clinical Cancer Research.

[22]  B. Karlan,et al.  Clinicopathological analysis of endometrial carcinomas harboring somatic POLE exonuclease domain mutations , 2015, Modern Pathology.

[23]  P. Pollock,et al.  Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative , 2015, Modern Pathology.

[24]  D. Lambrechts,et al.  Mutation profile and clinical outcome of mixed endometrioid-serous endometrial carcinomas are different from that of pure endometrioid or serous carcinomas , 2015, Virchows Archiv.

[25]  D. Lambrechts,et al.  Prognostic Significance of POLE Proofreading Mutations in Endometrial Cancer , 2014, Journal of the National Cancer Institute.

[26]  B. Clarke,et al.  ARID1A loss correlates with mismatch repair deficiency and intact p53 expression in high-grade endometrial carcinomas , 2014, Modern Pathology.

[27]  C Blake Gilks,et al.  Poor Interobserver Reproducibility in the Diagnosis of High-grade Endometrial Carcinoma , 2013, The American journal of surgical pathology.

[28]  Steven J. M. Jones,et al.  Integrated genomic characterization of endometrial carcinoma , 2013, Nature.

[29]  R. Soslow High‐grade endometrial carcinomas – strategies for typing , 2013, Histopathology.

[30]  P. Pollock,et al.  FGFR2 Point Mutations in 466 Endometrioid Endometrial Tumors: Relationship with MSI, KRAS, PIK3CA, CTNNB1 Mutations and Clinicopathological Features , 2012, PloS one.

[31]  Joan Valls,et al.  FGFR2 alterations in endometrial carcinoma , 2011, Modern Pathology.

[32]  I. Shih,et al.  Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis , 2011, Modern Pathology.

[33]  C. Sung,et al.  Minor Serous and Clear Cell Components Adversely Affect Prognosis in ‘‘Mixed-Type’’ Endometrial Carcinomas: A Clinicopathologic Study of 36 Stage-I Cases , 2010, Reproductive Sciences.

[34]  P. Pollock,et al.  Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes , 2007, Oncogene.

[35]  U. Moll,et al.  Cytoplasmically “Sequestered” Wild Type p53 Protein Is Resistant to Mdm2-mediated Degradation* , 1999, The Journal of Biological Chemistry.

[36]  J. Hecht,et al.  Morphologic and other clinicopathologic features of endometrial clear cell carcinoma: a comprehensive analysis of 50 rigorously classified cases. , 2013, American journal of cancer research.