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Targeted next-generation sequencing for molecular diagnosis of endometriosis-associated ovarian cancer

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Abstract

Recent molecular and pathological studies suggest that endometriosis may serve as a precursor of ovarian cancer (endometriosis-associated ovarian cancer, EAOC), especially of the endometrioid and clear cell subtypes. Accordingly, this study had two cardinal aims: first, to obtain mutation profiles of EAOC from Taiwanese patients; and second, to determine whether somatic mutations present in EAOC can be detected in preneoplastic lesions. Formalin-fixed paraffin-embedded (FFPE) tissues were obtained from ten endometriosis patients with malignant transformation. Macrodissection was performed to separate four different types of cells from FFPE sections in six patients. The four types of samples included normal endometrium, ectopic endometriotic lesion, atypical endometriosis, and carcinoma. Ultra-deep (>1000×) targeted sequencing was performed on 409 cancer-related genes to identify pathogenic mutations associated with EAOC. The most frequently mutated genes were PIK3CA (6/10) and ARID1A (5/10). Other recurrently mutated genes included ETS1, MLH1, PRKDC (3/10 each), and AMER1, ARID2, BCL11A, CREBBP, ERBB2, EXT1, FANCD2, MSH6, NF1, NOTCH1, NUMA1, PDE4DIP, PPP2R1A, RNF213, and SYNE1 (2/10 each). Importantly, in five of the six patients, identical somatic mutations were detected in atypical endometriosis and tumor lesions. In two patients, genetic alterations were also detected in ectopic endometriotic lesions, indicating the presence of genetic alterations in preneoplastic lesion. Genetic analysis in preneoplastic lesions may help to identify high-risk patients at early stage of malignant transformation and also shed new light on fundamental aspects of the molecular pathogenesis of EAOC.

Key messages

  • Molecular characterization of endometriosis-associated ovarian cancer genes by targeted NGS.

  • Candidate genes predictive of malignant transformation were identified.

  • Chromatin remodeling, PI3K-AKT-mTOR, Notch signaling, and Wnt/β-catenin pathway may promote cell malignant transformation.

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Acknowledgments

We thank ACT Genomics Co., Ltd. for their assistance with bioinformatics analysis. We are also grateful to Dr Shu-Jen Chen and Dr Yen-Jung Lu for their expertise in the field of next-generation sequencing and bioinformatics. This study was supported by grants from Kaohsiung Medical University Hospital (KMUH102-M207, KMUH103-3R64, and KMOH103-10V07) and the Ministry of Health and Welfare (MOHW103-TD-B-111-05, MOHW104-TDU-B-212-124-003, and MOHW103-TDU-212-114007). This work was supported by the Ministry of Science and Technology of Taiwan [grant numbers 103-2314-B-037-057, 102-2628-B-037-011-MY3 and 102-2632-B-037-001-MY3] and the Kaohsiung Medical University (Hospital) Research Fund [grant numbers KMU-TP104A02, KMU-TP103G01, KMU-TP103G04, KMUTP103G05, KMU-TP103A15, and KMUH103-10V07].

Author contributions

Concept and design of the experiments: TKE, YFS, CCW, CCC, THH, TCL, and EMT. Performance of the experiments: TKE, YFS, CCW, WTC, YTC, and CCC. Data analysis and discussion: TKE, YFS, CCW, CCC, JW, MHV, YTC, TCL, and EMT. Contribution of reagents/materials/analysis tools: TCL, CCW, THH, WTC, YTC, CHS, and EMT. Clinical information: CCW, YTC, CHS, and EMT. Manuscript preparation: TKE, YFS, CCW, CCC, JW, THH, MHV, YTC, TCL, CHS, and EMT. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Health and Nutrition Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan

    Tze-Kiong Er

  2. Division of Molecular Diagnostics, Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    Tze-Kiong Er & Ta-Chih Liu

  3. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Yu-Fa Su, Yi-Ting Chen & Eing-Mei Tsai

  4. Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Chun-Chieh Wu, Wan-Tzu Chen & Yi-Ting Chen

  5. Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan

    Chih-Chieh Chen

  6. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Jing Wang

  7. Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan

    Tsung-Hua Hsieh, Hung-Sheng Chen & Eing-Mei Tsai

  8. Department of Gastroenterology, Hospital Donostia/Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco UPV/EHU, San Sebastián, Spain

    Marta Herreros-Villanueva

  9. Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Ta-Chih Liu

  10. Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Eing-Mei Tsai

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  1. Tze-Kiong Er
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  2. Yu-Fa Su
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Correspondence to Eing-Mei Tsai.

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Table S1

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Supplementary data 1

ACTOnco™ CCP target gene list. (DOCX 16 kb)

Supplementary data 2

Mutation data includes allele frequency. (XLSX 68 kb)

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Er, TK., Su, YF., Wu, CC. et al. Targeted next-generation sequencing for molecular diagnosis of endometriosis-associated ovarian cancer. J Mol Med 94, 835–847 (2016). https://doi.org/10.1007/s00109-016-1395-2

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  • DOI: https://doi.org/10.1007/s00109-016-1395-2

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