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Multiregion whole-genome sequencing depicts intratumour heterogeneity and punctuated evolution in ovarian clear cell carcinoma
  1. Xia Yin1,2,
  2. Rui Bi3,
  3. Pengfei Ma1,
  4. Shengzhe Zhang1,
  5. Yang Zhang1,2,
  6. Yunheng Sun1,
  7. Yi Zhang1,2,
  8. Ying Jing1,2,
  9. Minhua Yu1,2,
  10. Wenjing Wang1,2,
  11. Li Tan4,
  12. Wen Di1,2,
  13. Guanglei Zhuang1,2,
  14. Mei-Chun Cai1,5
  1. 1 State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  2. 2 Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  3. 3 Department of Pathology, Fudan University Cancer Center, Shanghai, China
  4. 4 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
  5. 5 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  1. Correspondence to Dr Mei-Chun Cai, Shanghai Cancer Institute, Shanghai 200240, China; caimeichun{at}; Professor Wen Di; diwen163{at}; Professor Guanglei Zhuang; zhuangguanglei{at}


Background Ovarian clear cell carcinoma (OCCC) arises from endometriosis and represents a difficult-to-treat gynaecological malignancy, in part, because its spatial intratumour heterogeneity and temporal evolutionary trajectories have not been explicitly defined.

Methods We performed whole-genome sequencing on six pathologically confirmed patients with OCCC. An R package named KataegisPortal was developed to identify and annotate loci of localised hypermutations. Immunohistochemical staining was conducted on a tissue microarray containing 143 OCCC specimens.

Results Multiregion analysis demonstrated considerable degrees of subclonal diversification, ascribable to dynamic mutagenic processes, as well as macroevolutionary events including the acquisition of aneuploidy and chromoplexy. KataegisPortal unveiled APOBEC-mediated kataegis in the early phases of OCCC pathogenesis. We further showed evidence that APOBEC3A and APOBEC3B were frequently expressed in OCCC and possibly regulated by the MAPK pathway. Notably, APOBEC3B-expressing OCCC displayed favourable prognosis and appreciable immunogenicity manifested by marked cytotoxic T-cell infiltration.

Conclusions These results point to an appealing model of punctuated tumour evolution underlying OCCC neoplastic transformation and progression, which may pose formidable challenges of early detection and intervention, and indicate the intratumour heterogeneity of cancer-driving alterations, yielding important implications for molecular diagnosis and targeted treatment of this lethal disease.

  • ovarian clear cell carcinoma
  • intratumour heterogeneity
  • punctuated evolution
  • kataegis

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  • XY, RB, PM and SZ are joint first authors.

  • WD, GZ and M-CC contributed equally.

  • Contributors XY, WD, GZ and M-CC designed and supervised the study. XY, RB, PM, SZ, YZ, YS, YZ, YJ, MY, WW and LT performed the experiments and analysed the data. M-CC developed the bioinformatics pipeline. GZ and M-CC wrote the manuscript. All authors read and approved the final version of the manuscript.

  • Funding This work was supported by the National Natural Science Foundation of China (81672714 and 81922047 to GZ; 81772770 to WD; 81802809 to M-CC; 81802585 to XY, 81802734 to PM), National Key Research and Development Program (863) of China (2016YFC1302900 to WD), National Program on Key Basic Research Project of China (2016YFA0501900 and 2016YFA0501904 to LT), the Shanghai Municipal Key Clinical Specialty and the Program of Shanghai Hospital Development Center (16CR2001A to WD), the grants from Shanghai Jiao Tong University School of Medicine (DLY201505 to WD; YG2016MS51 to XY), Doctoral Innovation Fund of Shanghai Jiao Tong University School of Medicine (CBXJ201805 to YZ), Shanghai Pujiang Program (17PJ1410700 to LT), Shanghai Sailing Program (18YF1413200 to PM), the grant from Shanghai Key Laboratory of Gynecologic Oncology (FKZL-2018-02 to PM), the Incubating Program for Clinical Research and Innovation of Renji Hospital (PY2018-IIC-04 to PM), Shanghai Municipal Commission of Health and Family Planning (2017ZZ02016 and ZY(2018-2020)-FWTX-3006 to WD; 20174Y0043 to M-CC; 20174Y0189 to YJ) and the grants from Science and Technology Commission of Shanghai Municipality (18441904800 to WD; 16140904401 to XY).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.