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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}hotmail.com; Professor Wen Di; diwen163{at}163.com; Professor Guanglei Zhuang; zhuangguanglei{at}gmail.com

Abstract

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
  • APOBEC

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