Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability

  • EMBO Mol Med. 2024 Sep;16(9):2132-2145. doi: 10.1038/s44321-024-00102-5.
Peiyong Guan  #  1 ,  Jianfeng Chen  #  2 ,  Chengqiang Mo  #  3 ,  Tomoya Fukawa  #  4 ,  Chao Zhang  5 ,  Xiuyu Cai  2 ,  Mei Li  2  6 ,  Jing Han Hong  7 ,  Jason Yongsheng Chan  8 ,  Cedric Chuan Young Ng  9 ,  Jing Yi Lee  9 ,  Suet Far Wong  9 ,  Wei Liu  9 ,  Xian Zeng  2 ,  Peili Wang  2 ,  Rong Xiao  2 ,  Vikneswari Rajasegaran  9 ,  Swe Swe Myint  9 ,  Abner Ming Sun Lim  9 ,  Joe Poh Sheng Yeong  10  11 ,  Puay Hoon Tan  11  12  13 ,  Choon Kiat Ong  14 ,  Tao Xu  15 ,  Yiqing Du  15 ,  Fan Bai  16 ,  Xin Yao  17 ,  Bin Tean Teh  18  19  20  21 ,  Jing Tan  22  23  24
Affiliations
  • 1. Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Republic of Singapore.
  • 2. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
  • 3. Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China.
  • 4. Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
  • 5. Department of Genitourinary Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, P. R. China.
  • 6. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, PR China.
  • 7. Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore, Republic of Singapore.
  • 8. Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore.
  • 9. Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Republic of Singapore.
  • 10. Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
  • 11. Department of Anatomical Pathology, Singapore General Hospital, Singapore, Republic of Singapore.
  • 12. Division of Pathology, Singapore General Hospital, Singapore, Republic of Singapore.
  • 13. Luma Medical Centre, Singapore, Republic of Singapore.
  • 14. Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, Singapore, Republic of Singapore.
  • 15. Department of Urology, Peking University People's Hospital, Beijing, 100044, China.
  • 16. Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics (ICG), School of Life Sciences, Peking University, Beijing, 100871, China.
  • 17. Department of Genitourinary Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, P. R. China. [email protected].
  • 18. Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Republic of Singapore. [email protected].
  • 19. Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore, Republic of Singapore. [email protected].
  • 20. Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Republic of Singapore. [email protected].
  • 21. SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore, Republic of Singapore. [email protected].
  • 22. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China. [email protected].
  • 23. Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Republic of Singapore. [email protected].
  • 24. Hainan Academy of Medical Science, Hainan Medical University, Haikou, PR China. [email protected].
  • # Contributed equally.
PMID: 39122888 DOI: 10.1038/s44321-024-00102-5
Abstract

Collecting duct carcinoma (CDC) is an aggressive rare subtype of kidney Cancer with unmet clinical needs. Little is known about its underlying molecular alterations and etiology, primarily due to its rarity, and lack of preclinical models. This study aims to comprehensively characterize molecular alterations in CDC and identify its therapeutic vulnerabilities. Through whole-exome and transcriptome Sequencing, we identified KRAS hotspot mutations (G12A/D/V) in 3/13 (23%) of the patients, in addition to known TP53, NF2 mutations. 3/13 (23%) patients carried a mutational signature (SBS22) caused by aristolochic acid (AA) exposures, known to be more prevalent in Asia, highlighting a geologically specific disease etiology. We further discovered that cell cycle-related pathways were the most predominantly dysregulated pathways. Our drug screening with our newly established CDC preclinical models identified a CDK9 Inhibitor LDC000067 that specifically inhibited CDC tumor growth and prolonged survival. Our study not only improved our understanding of oncogenic molecular alterations of Asian CDC, but also identified cell-cycle machinery as a therapeutic vulnerability, laying the foundation for clinical trials to treat patients with such aggressive Cancer.

Keywords
Cell-Cycle Machinery; Collecting Duct Carcinoma; Drug Screening; Transcriptome Profiling; Whole Exome Sequencing.
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