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Nature medicine
Nov, 2017;23 (11): 1319-1330.

Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence.

Jian Yuan Goh, Min Feng, Wenyu Wang, Gokce Oguz, Siti Maryam J M Yatim, Puay Leng Lee, Yi Bao, Tse Hui Lim, Panpan Wang, Wai Leong Tam, Annette R Kodahl, Maria B Lyng, Suman Sarma, Selena Y Lin, Alexander Lezhava, Yoon Sim Yap, Alvin S T Lim, Dave S B Hoon, Henrik J Ditzel, Soo Chin Lee, Ern Yu Tan, Qiang Yu
Author Information
  1. Jian Yuan Goh: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
  2. Min Feng: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
  3. Wenyu Wang: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
  4. Gokce Oguz: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
  5. Siti Maryam J M Yatim: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
  6. Puay Leng Lee: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
  7. Yi Bao: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
  8. Tse Hui Lim: Cytogenetics Laboratory, Department of Pathology, Singapore General Hospital, Singapore.
  9. Panpan Wang: Cancer Research Institute and School of Pharmacy, Jinan University, Guangzhou, China.
  10. Wai Leong Tam: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore. ORCID
  11. Annette R Kodahl: Department of Oncology, Odense University Hospital, Odense, Denmark.
  12. Maria B Lyng: Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  13. Suman Sarma: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
  14. Selena Y Lin: Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, California, USA.
  15. Alexander Lezhava: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
  16. Yoon Sim Yap: Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
  17. Alvin S T Lim: Cytogenetics Laboratory, Department of Pathology, Singapore General Hospital, Singapore.
  18. Dave S B Hoon: Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, California, USA. ORCID
  19. Henrik J Ditzel: Department of Oncology, Odense University Hospital, Odense, Denmark. ORCID
  20. Soo Chin Lee: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  21. Ern Yu Tan: Department of General Surgery, Tan Tock Seng Hospital, Singapore.
  22. Qiang Yu: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
PMID: 28967919 DOI: 10.1038/nm.4405

Abstract

Tumor recurrence remains the main reason for breast cancer-associated mortality, and there are unmet clinical demands for the discovery of new biomarkers and development of treatment solutions to benefit patients with breast cancer at high risk of recurrence. Here we report the identification of chromosomal copy-number amplification at 1q21.3 that is enriched in subpopulations of breast cancer cells bearing characteristics of tumor-initiating cells (TICs) and that strongly associates with breast cancer recurrence. Amplification is present in ∼10-30% of primary tumors but in more than 70% of recurrent tumors, regardless of breast cancer subtype. Detection of amplification in cell-free DNA (cfDNA) from blood is strongly associated with early relapse in patients with breast cancer and could also be used to track the emergence of tumor resistance to chemotherapy. We further show that 1q21.3-encoded S100 calcium-binding protein (S100A) family members, mainly S100A7, S100A8, and S100A9 (S100A7/8/9), and IL-1 receptor-associated kinase 1 (IRAK1) establish a reciprocal feedback loop driving tumorsphere growth. Notably, this functional circuitry can be disrupted by the small-molecule kinase inhibitor pacritinib, leading to preferential impairment of the growth of 1q21.3-amplified breast tumors. Our study uncovers the 1q21.3-directed S100A7/8/9-IRAK1 feedback loop as a crucial component of breast cancer recurrence, serving as both a trackable biomarker and an actionable therapeutic target for breast cancer.

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MeSH Term

Animals
Antineoplastic Agents
Biomarkers, Tumor
Breast Neoplasms
Bridged-Ring Compounds
Cell-Free Nucleic Acids
Chromosomes, Human, Pair 1
Disease Progression
Female
Heterografts
Humans
In Situ Hybridization, Fluorescence
Mice
Neoplasm Recurrence, Local
Polymerase Chain Reaction
Pyrimidines
Treatment Outcome

Chemicals

11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
Antineoplastic Agents
Biomarkers, Tumor
Bridged-Ring Compounds
Cell-Free Nucleic Acids
Pyrimidines
Journal Article

Links to CNCB-NGDC Resources

GEN: GEND000024 (Transcriptome profiling of ER+ breast cancer primary tumor and its tumorsphere derivative)

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