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Proc Natl Acad Sci U S A. 2016 Apr 26;113(17):E2373-82. doi: 10.1073/pnas.1520010113. Epub 2016 Apr 7.

The tandem duplicator phenotype as a distinct genomic configuration in cancer.

Author information

1
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
2
The Jackson Laboratory, Bar Harbor, ME 04609;
3
Division of Hematology Oncology, Department of Medicine, and Cancer Research Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
4
The Jackson Laboratory, Sacramento, CA 95838.
5
The Jackson Laboratory, Bar Harbor, ME 04609; edison.liu@jax.org.

Abstract

Next-generation sequencing studies have revealed genome-wide structural variation patterns in cancer, such as chromothripsis and chromoplexy, that do not engage a single discernable driver mutation, and whose clinical relevance is unclear. We devised a robust genomic metric able to identify cancers with a chromotype called tandem duplicator phenotype (TDP) characterized by frequent and distributed tandem duplications (TDs). Enriched only in triple-negative breast cancer (TNBC) and in ovarian, endometrial, and liver cancers, TDP tumors conjointly exhibit tumor protein p53 (TP53) mutations, disruption of breast cancer 1 (BRCA1), and increased expression of DNA replication genes pointing at rereplication in a defective checkpoint environment as a plausible causal mechanism. The resultant TDs in TDP augment global oncogene expression and disrupt tumor suppressor genes. Importantly, the TDP strongly correlates with cisplatin sensitivity in both TNBC cell lines and primary patient-derived xenografts. We conclude that the TDP is a common cancer chromotype that coordinately alters oncogene/tumor suppressor expression with potential as a marker for chemotherapeutic response.

KEYWORDS:

BRCA1; TP53; cisplatin; tandem duplications; triple-negative breast cancer

PMID:
27071093
PMCID:
PMC4855596
DOI:
10.1073/pnas.1520010113
[Indexed for MEDLINE]
Free PMC Article

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