The tandem duplicator phenotype as a distinct genomic configuration in cancer.
Document Type
Article
Publication Date
4-7-2016
JAX Source
Proc Natl Acad Sci U S A 2016 Apr 26; 113(17): E2373-82.
ISSN
1091-6490
PMID
27071093
Grant
CA34196, R21HG007554, R21CA184851
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. Proc Natl Acad Sci U S A 2016 Apr 26; 113(17): E2373-82.
Recommended Citation
Menghi F,
Inaki K,
Woo X,
Kumar P,
Grzeda KR,
Malhotra A,
Yadav V,
Kim H,
Marquez E,
Ucar D,
Shreckengast P,
Wagner JP,
MacIntyre G,
Murthy Karuturi K,
Scully R,
Keck J,
Chuang J,
Liu E.
The tandem duplicator phenotype as a distinct genomic configuration in cancer. Proc Natl Acad Sci U S A 2016 Apr 26; 113(17): E2373-82.