title: The tandem duplicator phenotype as a distinct genomic configuration in cancer.
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.
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Francesca
authors.initials: F
authors.lastname: Menghi
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Koichiro
authors.initials: K
authors.lastname: Inaki
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: XingYi
authors.initials: X
authors.lastname: Woo
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Pooja A
authors.initials: PA
authors.lastname: Kumar
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Krzysztof R
authors.initials: KR
authors.lastname: Grzeda
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Ankit
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Vinod
authors.initials: V
authors.lastname: Yadav
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Hyunsoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Eladio J
authors.initials: EJ
authors.lastname: Marquez
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Duygu
authors.initials: D
authors.lastname: Ucar
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Phung T
authors.initials: PT
authors.lastname: Shreckengast
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Joel P
authors.initials: JP
authors.lastname: Wagner
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: George
authors.initials: G
authors.lastname: MacIntyre
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Krishna R
authors.initials: KR
authors.lastname: Murthy Karuturi
authors.affiliation: Division of Hematology Oncology, Department of Medicine, and Cancer Research Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
authors.forename: Ralph
authors.initials: R
authors.lastname: Scully
authors.affiliation: The Jackson Laboratory, Sacramento, CA 95838.
authors.forename: James
authors.initials: J
authors.lastname: Keck
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Chuang
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609; edison.liu@jax.org.
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D052138:Genes, Neoplasm / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics*; D010641:Phenotype; D056916:Segmental Duplications, Genomic / Q000235:genetics*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D005819:Genetic Markers
keywords: BRCA1; TP53; cisplatin; tandem duplications; triple-negative breast cancer