Replicative stress in gastroesophageal adenocarcinoma is associated with chromosomal instability and sensitivity to DNA damage response inhibitors.

CIN DNA damage response pathway inhibitors DNA-damage response Gastric cancer aneuploidy esophageal cancer irinotecan replication stress

Journal

bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187

Informations de publication

Date de publication:
28 Mar 2023
Historique:
pubmed: 11 4 2023
medline: 11 4 2023
entrez: 10 4 2023
Statut: epublish

Résumé

Gastroesophageal adenocarcinoma (GEA) is an aggressive, often lethal, malignancy that displays marked chromosomal instability (CIN). To understand adaptive responses that enable CIN, we analyzed paired normal, premalignant, and malignant gastric lesions from human specimens and a carcinogen-induced mouse model, observing activation of replication stress, DNA damage response (DDR), and cell cycle regulator p21 in neoplastic progression. In GEA cell lines, expression of DDR markers correlated with ploidy abnormalities, including high-level focal amplifications and whole-genome duplication (WGD). Moreover, high expression of DNA damage marker

Identifiants

DOI: 10.1101/2023.03.27.534412 PMID: 37034740 PMC: PMC10081209
pubmed: 37034740
doi: 10.1101/2023.03.27.534412
pmc: PMC10081209
pii:
doi:

Types de publication

Preprint

Langues

eng

Subventions

Organisme : NIDDK NIH HHS
ID : K08 DK120930
Pays : United States

Commentaires et corrections

Type : UpdateIn

Déclaration de conflit d'intérêts

DECLARATION OF INTERESTS N.S.S. is on the advisory board for Astrin Biosciences.

Auteurs

Pranshu Sahgal (P)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, 02142, USA.
Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, 02115, USA.

Deepa T Patil (DT)

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

Zsofia M Sztupinszki (ZM)

Danish Cancer Society Research Center, Copenhagen, 2100, Denmark.

Viktoria Tisza (V)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Sandor Spisak (S)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Brandon Huffman (B)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Aurel Prosz (A)

Danish Cancer Society Research Center, Copenhagen, 2100, Denmark.

Harshabad Singh (H)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Division of Gastrointestinal Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Jean-Bernard Lazaro (JB)

Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Center for DNA Damage and Repair (CDDR), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Zoltan Szallasi (Z)

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Danish Cancer Society Research Center, Copenhagen, 2100, Denmark.
Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, 02115, USA.

James M Cleary (JM)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Division of Gastrointestinal Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Nilay S Sethi (NS)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, 02142, USA.
Division of Gastrointestinal Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Lead Contact.

Classifications MeSH