title: DNA damage repair and survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy.
abstract: The DNA damage response (DDR) network is exploited by cancer cells to withstand chemotherapy. Gastric cancer (GC) carries deregulation of the DDR and harbors genetic defects that fuel its activation. The ATM-Chk2 and ATR-Chk1-Wee1 axes are deputed to initiate DNA repair. Overactivation of these pathways in cancer cells may represent an adaptive response for compensating genetic defects deregulating G1-S transition (e.g., TP53) and ATM/ATR-initiated DNA repair (e.g., ARID1A). We hypothesized that DDR-linked biomarkers may predict clinical outcomes in GC patients treated with chemotherapy. Immunohistochemical assessment of DDR kinases (pATM, pChk2, pChk1 and pWee1) and DNA damage markers (γ-H2AX and pRPA32) was performed in biological samples from 110 advanced GC patients treated with first-line chemotherapy, either in phase II trials or in routine clinical practice. In 90 patients, this characterization was integrated with targeted ultra-deep sequencing for evaluating the mutational status of TP53 and ARID1A. We recorded a positive association between the investigated biomarkers. The combination of two biomarkers (γ-H2AXhigh/pATMhigh) was an adverse factor for both progression-free survival (multivariate Cox: HR 2.23, 95%CI: 1.47-3.40) and overall survival (multivariate Cox: HR: 2.07, 95%CI: 1.20-3.58). The relationship between the γ-H2AXhigh/pATMhighmodel and progression-free survival was consistent across the different TP53 backgrounds and was maintained in the ARID1A wild-type setting. Conversely, this association was no longer observed in an ARID1A-mutated subgroup. The γ-H2AXhigh/pATMhighmodel negatively impacted survival outcomes in GC patients treated with chemotherapy. The mutational status of ARID1A, but apparently not TP53 mutations, affects its predictive significance.
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Ronchetti
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Melucci
authors.affiliation: SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Nicola
authors.affiliation: Oncogenomic and Epigenetic Unit, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Frauke
authors.initials: F
authors.lastname: Goeman
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Casini
authors.affiliation: Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sperati
authors.affiliation: SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pallocca
authors.affiliation: Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Terrenato
authors.affiliation: Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pizzuti
authors.affiliation: Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vici
authors.affiliation: Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Sergi
authors.affiliation: Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Lauro
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Carla Azzurra
authors.initials: CA
authors.lastname: Amoreo
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Gallo
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Diodoro
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Pescarmona
authors.affiliation: Department of Biology, University of Rome "Tor Vergata", Rome, Italy.|Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Ilio
authors.initials: I
authors.lastname: Vitale
authors.affiliation: Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Rome, Italy.|Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Barba
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Buglioni
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fanciulli
authors.affiliation: Institute of General Pathology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Rome, Italy.|Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Marcello
authors.identifier: 0000-0003-2287-9581
authors.initials: M
authors.lastname: Maugeri-Saccà
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D018797:Cell Cycle Proteins; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013270:Stomach / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D011494:Protein Kinases; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ARID1A; DNA damage repair; TP53; pATM; γ-H2AX