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 /pATMhigh model 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 /pATMhigh model 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: Livia Ronchetti, Elisa Melucci, Francesca De Nicola, Frauke Goeman, Beatrice Casini, Francesca Sperati, Matteo Pallocca, Irene Terrenato, Laura Pizzuti, Patrizia Vici, Domenico Sergi, Luigi Di Lauro, Carla Azzurra Amoreo, Enzo Gallo, Maria Grazia Diodoro, Edoardo Pescarmona, Ilio Vitale, Maddalena Barba, Simonetta Buglioni, Marcella Mottolese, Maurizio Fanciulli, Ruggero De Maria, Marcello Maugeri-Saccà
• Journal: International journal of cancer (Int J Cancer) Vol. 140 Issue 11 Pg. 2587-2595 (06 01 2017) ISSN: 1097-0215 [Electronic] United States
• PMID: 28233295 (Publication Type: Journal Article)
• Copyright: © 2017 UICC.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Cell Cycle Proteins
• DNA-Binding Proteins
• H2AX protein, human
• Histones
• Protein Kinases
• Ataxia Telangiectasia Mutated Proteins

Topics

• Aged
• Antineoplastic Agents (therapeutic use)
• Ataxia Telangiectasia Mutated Proteins (metabolism)
• Biomarkers, Tumor (metabolism)
• Cell Cycle Proteins
• DNA Damage (drug effects)
• DNA Repair (drug effects)
• DNA-Binding Proteins (metabolism)
• Disease-Free Survival
• Female
• Gastric Mucosa (metabolism)
• Histones (metabolism)
• Humans
• Male
• Middle Aged
• Protein Kinases (metabolism)
• Signal Transduction (drug effects)
• Stomach (drug effects)
• Stomach Neoplasms (drug therapy, genetics, metabolism)