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DNA damage repair and survival outcomes in advanced gastric cancer patients treated with first‐line chemotherapy
Author(s) -
Ronchetti Livia,
Melucci Elisa,
De Nicola Francesca,
Goeman Frauke,
Casini Beatrice,
Sperati Francesca,
Pallocca Matteo,
Terrenato Irene,
Pizzuti Laura,
Vici Patrizia,
Sergi Domenico,
Di Lauro Luigi,
Amoreo Carla Azzurra,
Gallo Enzo,
Diodoro Maria Grazia,
Pescarmona Edoardo,
Vitale Ilio,
Barba Maddalena,
Buglioni Simonetta,
Mottolese Marcella,
Fanciulli Maurizio,
De Maria Ruggero,
MaugeriSaccà Marcello
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30668
Subject(s) - dna damage , cancer , dna repair , chemotherapy , oncology , arid1a , proportional hazards model , medicine , cancer research , survival analysis , biology , mutation , dna , gene , genetics
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 G 1 ‐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‐H2AX high /pATM high ) 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‐H2AX high /pATM high 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‐H2AX high /pATM high 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.