title: Polymorphisms in DNA repair genes in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome.
abstract: DNA repair pathways play an essential role in cancer susceptibility by maintaining genomic integrity. This led us to investigate the influence of polymorphisms in the genes coding repair pathway enzymes on gastrointestinal stromal tumours (GIST) susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 20 polymorphisms in 11 genes in 81 cases and 147 controls. The XPD rs13181 wild-type allele and hOGG1 rs1052133 and XPF rs1800067 minor alleles were significantly associated with disease susceptibility. XPA rs1800975 and rs2808668 were associated with tumour size (P = 0.018), metastatic status at onset (P = 0.035) and mitotic index (P = 0.002). With regards to outcome treatment, the XPD rs50872 minor allele had a significant favourable impact on time to progression (TTP). Similarly, the XPC rs2228000 minor allele was correlated with a longer TTP (P = 0.03). On the contrary, the XPC rs2228001 and hOGG1 rs1052133 minor alleles were associated with a diminished TTP (P = 0.005 and P = 0.01, respectively). Regarding OS, we found the presence of at least one hOGG1 (rs1052133) minor allele that had a 60 % lower risk to die compared to the wild-type carriers (P = 0.04). Furthermore, the XRCC3 rs861539 variant allele is associated with a hazard of early death compared with the wild-type genotype (P = 0.04). To the best of our knowledge, this is the first study on polymorphisms in DNA repair genes, belonging to the different pathways, extensively evaluated in GIST patients. Through this multiple candidate gene approach, we report for the first time the significant associations between polymorphisms in DNA repair genes, susceptibility, clinical pathological features and clinical outcome in GIST.
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Gloria
authors.identifier: http://orcid.org/0000-0002-7774-402X
authors.initials: G
authors.lastname: Ravegnini
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Nannini
authors.affiliation: Laboratory of Pre-Clinical and Translational Research Reference Cancer Center of Basilicata, Scientific Institute of Hospitalization and Treatment, Rionero in Vulture, Potenza, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Simeon
authors.affiliation: Department of Public Health, Epidemiological Service, Local Health Authority of Bologna, Bologna, Italy.
authors.forename: Muriel
authors.initials: M
authors.lastname: Musti
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Sammarini
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Saponara
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Gatto
authors.affiliation: "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Urbini
authors.affiliation: "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Astolfi
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.|"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Biasco
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.|"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pantaleo
authors.affiliation: Immunohematology and Blood Transfusion, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Venturoli
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Hrelia
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. s.angelini@unibo.it.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Angelini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D015996:Survival Rate; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C095888:xeroderma pigmentosum group F protein; C086984:XPC protein, human; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D045643:DNA Repair Enzymes
keywords: DNA repair pathways; GIST; Imatinib; Polymorphisms