8-Oxo-7,8-dihydro-2'-deoxyguanosine and other lesions along the coding strand of the exon 5 of the tumour suppressor gene P53 in a breast cancer case-control study.
The next-generation sequencing studies of breast cancer have reported that the tumour suppressor P53 (TP53) gene is mutated in more than 40% of the tumours. We studied the levels of oxidative lesions, including 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), along the coding strand of the exon 5 in breast cancer patients as well as in a reactive oxygen species (ROS)-attacked breast cancer cell line using the ligation-mediated polymerase chain reaction technique. We detected a significant 'in vitro' generation of 8-oxodG between the codons 163 and 175, corresponding to a TP53 region with high mutation prevalence, after treatment with xanthine plus xanthine oxidase, a ROS-generating system. Then, we evaluated the occurrence of oxidative lesions in the DNA-binding domain of the TP53 in the core needle biopsies of 113 of women undergoing breast investigation for diagnostic purpose. An increment of oxidative damage at the -G- residues into the codons 163 and 175 was found in the cancer cases as compared to the controls. We found significant associations with the pathological stage and the histological grade of tumours. As the major news of this study, this largest analysis of genomic footprinting of oxidative lesions at the TP53 sequence level to date provided a first roadmap describing the signatures of oxidative lesions in human breast cancer. Our results provide evidence that the generation of oxidative lesions at single nucleotide resolution is not an event highly stochastic, but causes a characteristic pattern of DNA lesions at the site of mutations in the TP53, suggesting causal relationship between oxidative DNA adducts and breast cancer.
Senology Unit, ISPO-Cancer Prevention and Research Institute, 50139 - Florence, Italy.
Beniamino
B
Brancato
Cancer Risk Factor Branch, Cancer Prevention Laboratory, ISPO-Cancer Prevention and Research Institute, 50139 Florence, Italy.
Armelle
A
Munnia
Cancer Risk Factor Branch, Cancer Prevention Laboratory, ISPO-Cancer Prevention and Research Institute, 50139 Florence, Italy.
Filippo
F
Cellai
Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 - Florence, Italy.
Elisabetta
E
Ceni
Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 - Florence, Italy.
Tommaso
T
Mello
Pathological Anatomy Unit, Department of Surgery and Translational Medicine, University of Florence - Careggi University Hospital, 50139 - Florence, Italy.
Simonetta
S
Bianchi
Senology Unit, ISPO-Cancer Prevention and Research Institute, 50139 - Florence, Italy.
Sandra
S
Catarzi
Senology Unit, ISPO-Cancer Prevention and Research Institute, 50139 - Florence, Italy.
Gabriella G
GG
Risso
Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 - Florence, Italy.
Andrea
A
Galli
Cancer Risk Factor Branch, Cancer Prevention Laboratory, ISPO-Cancer Prevention and Research Institute, 50139 Florence, Italy m.peluso@ispo.toscana.it.
Marco E M
ME
Peluso
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D003062:Codon; D018736:DNA Adducts / Q000737:chemistry / Q000235:genetics; D004273:DNA, Neoplasm / Q000737:chemistry* / Q000235:genetics; D005091:Exons; D005260:Female; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D018384:Oxidative Stress; D017354:Point Mutation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C515742:8-oxo-7,8-dihydro-2'-deoxyguanosine-5'-monophosphate; D003062:Codon; D018736:DNA Adducts; D004273:DNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D006157:Guanosine Monophosphate
TP53; breast cancer; exon 5; oxidative DNA lesions; pT