Concomitant presence of mutations in mitochondrial genome and p53 in cancer development - a study in north Indian sporadic breast and esophageal cancer patients.
Mitochondrial DNA alterations in recent years have been suggested as modifier events, providing a possible proliferative advantage to the tumor cells. In order to provide further insight into the process of tumorigenesis, a study of whole mitochondria genome was conducted in 134 tissue samples obtained from 2 unrelated cancers (tumor and adjacent normal tissues from 36 breast cancer and 31 esophageal squamous cell carcinoma (ESCC) patients) with known p53 somatic mutation background. Fifteen of 36 (41.66%) breast and 12 of 31 (38.71%) ESCC tumors were found to contain at least 1 mtDNA somatic mutation, which correlated significantly with the concomitant presence of somatic mutation in DNA binding domain of the p53 gene (Breast cancer, p = 0.006; ESCC, p = 0.002). Interestingly, mutations in the non D-loop region of the mtDNA contributed significantly (Breast cancer, p = 0.004; ESCC, p = 0.032) in comparison to the hotspot-D-Loop-region. The concomitant presence of mutations in p53 and mtDNA were also predominant in breast cancer tumors with poor prognosis, that is, with the advanced stage, grade and the ER/PR negativity. Also, the observation made was apparently well explained in 10398A bearing N haplogroup genetic background with increased presence of novel and pathogenic germline mutation in mtDNA. Our study suggests that the concomitant presence of somatic alteration in mtDNA and the DNA binding domain of the p53 gene facilitates cell survival and tumorigenesis, requiring specialized therapeutic intervention because of a possible resistance to conventional chemotherapy.
Gochhait
Sailesh
S
National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University (JNU), Aruna Asafali Marg, New Delhi -110067, India.
Bhatt
Audesh
A
Sharma
Swarkar
S
Singh
Yoginder Pal
YP
Gupta
Pawan
P
Bamezai
Rameshwar N K
RN
D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D004938:Esophageal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D054629:Genome, Mitochondrial / Q000235:genetics*; D006801:Humans; D007194:India / Q000453:epidemiology; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D010802:Phylogeny; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016159:Tumor Suppressor Protein p53