Association between newly identified variant form of DNA polymerase beta (Δ 208-304) and ovarian cancer.

BACKGROUND: Base excision repair (BER) is a key pathway for maintaining genomic stability. A key enzyme in the BER pathway is DNA polymerase beta (polß), which removes the deoxyribose phosphate group (dRP) and fills in the gap with a nucleotide after the DNA lesion is excised. It has been shown that more than thirty percent of breast, bladder, esophageal, colon, and gastric cancer samples studied so far have exhibited DNA polymerase beta mutation. AIM: To examine the association between polß polymorphism and ovarian cancer, case control study was performed using one hundred fifty two cancer samples and non-metastatic normal samples from the same patients in Indian population. DESIGN: The polß polymorphism was studied in ovarian carcinoma tissues samples initially by RT-PCR followed by sequencing and then by western blot analysis. RESULT: A new type of variant was detected along with the WT allele (polßΔ _{208-304}). Stage IV samples have shown a significant factor for cancer progression in ovarian cancer patients of India [OR=3.58; 95% CI (1.6-7.9); and p=0.001]. The association study involving serous type and the variant showed a tendency towards ovarian carcinogenesis [OR=1.57; 95% CI (0.8-3.1); p=0.19]. The western blot analysis result indicates that the specific deletion appears to be associated with disease progression. CONCLUSION: The result reveals that this variant form of polß is a predisposing factor for stage IV ovarian cancer samples in Indian population.

Exon 8-9 mutations of DNA polymerase ß in ovarian carcinoma patients from Haldia, India.

BACKGROUND: Ovarian cancer is the number one killer among all the gynecological cancers. We undertook association study to identify potential alterations in the genomic DNA of a DNA repair gene, DNA polymerase beta (polß), involved in base excision repair (BER), in ovarian carcinomas of patients from Haldia, India. Mutations, splice variants have been reported earlier in different tumors other than ovarian tumors. AIM: In this study we explored the possibility of association of any mutation of pol beta (Exon 8) with prognosis in 152 ovarian cancer samples. RESULTS: Alteration in the exon 8 region (Exon 8:468, AgC; 15.1%) was noted among fifty seven polymorphism positive samples. Alteration in the intervening sequence 8 (IVS8, -25, AgC; 3.9%) was also noted. All alterations are heterozygous in nature. CONCLUSIONS: We found no significant association among the samples from serous type, stage IV, and the polß mutations (P ≤ 0.01). Only a slight tendency of association was evident between IVS8, -25, A to C; and stage III. Further analysis with a larger number of samples is needed.

Association of a newly identified variant of DNA polymerase beta (polßΔ63-123, 208-304) with the risk factor of ovarian carcinoma in India.

BACKGROUND: DNA polymerase is a single-copy gene that is considered to be part of the DNA repair machinery in mammalian cells. The encoded enzyme is a key to the base excision repair (BER) pathway. It is evident that pol beta has mutations in various cancer samples, but little is known about ovarian cancer. AIM: Identification of any variant form of polß cDNA in ovarian carcinoma and determination of association between the polymorphism and ovarian cancer risk in Indian patients. We used 152 samples to isolate and perform RT-PCR and sequencing. RESULTS: A variant of polymerase beta (deletion of exon 4-6 and 11-13, comprising of amino acid 63-123, and 208-304) is detected in heterozygous condition. The product size of this variant is 532 bp while wild type pol beta is 1 kb. Our study of association between the variant and the endometrioid type shows that it is a statistically significant factor for ovarian cancer [OR=31.9 (4.12-246.25) with p<0.001]. The association between variant and stage IV patients further indicated risk (χ2 value of 29.7, and OR value 6.77 with 95% CI values 3.3-13.86). The correlation study also confirms the association data (Pearson correlation values for variant/stage IV and variant/endometrioid of 0.44 and 0.39). CONCLUSION: Individuals from this part of India with this type of variant may be at risk of stage IV, endometrioid type ovarian carcinoma.

Association of two polymorphisms of DNA polymerase beta in exon-9 and exon-11 with ovarian carcinoma in India.

BACKGROUND: DNA polymerase beta (polß ) is a key enzyme in the base excision repair pathway. It is 39 kDa protein, with two subunits, one large subunit of 31 kDa having catalytic activity between exon V to exon XIV, and an 8 kDa smaller subunit having single strand DNA binding activity. Exons V to VII have double strand DNA binding activity, whereas exons VIII to XI account for the nucleotidyl transferase activity and exons XII to XIV the dNTP selection activity. AIM: To examine the association between polß polymorphisms and the risk of ovarian cancer, the present case control study was performed using 152 cancer samples and non-metastatic normal samples from the same patients. In this study, mutational analysis of polß genomic DNA was undertaken using primers from exons IX to XIV - the portion having catalytic activity. RESULTS: We detected alteration in DNA polymerase beta by SSCP. Two specific heterozygous point mutations of polß were identified in Exon 9:486, A->C (polymorphism 1; 11.18%) and in Exon 11:676, A->C (polymorphism 2; 9.86%). The correlation study involving polymorphism 1 and 4 types of tissue showed a significant correlation between mucinous type with a Pearson correlation value of 4.03 (p=0.04). The association among polymorphism 2 with serous type and stage IV together have shown Pearson χ2 value of 3.28 with likelihood ratio of 4.4 (p=0.07) with OR =2.08 (0.3- 14.55). This indicates that there is a tendency of correlation among polymorphism 2, serous type and stage IV, indicating a risk factor for ovarian cancer. CONCLUSION: Hence, the results indicate that there is a tendency for polß polymorphisms being a risk factor for ovarian carcinogenesis in India.