Human DNA polymerase β polymorphism, Arg137Gln, impairs its polymerase activity and interaction with PCNA and the cellular base excision repair capacity

DNA polymerase β (Pol β) is a key enzyme in DNA base excision repair, and an important factor for maintaining genome integrity and stability. More than 30% of human tumors characterized to date express DNA Pol β variants, many of which result from a single nucleotide residue substitution. However, in most cases, their precise functional deficiency and relationship to cancer susceptibility are still unknown. In the current work, we show that a polymorphism encoding an arginine to glutamine substitution, R137Q, has lower polymerase activity. The substitution also affects the interaction between Pol β and proliferating cell nuclear antigen (PCNA). These defects impair the DNA repair capacity of Pol β in reconstitution assays, as well as in cellular extracts. Expression of wild-type Pol β in pol β−/− mouse embryonic fibroblast (MEF) cells restored cellular resistance to DNA damaging reagents such as methyl methanesulfonate (MMS) and N-methyl-N-nitrosourea (MNU), while expression of R137Q in pol β−/− MEF cells failed to do so. These data indicate that polymorphisms in base excision repair genes may contribute to the onset and development of cancers

The association of polymorphisms in hormone metabolism pathway genes, menopausal hormone therapy, and breast cancer risk: a nested case-control study in the California Teachers Study cohort

Abstract Introduction The female sex steroids estrogen and progesterone are important in breast cancer etiology. It therefore seems plausible that variation in genes involved in metabolism of these hormones may affect breast cancer risk, and that these associations may vary depending on menopausal status and use of hormone therapy. Methods We conducted a nested case-control study of breast cancer in the California Teachers Study cohort. We analyzed 317 tagging single nucleotide polymorphisms (SNPs) in 24 hormone pathway genes in 2746 non-Hispanic white women: 1351 cases and 1395 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by fitting conditional logistic regression models using all women or subgroups of women defined by menopausal status and hormone therapy use. P values were adjusted for multiple correlated tests (P ACT). Results The strongest associations were observed for SNPs in SLCO1B1, a solute carrier organic anion transporter gene, which transports estradiol-17β-glucuronide and estrone-3-sulfate from the blood into hepatocytes. Ten of 38 tagging SNPs of SLCO1B1 showed significant associations with postmenopausal breast cancer risk; 5 SNPs (rs11045777, rs11045773, rs16923519, rs4149057, rs11045884) remained statistically significant after adjusting for multiple testing within this gene (P ACT = 0.019-0.046). In postmenopausal women who were using combined estrogen-progestin therapy (EPT) at cohort enrollment, the OR of breast cancer was 2.31 (95% CI = 1.47-3.62) per minor allele of rs4149013 in SLCO1B1 (P = 0.0003; within-gene P ACT = 0.002; overall P ACT = 0.023). SNPs in other hormone pathway genes evaluated in this study were not associated with breast cancer risk in premenopausal or postmenopausal women. Conclusions We found evidence that genetic variation in SLCO1B1 is associated with breast cancer risk in postmenopausal women, particularly among those using EPT

CONGENITAL ADRENAL HYPERPLASIA WITH COMPOUND HETEROZYGOUS I2 SPLICE AND P453S MUTATIONS

Background. Congenital adrenal hyperplasia (CAH) is an autosomal recessive inherited disorder caused by congenital deficiency of enzymes involved in cortisol biosynthesis from cholesterol in the adrenal cortex. In this Article, we aimed to present a 29-year-old female patient with I2 splice point mutation detected in one allele and P453S mutation on the other allele of CYP21A2 gene associated with 21-hydroxylase deficiency. Her further investigation revealed that her mother had P453S mutation and her father had I2 splice mutation. Case report. A 29-year-old woman with CAH was admitted to our clinic with the request of pregnancy. Her physical examination revealed a height of 151 cm, weight 59 kg, body mass index 25.8 kg/m2. According to Tanner staging, she had Stage 3 breast development and pubic hair. Her laboratory test results were as follows: Glucose: 79 mg/dL (70-100 mg/dL), Creatinine: 0.6 (0.5-0.95 mg/ dL), Sodium: 138 mEq/L (135-145 mEq/L), Potassium: 4.4 mEq/L (3.5-5.1 mEq/L), Cortisol: 0.05 mu g/dL, ACTH: 5.00 pg/mL (5-46 pg/mL), 17-OH progesterone: 7.67 ng/mL (0-3 ng/mL). Chromosome analysis revealed a 46, XX karyotype. CYP21A2 gene mutation analysis was performed for the patient whose clinical history and laboratory results were compatible with congenital adrenal hyperplasia. During the reverse dot blot analysis, I2 splice mutation in one allele and P453S mutation in the other allele were detected. Conclusion. Although the I2 splice mutation detected in our case was mostly associated with a saltwasting form of CAH, it was thought that the other P453S mutation detected may explain the relatively good clinical course in our case

Multigene Methylation Analysis of Conventional Renal Cell Carcinoma

WOS: 000268680200019PubMed ID: 19641369Renal cell carcinoma (RCC) is the most common malignancy of the kidney. Since RCC is curable when it is confined to the renal capsule, early diagnosis is extremely important. Promoter hypermethylation is the most common mechanism for the inactivation of the tumor suppressor genes (TSG) in the development of human cancer. This study aimed to investigate the methylation profiles of 7 TSG (RASSF1A, ECAD, TIMP3, APC, MGMT, p16 and RAR beta 2) in 3 different tissue samples (normal, premalign, malign) of patients with RCC. Twenty-one patients diagnosed with RCC were included in the study. Methylation-specific polymerase chain reaction was performed to detect the methylation patterns of the 7 TSG. High methylation rates for the genes RASSF1A (76%), p16 (80%), ECAD (42%), TIMP3 (33%) and MGMT (33%) were observed in the patients with RCC. The APC (14%) and RAR beta 2 (19%) genes showed low methylation rates. In conclusion, 5 TSG (RASSF1A, ECAD, TIMP3, MGMT and p16) showed high methylation rates in RCC patients. A methylation-based gene test including these genes may be useful in the early detection of RCC. Copyright (C) 2009 S. Karger AG, Base

Can mycoplasma-mediated oncogenesis be responsible for formation of conventional renal cell carcinoma?

Objectives. To investigate the association between Mycoplasmo sp. infection and conventional renal cell carcinoma (RCC)

The Effect of Vitamin D Levels and Fok 1 VDR Gene Polymorphism on Long Term Bone Health in Pediatric Cancer Survivors

WOS: 00040897820408