The association between exposure to aflatoxin, mutation in TP53, infection with hepatitis B virus, and occurrence of liver disease in a selected population in Hyderabad, India

Aflatoxin B1 is a carcinogen produced by Aspergillus flavus and a few related fungi that are often present in many food substances. It interacts synergistically with Hepatitis B or C virus (HBV, HBC) infection, thereby increasing the risk of hepatocellular carcinoma (HCC). The G to T transversion at the third position of codon 249 (AGG) of the TP53 gene, substituting arginine to serine, is the most common aflatoxin-induced mutation linked to HCC. This study examined mutations in TP53 by PCR-RFLP analysis and by measurement of an aflatoxin-albumin adduct as a biomarker for human exposure of aflatoxin B1 by indirect-competitive ELISA, in samples collected from healthy controls as well as patients with hepatitis in Hyderabad, Andhra Pradesh, India. A total of 238 blood samples were analyzed the presence of the G to T mutation. Eighteen of these samples were from HBV-positive subjects, 112 of these were from subjects who had HBV-induced liver cirrhosis, and 108 samples were taken from subjects without HBV infection or liver cirrhosis (control group). The G to T mutation was detected in 10 samples, 8 of which were from subjects positive to both HBV and aflatoxin-albumin adduct in blood (p = 0.07); whilst two were from individuals who were HBV-negative, but positive for the aflatoxin-albumin adduct (p = 0.14). The aflatoxin-albumin adduct was detected in 37 of 238 samples, 29 samples were from HBV-positive subjects and eight were from individuals who were positive for both HBV and the TP53 mutation (p = 0.07). The concentration of aflatoxin-albumin adduct ranged from 2.5 to 667 pg/mg albumin. Despite low incidence of the G to T mutation, its detection in subjects positive to aflatoxin-adducts is indicative of a strong association between the mutation and aflatoxin exposure in India

PvuII polymorphism of estrogen receptor-α gene in breast cancer

Background: Estrogen receptor (ER) is a ligand-inducible transcription factor that mediates estrogen action in target tissue. Several common polymorphisms of the ERα gene have been reported to be associated with alterations in receptor expression in breast cancer. Materials and Methods: A case-control study was designed to compare 250 breast cancer patients with 250 age-matched healthy controls. The frequency distribution of PvuII polymorphism in the ERα gene was assessed by PCR-RFLP method. Results: The frequency of the PP genotype (35.3%) was increased significantly in breast cancer patients when compared to controls (19.8%), with a corresponding increase in P allele frequency (χ2 = 16.4; P = 0.0003). The OR for genotypes PP vs. Pp was 1.989 (95% CI: 1.2708 to 3.113). Premenopausal women with breast cancer had an elevated frequency of the PP genotype (22.8%) as compared to postmenopausal women (16.8%). The frequency of the PP genotype was increased in patients positive for ER and HER-2/neu as compared to those with receptor-negative status. The pp and p allele frequencies were increased in progesterone-receptor-negative status. When stage of the disease was considered, both Pp and pp genotype frequencies were elevated in patients with advanced stage breast cancer. The frequency of the P allele and PP genotype frequencies tended to increase with increase in body mass index, whereas the Pp genotype frequency was elevated only in obese patients. The reverse was observed in the case of pp genotype frequency. Conclusion: The study thus highlighted the influence of ERα PvuII polymorphism on the development and progression of breast cancer

Therapy-related acute promyelocytic leukemia following etoposide-based chemotherapy in non-seminomatous germ cell tumor

Therapy related AML (t- AML) accounts for 10-20% of all cases of AML. Cytotoxic agents implicated are alkylating agents, topoisomerase II inhibitors and rarely anti metabolites and anti tubulin agents. A growing incidence of therapy related acute promyelocytic leukemia (t-APL) has been reported over the last few decades in malignant and non malignant conditions. To the best of our knowledge this is the first t-APL case report to be reported in NSGCT post etoposide based therapy

PvuII polymorphism of estrogen receptor-\u3b1 gene in breast cancer

Background: Estrogen receptor (ER) is a ligand-inducible transcription factor that mediates estrogen action in target tissue. Several common polymorphisms of the ER\u3b1 gene have been reported to be associated with alterations in receptor expression in breast cancer. Materials and Methods: A case-control study was designed to compare 250 breast cancer patients with 250 age-matched healthy controls. The frequency distribution of PvuII polymorphism in the ER\u3b1 gene was assessed by PCR-RFLP method. Results: The frequency of the PP genotype (35.3%) was increased significantly in breast cancer patients when compared to controls (19.8%), with a corresponding increase in P allele frequency (\u3c72 = 16.4; P = 0.0003). The OR for genotypes PP vs. Pp was 1.989 (95% CI: 1.2708 to 3.113). Premenopausal women with breast cancer had an elevated frequency of the PP genotype (22.8%) as compared to postmenopausal women (16.8%). The frequency of the PP genotype was increased in patients positive for ER and HER-2/neu as compared to those with receptor-negative status. The pp and p allele frequencies were increased in progesterone-receptor-negative status. When stage of the disease was considered, both Pp and pp genotype frequencies were elevated in patients with advanced stage breast cancer. The frequency of the P allele and PP genotype frequencies tended to increase with increase in body mass index, whereas the Pp genotype frequency was elevated only in obese patients. The reverse was observed in the case of pp genotype frequency. Conclusion: The study thus highlighted the influence of ER\u3b1 PvuII polymorphism on the development and progression of breast cancer

Association of CYP1A1*2 Polymorphisms with Breast Cancer Risk : A Case Control Study

Background :The Cytochrome P-4501A1 (CYP1A1) gene, located on chromosome 15q, is involved in the metabolism of carcinogens mainly polycyclic aromatic hydrocarbons as well as estrogen. It is considered as candidate gene for low-penetrance breast cancer susceptibility. Hence the present study aims to discuss the role of CYP1A1 polymorphisms in breast cancer. Materials and Methods :A total of 250 breast cancer patients and the same number of healthy age-matched controls were analyzed for the polymorphism of CYP1A1FNx012 by polymerase chain reaction-restriction fragment length polymorphism. Results :In the present study, association of CYP1A1FNx012 (Ile 462Val) polymorphism with breast cancer was studied. Only one breast cancer patient was observed to be homozygous for Val allele but none among controls. The frequency of heterozygous Ile/Val genotype was found to be increased significantly in breast cancer patients (68.1%) as compared to controls (51.0%). Higher frequency of heterozygotes for Val allele was observed among premenopausal breast cancer patients and patients with high BMI, positive for HER2/neu status and advanced stage of the disease in comparison to the corresponding groups. No significant association of CYP1A1FNx012 polymorphism was observed with occupation, estrogen receptor and progesterone receptor status of breast cancer patients. Conclusions :In conclusion, our results suggest a significant correlation between CYP1A1FNx012 expression and the occurrence of breast cancer

Association of CYP3A5*3 polymorphism with development of acute leukemia

Background : CYP3A5 was observed to be an important genetic contributor to inter individual differences in CYP3A-dependent drug metabolism in acute leukemic patients. Loss of CYP3A5 expression was mainly conferred by a single nucleotide polymorphism at 6986A>G (CYP3A5*3). We investigated the association between CYP3A5*3 polymorphism and acute leukemia. Materials and Methods : Two hundred and eighty nine acute leukemia cases comprising of 145 acute lymphocytic leukemia (ALL), 144 acute myeloid leukemia and 241 control samples were analyzed for CYP3A5*3 polymorphism using PCR-RFLP method. Statistical analysis was performed with SPSS version (15.0) to detect the association between CYP3A5*3 polymorphism and acute leukemia. Results : The CYP3A5*3 polymorphism 3/3 genotype was significantly associated with acute leukemia development (\u3c72 - 133.53; df-2, P 0.000). When the data was analyzed with respect to clinical variables, mean WBC, blast % and LDH levels were increased in both ALL and AML cases with 3/3 genotype. The epidemiological variables did not contribute to the genotype risk to develop either AML or ALL. Conclusion : The results suggest that the CYP3A5*3 polymorphism might confer the risk to develop ALL or AML emphasizing the significance of effective phase I detoxification in carcinogenesis. Association of the polymorphism with clinical variables indicate that the 3/3 genotype might also contribute to poorer survival of the patients

Association of CYP3A5*3 polymorphism with development of acute leukemia

Background : CYP3A5 was observed to be an important genetic contributor to inter individual differences in CYP3A-dependent drug metabolism in acute leukemic patients. Loss of CYP3A5 expression was mainly conferred by a single nucleotide polymorphism at 6986A>G (CYP3A5FNx013). We investigated the association between CYP3A5FNx013 polymorphism and acute leukemia. Materials and Methods : Two hundred and eighty nine acute leukemia cases comprising of 145 acute lymphocytic leukemia (ALL), 144 acute myeloid leukemia and 241 control samples were analyzed for CYP3A5FNx013 polymorphism using PCR-RFLP method. Statistical analysis was performed with SPSS version (15.0) to detect the association between CYP3A5FNx013 polymorphism and acute leukemia. Results : The CYP3A5FNx013 polymorphism 3/3 genotype was significantly associated with acute leukemia development (χ2 - 133.53; df-2, P 0.000). When the data was analyzed with respect to clinical variables, mean WBC, blast % and LDH levels were increased in both ALL and AML cases with 3/3 genotype. The epidemiological variables did not contribute to the genotype risk to develop either AML or ALL. Conclusion : The results suggest that the CYP3A5FNx013 polymorphism might confer the risk to develop ALL or AML emphasizing the significance of effective phase I detoxification in carcinogenesis. Association of the polymorphism with clinical variables indicate that the 3/3 genotype might also contribute to poorer survival of the patients

The association between exposure to aflatoxin, mutation in TP53,infection with hepatitis B virus, and occurrence of liver disease in a selected population in Hyderabad, India

Aflatoxin B1 is a carcinogen produced by Aspergillus flavus and a few related fungi that are often presentin many food substances. It interacts synergistically with Hepatitis B or C virus (HBV, HBC) infection,thereby increasing the risk of hepatocellular carcinoma (HCC). The G to T transversion at the third positionof codon 249 (AGG) of the TP53 gene, substituting arginine to serine, is the most common aflatoxininducedmutation linked to HCC. This study examined mutations in TP53 by PCR-RFLP analysis and bymeasurement of an aflatoxin-albumin adduct as a biomarker for human exposure of aflatoxin B1 byindirect-competitive ELISA, in samples collected from healthy controls as well as patients with hepatitisin Hyderabad, Andhra Pradesh, India. A total of 238 blood samples were analyzed the presence of the G toT mutation. Eighteen of these samples were from HBV-positive subjects, 112 of these were from subjectswho had HBV-induced liver cirrhosis, and 108 samples were taken from subjects without HBV infectionor liver cirrhosis (control group). The G to T mutation was detected in 10 samples, 8 of which werefrom subjects positive to both HBV and aflatoxin-albumin adduct in blood (p = 0.07); whilst two werefrom individuals who were HBV-negative, but positive for the aflatoxin-albumin adduct (p = 0.14). Theaflatoxin-albumin adduct was detected in 37 of 238 samples, 29 samples were from HBV-positive subjectsand eight were from individuals who were positive for both HBV and the TP53 mutation (p = 0.07). Theconcentration of aflatoxin-albumin adduct ranged from 2.5 to 667 pg/mg albumin. Despite low incidenceof the G to T mutation, its detection in subjects positive to aflatoxin-adducts is indicative of a strongassociation between the mutation and aflatoxin exposure in India