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PubMed2006

Familial clustering of autoimmune diseases in patients with type 1 diabetes mellitus.

We investigated the familial aggregation of autoimmune diseases (AIDs) among first-degree relatives (FDR) of patients with type 1 diabetes mellitus (T1D). Relatives of 98 T1D patients defined according to the guidelines diagnosis of the American Diabetes Association and 113 matched controls without any AID, were interviewed using a questionnaire that sought information about demographic and medical characteristics including a list of 18 AIDs. Genetic analysis was performed using the program ASSOC and by calculating recurrent risk ratios. In cases, 25.5% of the families had at least one member having an AID, while in controls there were 9% (odds ratio [OR]: 3.96, 95% confidence interval [CI]=1.74-9.0, p=0.0006). An AID was registered in 8.3% of 312 FDR of patients as compared with 2.4% of 362 FDR in controls (OR: 3.56, 95% CI=1.64-7.73, p=0.0008). The most frequent AIDs registered in FDR of cases were autoimmune thyroid disease (AITD) and T1D, which disclosed coefficients of aggregation. These results indicate that AIDs cluster within families of T1D patients adding further evidence to consider that clinically different autoimmune phenotypes may share common susceptibility gene variants, which may act pleiotropically as risk factors for autoimmunity.

Autoimmune Diseases↗

PubMed1989

Galactose-1-phosphate uridyl transferase activity associated with age at menopause and reproductive history.

Reproductive history was obtained and the activity and electrophoretic pattern of the blood enzyme galactose-1-phosphate uridyl transferase (transferase) was measured in 104 adult Caucasian women, less than 70 years of age, sampled from the general population. Fifteen women were identified as carriers for the Duarte (GtD) or galactosemia (gt) variants of transferase--genes associated with reduced transferase activity compared with normal (Gt+). The mean age at menopause for 8 women with a natural menopause who were GtD/Gt+ or gt/Gt+ was 44.8, significantly younger (P = 0.007) than the mean age of 49.2 reported by 31 naturally postmenopausal subjects with Gt+/Gt+ genotypes and normal transferase activity. Compared with the latter group, women who were Duarte or galactosemia carriers were 13.7 times more likely to have a menopause before age 48 (with 95% confidence limits of 2.0 to 95.5). Six of 13 (46%) married women who were GtD/Gt+ or gt/Gt+ reported more than 2 years' trying to achieve a pregnancy, compared with 11 of 74 (15%) with normal genotypes and activity (P = 0.02). The authors conclude that genetic deficiency of transferase may be associated with infertility and early menopause.

Adult↗

PubMed2002

Distinct prevalence of the CYP19 Delta3(TTTA)(7) allele in premenopausal versus postmenopausal breast cancer patients, but not in control individuals.

The CYP19 gene encodes the enzyme aromatase, which plays a key role in the conversion of androgens to oestrogens. A polymorphism in CYP19 in intron 4 (TTTA)n has been reported to be associated with breast cancer (BC) risk, although conflicting evidence has also been published. Here, we employ a non-traditional, highly demonstrative design of a molecular epidemiological study, where the comparison of BC cases and healthy middle-aged female donors was supplemented by an analysis of groups with extreme characteristics of either BC risk (bilateral breast cancer (biBC) patients) or cancer tolerance (tumour-free elderly women aged >or=75 years). None of the (TTTA)n polymorphic variants was significantly overrepresented among the affected women compared with any of the control groups. However, a 3-bp deletion/insertion CYP19 polymorphism, which is located in the same intron approximately 50 bp upstream to the (TTTA)n repeat, was evidently associated with the menopausal status in both the BC and biBC cohorts. In particular, the Delta3(TTTA)(7) allele occurred significantly more frequently in premenopausal than in postmenopausal BC patients (65/172 (38%) versus 67/310 (22%); P=0.0001; Odds Ratio (OR)=2.20 (95% Confidence Interval (CI) 1.46-3.32)), while the perimenopausal cases demonstrated an intermediate value (9/34 (26%)). In the biBC cohort, women who developed both tumours during their premenopausal period had a significantly higher prevalence of the Delta3(TTTA)(7) allele than patients with a postmenopausal onset of bilateral disease (16/46 (35%) versus 8/50 (16%); P=0.035; OR=2.80 (1.08-7.23)); those biBC patients, whose tumours were diagnosed before and after the cessation of menses, displayed an intermediate occurrence of the Delta3(TTTA)(7) allele (7/32 (22%)). Similar tendencies in the Delta3(TTTA)(7) allele distribution in BC and biBC patients suggest that its association with the menopausal status of the patients is truly non-random and thus this observation deserves further detailed investigation.

Adult↗

PubMed2004

Polymorphisms in XPD and TP53 and mutation in human lung cancer.

The pattern of somatic mutations in TP53 is distinct for particular cancers and carcinogenic exposures, providing clues to disease etiology, e.g. G:C-->T:A mutations in TP53 are more frequently observed in smoking-associated lung cancers. In order to investigate possible causes and mechanisms of lung cancer susceptibility differences, the TP53 gene was sequenced in a case-only study of lung cancers (206 men and 103 women). Our primary hypothesis was that the TP53 mutation spectrum is influenced by polymorphisms in genes involved in DNA repair and apoptosis. We observed a TP53 mutation frequency in exons 5-8 of 25%. Functional polymorphisms in XPD (Asp312Asn, rs1799793 and Lys751Gln, rs1052559), a protein required for nucleotide excision repair and with roles in p53-mediated apoptosis, were modestly associated with G:C-->T:A mutations in TP53 in lung tumors [Asp/Asn312 + Asn/Asn312 and/or Lys/Gln751 + Gln/Gln751 versus Asp/Asp312 + Lys/Lys751; odds ratio (OR) 2.73, 95% confidence interval (CI) 0.98-7.61], consistent with the role of this protein in repair of bulky carcinogen-DNA adducts. In addition, a TP53 polymorphism (Arg72Pro, rs1042522) with a known role in the efficiency of apoptosis was also associated with the presence of a TP53 mutation (Pro/Arg72 or Pro/Pro72 versus Arg/Arg72; OR 2.25, 95% CI 1.21-4.17) or a G:C-->T:A mutation in TP53 (Pro/Arg72 or Pro/Pro72 versus Arg/Arg72; OR 2.42, 95% CI 0.97-6.04). An interaction between the XPD variant alleles (Asn312 and Gln751) and the TP53 Pro72 allele was observed for TP53 mutations (any TP53 mutation P(int) = 0.027, G:C-->T:A TP53 mutation P(int) = 0.041). The statistical interaction observed in our study is consistent with the observed biological interaction for XPD and p53 in nucleotide excision repair and apoptosis. In conclusion, differences in TP53 mutation spectra in lung tumors are associated with several genetic factors and may reflect differences in lung cancer susceptibility and carcinogenesis.

Base Sequence↗

PubMed2003

The Glu298Asp polymorphism in the endothelial nitric oxide synthase gene is strongly associated with coronary spasm.

BACKGROUND: Coronary spasm seems to be associated with coronary nitric oxide deficiency. OBJECTIVES: We investigated whether the Glu298Asp polymorphism in the endothelial nitric oxide synthase (eNOS) gene is a definite risk factor for coronary spasm and whether diffuse spasm involving normal-looking coronary artery correlates significantly with the Glu298Asp polymorphism, in contrast with focal spasm superimposed on an atherosclerotic plaque. METHODS: A polymerase chain reaction followed by restriction fragment length polymorphism analysis was performed in 118 control participants and in 102 patients with variant angina and a similar degree of atherosclerotic burden. Patients with coronary spasm were divided into diffuse spasm and focal spasm subgroups according to morphological criteria. RESULTS: There was a significantly higher incidence of the Glu298Asp polymorphism in the coronary spasm group than in the control group (21.5% compared with 8.5%, P=0.006). Multiple logistic regression analysis using risk factors and the Glu298Asp polymorphism showed that the most important predictive factor for coronary spasm was the Glu298Asp polymorphism (odds ratio 2.83, 95% confidence interval 1.25-6.41, P=0.009). The diffuse spasm subgroup had a significantly higher frequency of the Glu298Asp polymorphism than the control group (25.9% compared with 8.5%, P=0.002). However, the focal spasm subgroup did not differ from the control group in the frequency of Glu298Asp polymorphism. CONCLUSION: The Glu298Asp polymorphism in the eNOS gene is a definite risk factor for coronary spasm, especially for diffuse coronary spasm. This result supports the notion that diffuse coronary spasm is significantly associated with endothelial dysfunction, in contrast to focal spasm.

Coronary Vasospasm↗

PubMed2006

Death receptor 4 variants and colorectal cancer risk.

The tumor necrosis factor-related apoptosis-inducing ligand receptor modulates apoptotic response by binding to the proapoptotic death receptor 4 (DR4). Perturbed apoptosis due to missense alterations in the candidate tumor suppressor gene DR4 leads to deregulated cell proliferation and cancer predisposition. Recent studies have discussed the association of DR4 variants with cancer risk. We evaluated, for the first time, the role of the Thr(209)Arg (626C>G) and Glu(228)Ala (683A>C) polymorphisms on colorectal cancer risk by genotyping 659 incident cases and 607 healthy controls drawn from the German population-based Darmkrebs: Chancen der Verhütung durch Screening (DACHS) study. Whereas DR4 Glu(228)Ala was not associated with colorectal cancer, Thr(209)Arg heterozygotes were at a significantly decreased colorectal cancer risk [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.54-0.97]. Stratification according to sex and age exhibited a significant association of Thr(209)Arg with a decreased risk for male heterozygotes (OR, 0.68; 95% CI, 0.46-0.99) and for Arg(209) carriers > or =65 years of age (OR, 0.65; 95% CI, 0.46-0.92) as well as an enhanced risk for female Ala(228) carriers in a allele dose-dependent manner (P(trend) = 0.01). Subsite analysis revealed a protective effect of Thr(209)Arg for rectal cancer risk (OR, 0.67; 95% CI, 0.48-0.95) and a significant risk increase for Ala(228) carriers with advanced colorectal cancer stages (P(trend) = 0.04). Haplotype analysis revealed a 2.4-fold risk for carriers of the rare 626C-683C haplotype (1% prevalence in the general population; OR, 2.37; 95% CI, 0.98-5.76). The score statistic yielded an empirical P of 0.03 of the haplotype-specific test for 626C-683C based on 20,000 simulations, suggesting that DR4 626C-683C may affect colorectal cancer predisposition.

Adult↗

PubMed1999

hOGG1 Ser326Cys polymorphism and lung cancer susceptibility.

The human homologue of the yeast OGG1 gene, hOGG1, has been cloned, and its genetic structure has been determined. Several polymorphisms in the hOGG1 gene were detected in the Japanese populations, and among them, the Ser-Cys polymorphism at codon 326 has been shown to have a functional difference in complementation of mutant Escherichia coli that is defective in the repair of 8-hydroxyguanine. Activity in the repair of 8-hydroxyguanine is greater in hOGG1-Ser326 protein than in hOGG1(326) protein. Because many environmental carcinogens produce 8-hydroxyguanine residue and mismatching to this modified base potentially causes oncogenic mutations, the capacity to repair these lesions can be involved in cancer susceptibility in human beings. We, therefore, examined allele distributions of the Ser326Cys polymorphism in a case-control study of male lung cancer in Okinawa. The analyses based on 241 cases and 197 hospital controls disclosed the following findings. (a) Those with the Cys/Cys genotype were at an increased risk of squamous cell carcinoma and nonadenocarcinoma compared to those with the Ser/Cys and those with the Ser/Ser genotypes combined. The odds ratios adjusted for age and smoking history were 3.01 (95% confidence interval, 1.33-6.83) and 2.18 (95% confidence interval, 1.05-4.54), respectively. (b) The odds ratios for other histological subtypes of lung cancer or those in total were not significant. Those for Cys/Cys or Ser/Cys genotype against Ser/Ser did not reach statistical significance in any cell type. (c) The distributions of this polymorphism varied for different populations (Chinese, Japanese, Micronesians, Melanesians, Hungarians, and Australian Caucasians), with much less prevalence of Cys allele in the latter three populations. Although our sample size was limited, these results indicate that the Ser326Cys variant may be related to squamous cell lung cancer susceptibility. The Cys/Cys genotype appears to be more susceptible to squamous cell carcinoma, although the risk is less than that previously reported to be associated with the CYP1A1 gene. Further studies are needed to assess the importance of the interpopulation variation to cancer susceptibility.

Adult↗

PubMed2006

Distribution of common CARD15 variants in patients with sporadic Crohn's disease: cases from Turkey.

Three common genetic variations, namely, R702W, G908R, and 1007fs, on CARD15 have been shown to increase the risk for Crohn's disease (CD) in Caucasian populations. In this study the frequencies of these CARD15 variants were determined by genotyping in 56 patients with CD and 100 healthy ethnically matched controls from Turkey. Overall frequency of all three variants was 10.7% in CD patients, compared with 1.5% in controls (odds ratio [OR]: 7.9). Among them, the frequency of the G908R variant allele was 8% in CD cases, compared with 0% in controls (OR: 36.8). The allele frequencies of three CD-related CARD15 variants were considerably lower in the control group compared to the reported Caucasian populations. Among the described CARD15 variants, G908R confers an increased susceptibility to CD, whereas the more frequently reported associations in Europeans with R702W and 1007fs are not confirmed in this Turkish population.

Adolescent↗

PubMed2003

Weekly regimen of irinotecan/docetaxel in previously treated non-small cell lung cancer patients and correlation with uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism.

PURPOSE: Inherited variations in drug metabolizing enzymes may influence drug efficacy. This phase II study assesses the impact of second-line weekly irinotecan (CPT-11)/docetaxel in non-small cell lung cancer (NSCLC) patients, and gauges the uridine diphosphate glucuronosyl transferase (UGT1A1) polymorphism influence in toxicity and antitumor activity. EXPERIMENTAL DESIGN: Fifty-one patients with NSCLC treated with at least one prior chemotherapy regimen were enrolled. Patients received irinotecan 70 mg/m(2) followed by docetaxel 25 mg/m(2). Both drugs were given on days 1, 8, and 15 every 28 days. UGT1A1 polymorphism were analyzed in blood samples of 47 patients. The UGT1A1 polymorphism are classified according to the number of TA repeats in the promoter region of this gene. RESULTS: Three patients (6%) achieved a partial response and nineteen patients (37%) had stable disease. Median survival was 8 months (95% CI: 4.8-11.2) and 1-year survival 30%. Grade 3-4 hematologic toxicity was low (less than 10% of patients); 15% of patients had grade 3 asthenia and 25% of patients had grade 3/4 diarrhea. The frequency of UGT1A1 genotypes was as follows: 6/6 49%, 6/7 36%, and 7/7 15%. No differences in toxicity were observed according to UGT1A1 polymorphism. A nonsignificant improvement in time to progression (4 vs. 3 months) and median survival (11 vs. 8 months) was detected in patients with the variant alleles (6/7 and 7/7). CONCLUSIONS: This weekly irinotecan/docetaxel regimen has shown an acceptable toxicity profile while encouraging median and 1-year survival in heavily pretreated NSCLC patients. The tendency to better prognosis in patients carrying the variant genotypes 6/7 and 7/7 of UGT1A1 gene requires further validation.

Adult↗

PubMed2000

The correlation between intron length and recombination in drosophila. Dynamic equilibrium between mutational and selective forces.

Intron length is negatively correlated with recombination in both Drosophila melanogaster and humans. This correlation is not likely to be the result of mutational processes alone: evolutionary analysis of intron length polymorphism in D. melanogaster reveals equivalent ratios of deletion to insertion in regions of high and low recombination. The polymorphism data do reveal, however, an excess of deletions relative to insertions (i.e., a deletion bias), with an overall deletion-to-insertion events ratio of 1.35. We propose two types of selection favoring longer intron lengths. First, the natural mutational bias toward deletion must be opposed by strong selection in very short introns to maintain the minimum intron length needed for the intron splicing reaction. Second, selection will favor insertions in introns that increase recombination between mutations under the influence of selection in adjacent exons. Mutations that increase recombination, even slightly, will be selectively favored because they reduce interference among selected mutations. Interference selection acting on intron length mutations must be very weak, as indicated by frequency spectrum analysis of Drosophila intron length polymorphism, making the equilibrium for intron length sensitive to changes in the recombinational environment and population size. One consequence of this sensitivity is that the advantage of longer introns is expected to decrease inversely with the rate of recombination, thus leading to a negative correlation between intron length and recombination rate. Also in accord with this model, intron length differs between closely related Drosophila species, with the longest variant present more often in D. melanogaster than in D. simulans. We suggest that the study of the proposed dynamic model, taking into account interference among selected sites, might shed light on many aspects of the comparative biology of genome sizes including the C value paradox.

Animals↗

PubMed2002

Evaluation of the validity and reliability of A-scan ultrasound biometry with a single use disposable cover.

BACKGROUND: The UK Medical Devices Agency has suggested that ophthalmic practitioners should, where practicable and not compromising clinical outcome, restrict corneal contact devices to single patient use to minimise a remote theoretical risk of transmission of new variant Creutzfeldt-Jakob disease (vCJD). This study reports on a modified technique of ultrasound A-scan biometry that complies with the MDA recommendations. METHODS: The right eyes of 37 consecutive hospital patients had a series of biometry readings taken with a Humphrey 820 A-scan instrument with a plane wave transducer use d conventionally and with the addition of a disposable latex cover. RESULTS: Intrasessional repeatability of axial length measurements was similar for conventional readings--mean difference 0.027 mm, 95% confidence intervals (CI) +/- 0.44 mm and those taken with a disposable cover (0.028 mm, CI +/- 0.38). Intersessional repeatability was equivalent with (0.002 mm, CI +.- 0.51) and without a cover (0.03 mm, CI +/- 0.51). Readings with a cover were not significantly different from those without (paired t test; p >0.05), but tended to be greater (mean difference 0.085 mm, CI +/- 0.60). CONCLUSIONS: These findings suggest that corneal contact biometry with a disposable cover is a viable and theoretically safer alternative to the conventional technique.

Adult↗

PubMed2002

High hepatitis B virus (HBV) DNA viral load as the most important risk factor for HBV reactivation in patients positive for HBV surface antigen undergoing autologous hematopoietic cell transplantation.

The risk factors for hepatitis due to hepatitis B virus (HBV) reactivation in patients positive for hepatitis B surface antigen (HBsAg) treated with autologous hematopoietic cell transplantation (HCT) are unknown. We evaluated 137 consecutive patients (23 positive for HBsAg, 37 positive for hepatitis B surface antibody, and 77 negative for HBV) who underwent HCT. Serial serum ALT were measured before transplant and after transplant at 1 to 4 weekly intervals for the first year and then at 2 to 12 weekly intervals thereafter. Before HCT, basic core promoter (T(1762)/A(1764)) and precore (A(1896)) HBV variants were determined in HBsAg-positive and HBV DNA-positive (by polymerase chain reaction assay) patients by direct sequencing and serum HBV DNA quantitation using the Digene Hybrid Capture II assay. Cox proportional hazards analysis was used to assess the association between pretransplantation HBV virologic and host factors and occurrence of hepatitis due to HBV reactivation. After HCT, hepatitis due to HBV reactivation was more common in HBsAg-positive patients than in HBsAg-negative patients (hazard ratio, 33.3; 95% confidence interval [CI], 7.35-142.86; P <.0001). HBsAg-positive patients with detectable serum HBV DNA before HCT (on Digene assay) had a significantly higher risk of hepatitis due to HBV reactivation than HBsAg-positive patients with no detectable serum HBV DNA (adjusted hazard ratio, 9.35; 95% CI, 1.65-52.6; P =.012). Thus, we found that hepatitis due to HBV reactivation is common in HBsAg-positive patients undergoing autologous HCT. A high HBV DNA level (>10(5) copies/mL) was the most important risk factor for HBV reactivation, and its lowering by administration of nucleoside analogues before transplantation should be considered.

Adolescent↗

PubMed2006

[Polymorphisms of the DNA repair genes XRCC1 and XPC: relationship to pancreatic cancer risk].

OBJECTIVE: To determine whether genetic polymorphisms in XRCC1 and XPC are associated with risk of pancreatic cancer. METHODS: A case-control study was conducted in 101 incident cases with pancreatic cancer and 337 controls (matched for age, sex and ethnicity) to investigate whether genetic polymorphisms in DNA repair genes XRCC1 (Arg194Trp and Arg399Gln) and XPC (an intronic biallelic poly (AT) insertion/deletion polymorphism, XPC-PAT) were associated with risk of pancreatic cancer. The odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated by unconditional logistic regression models and adjusted for potential confounding factors. RESULTS: There was a small, non-significant decrease in risk for pancreatic cancer in those carrying Gln/Gln genotype at XRCC1 Arg399Gln site (OR 0.64, 95% CI 0.21 - 1.66, P = 0.30) compared with those having Arg/Arg genotypes. And the XRCC1 Arg194Trp polymorphism was not significantly associated with risk of pancreatic cancer. For XPC-PAT polymorphism, 5.0% of cases and 13.4% of controls were homozygous for the variant allele (PAT+/+), resulting in an OR of 0.30 (95% CI 0.10 - 0.76, P = 0.02), which suggested that the PAT +/+ genotype might have protective effect against pancreatic carcinogenesis. CONCLUSIONS: This study suggest that XPC-PAT polymorphisms may contribute to the risk of pancreatic cancer in our study population.

Adult↗

PubMed2006

Comparative biological activities of a plaque-purified variant and a Turkish native isolate of SpliNPV-B against Spodoptera littoralis (Lepidoptera: Noctuidae).

The noctuid moth Spodoptera littoralis (Boisduval) is an important pest of many cultivated plants worldwide and five different geographical Nucleopolyhedrovirus (NPV) strains of this pest have been isolated to date. Two of these, a plaque-purified variant of the S. littoralis NPV from Morocco (SpliNPV-M2) and a SpliNPV isolated from field-infected S. littoralis larvae found in Turkey (SpliNPV-TR1), were compared biologically in terms of infectiveness (median lethal dose, LD50) for third instars and in terms of virulence (median lethal time, LT50) for neonates and third-instar S. littoralis larvae. The LD50 values of SpliNPV-TR1 and SpliNPV-M2 were 20.73 and 185.21 occlusion bodies (OBs)/larva, respectively, with non-overlapping confidence limits indicating they were significantly different. Thus, SpliNPV-M2 was found to be significantly less infective (about nine times higher LD50) than SpliNPV-TR1. The LT50 values of neonates for SpliNPV-M2 and SpliNPV-TR1 were 37 and 43.9 h at a concentration of 10(6) OBs ml(-1), respectively. For these same isolates, the LT50 values at a concentration of 3 x 10(6) OBs ml(-1) were calculated as 35.6 and 41.7 h, respectively. The LT(50) values of third instars for SpliNPV-M2 and SpliNPV-TR1 were 147.4 and 160.5 h, respectively, at a dose of 3000 OBs/larva and 145.4 and 152.4 h, respectively, for the same isolates at a dose of 20,000 OBs/larva. On the other hand, Helicoverpa armigera (Hübner) and Agrotis ipsilon (Hufnagel) revealed a lack of lethality of the SpliNPV-TR1 isolate.

Animals↗

PubMed2001

Polymorphisms in inflammatory cytokines and Fcgamma receptors in childhood chronic immune thrombocytopenic purpura: a pilot study.

Inflammatory cytokines and low-affinity Fcgamma receptor (FcgammaR) polymorphisms were investigated in 37 children with chronic immune thrombocytopenic purpura (cITP) and 218 controls. Genotype analysis included common variants in the regulatory regions of cytokines, TNF, LTA, IL1RN, IL1A, IL1B, IL4, IL6 and IL10, and structural variants of the low affinity FcgammaRs, FCGR2A, FCGR3A and FCGR3B. Associations were observed for TNF (P = 0.0032), LTA (P = 0.019), FCGR3A (P = 0.038) and FCGR3B (P = 0.0034). Two combinations of genotypes (TNF and FCGR3A; P = 0.0003, and LTA and FCGR3B; P = 0.011) were significantly associated with cITP. These results provide preliminary evidence that variant genotypes of FcgammaRs and cytokines contribute to cITP pathogenesis.

Case-Control Studies↗

PubMedDate not supplied

Genetic polymorphisms in GSTM1, GSTT1, GSTP1, GSTM3 and the susceptibility to gallbladder cancer in North India.

The glutathione S-transferase (GSTs) are polymorphic supergene family of detoxification enzymes that are involved in the metabolism of numerous potential carcinogens. Several allelic variants of polymorphic GSTs show impaired enzyme activity and are suspected to increase the susceptibility to various cancers. To find out the association of GST variants with risk of gallbladder cancer, the distribution of polymorphisms in the GST family of genes (GSTT1, GSTM1, GSTP1, and GSTM3) were studied in 106 cancer patients and 201 healthy controls. Genotypes were analysed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP). The frequencies of GSTM1 null and GSTM3*BB genotypes did not differ between patients and controls. The overall frequency of GSTT1 null was lower in cases as compared with controls (p=0.003, Odds ratio (OR) = 0.2, 95% confidence interval (CI), 0.1-0.6). After sex stratification, the GSTT1 null frequency was reduced only in female patients (p=0.008, OR = 0.2, 95% CI = 0.1-0.6). However, the GSTP1, ile/val genotype and the val allele were significantly higher in cases than controls (p=0.013, OR = 1.9, 95% CI = 1.1-3.1; p=0.027, OR = 1.5, 95% CI = 1.0-2.1), respectively. To study gene-gene interactions, a combined risk of gallbladder cancer due to ile/val or val/val were calculated in combination with null alleles of GSTM1 and GSTT1 or the *B allele of GSTM3, but there was no enhancement of risk. Gallstones were present in 57.5% of patients with gallbladder cancer, but there were no significant differences between allelic/genotype frequencies of the studied GST genes polymorphisms between patients with or without gallstones. To best of our knowledge, this is the first paper showing ile/val genotypes and val allele of GSTP1 to be associated with higher risk of gallbladder cancer.

Adult↗

PubMed2006

Genotypes, haplotypes and diplotypes of XPC and risk of bladder cancer.

Xeroderma pigmentosum complementation group C (XPC) is responsible for DNA damage recognition in the initial steps of the nucleotide excision repair pathway. Genetic variations in the XPC gene may be associated with impaired protein function and increased risk for bladder cancer. To elucidate the roles of common polymorphisms of XPC in the etiology of bladder cancer, we conducted a hospital-based case-control study including 578 Caucasian incident bladder cancer patients and 578 age- and gender-matched Caucasian controls. We analyzed the associations of the genotypes, haplotypes and diplotypes of three XPC polymorphisms, Ala499Val (C-->T), PAT (-/+) and Lys939Gln (A-->C), with the risk of bladder cancer. No significant association was found for any individual polymorphism. However, the C-C and T-A (indicated as in the order of Ala499Val-PAT-Lys939Gln) haplotypes were associated with reduced bladder cancer risks, with odds ratios (ORs) of 0.51 [95% confidence interval (CI) = 0.34-0.78] and 0.79 (0.60-1.04), respectively. The protective effects were more evident in men, people younger than 59 years, and ever-smokers. We also found that four diplotypes were significantly associated with reduced bladder cancer risk, with ORs (and 95% CIs) of 0.53 (0.34-0.82) for C-A/T-A, 0.48 (0.27-0.84) for C-A/C-C, 0.18 (0.053-0.60) for C-C/C-C and 0.57 (0.36-0.90) for C+C/C+C. These results suggest that sequence variants in the XPC gene might modulate the risk of bladder cancer.

Aged↗

PubMed2026

PDGFRA amplification could be a poor prognostic factor of advanced undifferentiated pleomorphic sarcoma in a comprehensive genomic profiling cohort.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is the most common pleomorphic sarcoma, and its genomic landscape has been analysed, albeit in small numbers. This study aimed to clarify the relationship between gene variants and the prognosis of patients with advanced UPS. METHODS: This retrospective cohort study was conducted to analyse the data of patients with advanced UPS using a registry of the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database up to Oct 2025 in Japan, analysed using comprehensive genomic profiling assay. RESULTS: A total of 233 patients with advanced UPS were identified in the C-CAT database; 151 men (64.8%), median age: 60.2 years. TP53 variant (55%) was the most frequent event and the rate of Platelet-derived growth factor receptor alpha (PDGFRA) and KDR amplification were 9% and 6%, respectively. PDGFRA amplification co-occurred with KDR amplification (P < 0.001). Survival from the initiation of chemotherapy was analysed by adjusting for length bias inherent in the database using the Kaplan-Meier estimator, an established method of adjustment. Patients with PDGFRA amplification (11 patients) had a worse prognosis than those without PDGFRA amplification [hazard ratio 2.9, 95% confidence interval 1.2-6.9 (P = 0.02)]. TP53 alterations (P = 0.24) were not associated with prognosis. In addition, treatment time with pazopanib with PDGFRA amplification [4 patients, 2.3 months (1.2-11.2 months)] was not different with those without PDGFRA amplification [28 patients, 3.8 months (0.9 months-not reached)] (P = 0.52). CONCLUSIONS: For patients with advanced UPS, PDGFRA amplification was a poor prognostic factor and is not related to the efficacy of pazopanib treatment.

PDGFRA amplification↗