[show abstract][hide abstract] ABSTRACT: The Wellcome Trust Case Control Consortium 3 anorexia nervosa genome-wide association scan includes 2907 cases from 15 different populations of European origin genotyped on the Illumina 670K chip. We compared methods for identifying population stratification, and suggest list of markers that may help to counter this problem. It is usual to identify population structure in such studies using only common variants with minor allele frequency (MAF) >5%; we find that this may result in highly informative SNPs being discarded, and suggest that instead all SNPs with MAF >1% may be used. We established informative axes of variation identified via principal component analysis and highlight important features of the genetic structure of diverse European-descent populations, some studied for the first time at this scale. Finally, we investigated the substructure within each of these 15 populations and identified SNPs that help capture hidden stratification. This work can provide information regarding the designing and interpretation of association results in the International Consortia
European Journal of HumanGenetics 02/2014; · 4.32 Impact Factor
[show abstract][hide abstract] ABSTRACT: Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge–purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10−7) in SOX2OT and rs17030795 (P=5.84 × 10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10−6) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10−6) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10−6), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
[show abstract][hide abstract] ABSTRACT: Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome-wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r(2) = 0.64, D ' = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 × 10(-10) and P = 6.07 × 10(-9), respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13-1.26] for rs718314 and 1.18 (95% CI: 1.12-1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist-hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR.
Human Molecular Genetics 01/2012; 21(2):456-62. · 7.69 Impact Factor
[show abstract][hide abstract] ABSTRACT: Analysis of the major breast cancer (BC) predisposition genes BRCA1 and BRCA2 enables identification of high-risk individuals. Specialized programs enrolling the carriers of BRCA1/2 mutations facilitate an improvement in prevention and early diagnostics in asymptomatic individuals and rationalize the selection of individualized treatment in case of a BC onset. However, the carriers of mutations in the major predisposition genes represent only approximately 25% of cases among high-risk BC patients. Numerous candidate predisposing genes for breast and other cancers have recently been identified. The risk of cancer development associated with alterations in these genes is lower, and there is a considerable population variability in different regions worldwide.
We have performed mutation analyses of moderate-risk cancer susceptibility genes to evaluate their clinical importance for genetic counseling in high-risk patients suffering from breast and other cancers in the Czech population.
Czech oncological patients were analysed for mutation in ATM, CHEK2, NBS1 (NBN) and PALB2 genes. The majority of analyzed individuals represent the population of high-risk BRCA1/2-negative BC patients.
Based on results of this study, we recommend an analysis of recurrent truncating mutations in the CHEK2 gene (the c.1100delC mutation and a large deletion affecting exons 9-10) in BRCA1/2-negative patients from high-risk BC families. A clinical assessment of missense variants in CHEK2 is not suitable. A routine mutation analysis of the ATM and NBS1 (NBN) genes is not recommended in BC patients due to the low frequency of alterations in these genes in the Czech Republic. An identification of truncating mutations in the PALB2 gene is important in BRCA1/2-negative BC patients from families with a strong history of BC (HBC families). The frequency of PALB2 mutations may be comparable to the frequency of mutations in the BRCA2 gene in Czech HBC families.
Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti 01/2012; 25 Suppl:S59-66.
[show abstract][hide abstract] ABSTRACT: Array comparative genomic hybridization was used to identify copy number alterations in clear cell renal cell carcinoma (ccRCC) patient tumors to identify associations with patient/clinical characteristics. Of 763 ccRCC patients, 412 (54%) provided frozen biopsies. Clones were analyzed for significant copy number differences, adjusting for multiple comparisons and covariates in multivariate analyses. Frequent alterations included losses on: 3p (92.2%), 14q (46.8%), 8p (38.1%), 4q (35.4%), 9p (32.3%), 9q (31.8%), 6q (30.8%), 3q (29.4%), 10q (25.7%), 13q (24.5%), 1p (23.5%) and gains on 5q (60.2%), 7q (39.6%), 7p (30.6%), 5p (26.5%), 20q (25.5%), 12q (24.8%), 12p (22.8%). Stage and grade were associated with 1p, 9p, 9q, 13q and 14q loss and 12q gain. Males had more alterations compared with females, independent of stage and grade. Significant differences in the number/types of alterations were observed by family cancer history, age at diagnosis and smoking status. Von Hippel-Lindau (VHL) gene inactivation was associated with 3p loss (P<E-05), and these cases had fewer alterations than wild-type cases. The fragile site flanking the FHIT locus (3p14.2) represented a unique breakpoint among VHL hypermethylated cases, compared with wild-type cases and those with sequence changes. This is the first study of its size to investigate copy number alterations among cases with extensive patient, clinical/risk factor information. Patients characterized by VHL wild-type gene status (vs sequence alterations) and male (vs female) cases had more copy number alterations regardless of diagnostic stage and grade, which could relate to poor prognosis.
[show abstract][hide abstract] ABSTRACT: Li-Fraumeni syndrome (LFS) is one of the most serious hereditary cancer syndromes with high risk of malignancy already in childhood. Adrenocortical carcinoma, brain tumor, leukemia, sarcoma are the most frequent malignancies in children. Early breast cancer, brain tumor, sarcoma, skin cancer, gastrointestinal, lung, gynecological, hematological and other malignancies can be seen in adults. Predictive testing in families with detected LFS and TP53 mutation is offered from the age of 18 for various reasons. One of the most important reasons is a very limited effectivity of prevention especially in children, also the possible risk of psychological harm to the child and his family caused by the diagnosis of this syndrome. Progress in diagnostic methods, especially total body MRI, enables to propose preventive care for early cancer diagnoses for children and adults. Biochemical tests, ultrasound, MRI may improve survival of these high risk individuals and support the possibility of predictive testing in children.
Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti 01/2012; 25 Suppl:S49-54.
[show abstract][hide abstract] ABSTRACT: Preventive oncology clinic of MMCI provides complex preventive care for women with high hereditary risk of breast and ovarian cancer due to germline mutations in BRCA1 and BRCA2 genes. Clinical follow-up is also provided to women with mutations in other genes causing a higher risk of different tumors, and also to women with increased lifetime empirical risk of breast cancer due to positive family history. Our clinic was established in 2000 and takes care for about 700 women. The goal of the clinic is to extend the life expectancy of these women to the level of the regular population. The risk of breast cancer can be reduced by prophylactic surgeries. Prophylactic mastectomy and oophorectomy are offered to women at a high risk. Other modality in breast cancer risk reduction is a chemoprevention by Tamoxifen. Most women accept only secondary prevention with the goal of the detection of breast cancer in clinical stage I, where the tumor is smaller than 1 cm and the risk of recurrence is less than 10%. The algorithm of prevention care was changed over the time and our diagnostic methods were improved by magnetic resonance imaging of breasts. During the 11 years of clinical follow-up 32 breast cancers in 31 women were detected. High risk women are examined every 6 month by physical examination, breast ultrasound and MRI plus mammography yearly.
Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti 01/2012; 25 Suppl:S96-8.
[show abstract][hide abstract] ABSTRACT: In follow-up of a recent genome-wide association study (GWAS) that identified a locus in chromosome 2p21 associated with risk for renal cell carcinoma (RCC), we conducted a fine mapping analysis of a 120 kb region that includes EPAS1. We genotyped 59 tagged common single-nucleotide polymorphisms (SNPs) in 2278 RCC and 3719 controls of European background and observed a novel signal for rs9679290 [P = 5.75 × 10(-8), per-allele odds ratio (OR) = 1.27, 95% confidence interval (CI): 1.17-1.39]. Imputation of common SNPs surrounding rs9679290 using HapMap 3 and 1000 Genomes data yielded two additional signals, rs4953346 (P = 4.09 × 10(-14)) and rs12617313 (P = 7.48 × 10(-12)), both highly correlated with rs9679290 (r(2) > 0.95), but interestingly not correlated with the two SNPs reported in the GWAS: rs11894252 and rs7579899 (r(2) < 0.1 with rs9679290). Genotype analysis of rs12617313 confirmed an association with RCC risk (P = 1.72 × 10(-9), per-allele OR = 1.28, 95% CI: 1.18-1.39) In conclusion, we report that chromosome 2p21 harbors a complex genetic architecture for common RCC risk variants.
Human Molecular Genetics 11/2011; 21(5):1190-200. · 7.69 Impact Factor
[show abstract][hide abstract] ABSTRACT: Renal tumor heterogeneity studies have utilized the von Hippel-Lindau VHL gene to classify disease into molecularly defined subtypes to examine associations with etiologic risk factors and prognosis. The aim of this study was to provide a comprehensive analysis of VHL inactivation in clear cell renal tumors (ccRCC) and to evaluate relationships between VHL inactivation subgroups with renal cancer risk factors and VHL germline single nucleotide polymorphisms (SNPs). VHL genetic and epigenetic inactivation was examined among 507 sporadic RCC/470 ccRCC cases using endonuclease scanning and using bisulfite treatment and Sanger sequencing across 11 CpG sites within the VHL promoter. Case-only multivariate analyses were conducted to identify associations between alteration subtypes and risk factors. VHL inactivation, either through sequence alterations or promoter methylation in tumor DNA, was observed among 86.6% of ccRCC cases. Germline VHL SNPs and a haplotype were associated with promoter hypermethylation in tumor tissue (OR = 6.10; 95% CI: 2.28-16.35, p = 3.76E-4, p-global = 8E-5). Risk of having genetic VHL inactivation was inversely associated with smoking due to a higher proportion of wild-type ccRCC tumors [former: OR = 0.70 (0.20-1.31) and current: OR = 0.56 (0.32-0.99); P-trend = 0.04]. Alteration prevalence did not differ by histopathologic characteristics or occupational exposure to trichloroethylene. ccRCC cases with particular VHL germline polymorphisms were more likely to have VHL inactivation through promoter hypermethylation than through sequence alterations in tumor DNA, suggesting that the presence of these SNPs may represent an example of facilitated epigenetic variation (an inherited propensity towards epigenetic variation) in renal tissue. A proportion of tumors from current smokers lacked VHL alterations and may represent a biologically distinct clinical entity from inactivated cases.
[show abstract][hide abstract] ABSTRACT: Occupational exposures to dusts have generally been examined in relation to cancers of the respiratory system and have rarely been examined in relation to other cancers, such as renal cell carcinoma (RCC). Although previous epidemiological studies, though few, have shown certain dusts, such as asbestos, to increase renal cancer risk, the potential for other occupational dust exposures to cause kidney damage and/or cancer may exist. We investigated whether asbestos, as well as 20 other occupational dust exposures, were associated with RCC risk in a large European, multi-center, hospital-based renal case-control study.
General occupational histories and job-specific questionnaires were reviewed by occupational hygienists for subject-specific information. Odds ratios (ORs) and 95% confidence intervals (95% CIs) between RCC risk and exposures were calculated using unconditional logistic regression.
Among participants ever exposed to dusts, significant associations were observed for glass fibres (OR: 2.1; 95% CI: 1.1-3.9), mineral wool fibres (OR: 2.5; 95% CI: 1.2-5.1), and brick dust (OR: 1.5; 95% CI: 1.0-2.4). Significant trends were also observed with exposure duration and cumulative exposure. No association between RCC risk and asbestos exposure was observed.
Results suggest that increased RCC risk may be associated with occupational exposure to specific types of dusts. Additional studies are needed to replicate and extend findings.
British Journal of Cancer 05/2011; 104(11):1797-803. · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: To investigate whether occupational exposure to polycyclic aromatic hydrocarbons and certain plastic monomers increased renal cell carcinoma (RCC) risk.
Unconditional logistic regression was used to calculate RCC risk in relation to exposure.
No association between RCC risk and having ever been occupationally exposed to any polycyclic aromatic hydrocarbons or plastics was observed. Duration of exposure and average exposure also showed no association with risk. Suggestive positive associations between RCC risk and cumulative exposure to styrene (P-trend = 0.02) and acrylonitrile (P-trend = 0.06) were found. Cumulative exposure to petroleum/gasoline engine emissions was inversely associated with risk (P-trend = 0.02).
Results indicate a possible association between occupational styrene and acrylonitrile exposure and RCC risk. Additional studies are needed to replicate findings, as this is the first time these associations have been reported and they may be due to chance.
Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine 02/2011; 53(2):218-23. · 1.88 Impact Factor
[show abstract][hide abstract] ABSTRACT: Epidemiologic studies are reporting associations between lead exposure and human cancers. A polymorphism in the 5-aminolevulinic acid dehydratase (ALAD) gene affects lead toxicokinetics and may modify the adverse effects of lead.
The objective of this study was to evaluate single-nucleotide polymorphisms (SNPs) tagging the ALAD region among renal cancer cases and controls to determine whether genetic variation alters the relationship between lead and renal cancer. Occupational exposure to lead and risk of cancer was examined in a case-control study of renal cell carcinoma (RCC). Comprehensive analysis of variation across the ALAD gene was assessed using a tagging SNP approach among 987 cases and 1298 controls. Occupational lead exposure was estimated using questionnaire-based exposure assessment and expert review. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression.
The adjusted risk associated with the ALAD variant rs8177796(CT/TT) was increased (OR = 1.35, 95%CI = 1.05-1.73, p-value = 0.02) when compared to the major allele, regardless of lead exposure. Joint effects of lead and ALAD rs2761016 suggest an increased RCC risk for the homozygous wild-type and heterozygous alleles ((GG)OR = 2.68, 95%CI = 1.17-6.12, p = 0.01; (GA)OR = 1.79, 95%CI = 1.06-3.04 with an interaction approaching significance (p(int) = 0.06). No significant modification in RCC risk was observed for the functional variant rs1800435(K68N). Haplotype analysis identified a region associated with risk supporting tagging SNP results.
A common genetic variation in ALAD may alter the risk of RCC overall, and among individuals occupationally exposed to lead. Further work in larger exposed populations is warranted to determine if ALAD modifies RCC risk associated with lead exposure.
PLoS ONE 01/2011; 6(7):e20432. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Folate and one-carbon metabolism are linked to cancer risk through their integral role in DNA synthesis and methylation. Variation in one-carbon metabolism genes, particularly MTHFR, has been associated with risk of a number of cancers in epidemiologic studies, but little is known regarding renal cancer.
Tag single nucleotide polymorphisms (SNPs) selected to produce high genomic coverage of 13 gene regions of one-carbon metabolism (ALDH1L1, BHMT, CBS, FOLR1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, TYMS) and the closely associated glutathione synthesis pathway (CTH, GGH, GSS) were genotyped for 777 renal cell carcinoma (RCC) cases and 1,035 controls in the Central and Eastern European Renal Cancer case-control study. Associations of individual SNPs (n = 163) with RCC risk were calculated using unconditional logistic regression adjusted for age, sex and study center. Minimum p-value permutation (Min-P) tests were used to identify gene regions associated with risk, and haplotypes were evaluated within these genes.
The strongest associations with RCC risk were observed for SLC19A1 (P(min-P) = 0.03) and MTHFR (P(min-P) = 0.13). A haplotype consisting of four SNPs in SLC19A1 (rs12483553, rs2838950, rs2838951, and rs17004785) was associated with a 37% increased risk (p = 0.02), and exploratory stratified analysis suggested the association was only significant among those in the lowest tertile of vegetable intake.
To our knowledge, this is the first study to comprehensively examine variation in one-carbon metabolism genes in relation to RCC risk. We identified a novel association with SLC19A1, which is important for transport of folate into cells. Replication in other populations is required to confirm these findings.
PLoS ONE 01/2011; 6(10):e26165. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Leukocyte global DNA methylation levels are currently being considered as biomarkers of cancer susceptibility and have been associated with risk of several cancers. In this study, we aimed to examine the association between long interspersed nuclear elements (LINE-1) methylation levels, as a biomarker of global DNA methylation in blood cell DNA, and renal cell cancer risk.
LINE-1 methylation of bisulfite-converted genomic DNA isolated from leukocytes was quantified by pyrosequencing measured in triplicate, and averaged across 4 CpG sites. A total of 328 RCC cases and 654 controls frequency-matched(2∶1) on age(±5years), sex and study center, from a large case-control study conducted in Central and Eastern Europe were evaluated.
LINE-1 methylation levels were significantly higher in RCC cases with a median of 81.97% (interquartile range[IQR]: 80.84-83.47) compared to 81.67% (IQR: 80.35-83.03) among controls (p = 0.003, Wilcoxon). Compared to the lowest LINE-1 methylation quartile(Q1), the adjusted ORs for increasing methylation quartiles were as follows: OR(Q2) = 1.84(1.20-2.81), OR(Q3) = 1.72(1.11-2.65) and OR(Q4) = 2.06(1.34-3.17), with a p-trend = 0.004. The association was stronger among current smokers (p-trend<0.001) than former or never smokers (p-interaction = 0.03). To eliminate the possibility of selection bias among controls, the relationship between LINE-1 methylation and smoking was evaluated and confirmed in a case-only analysis, as well.
Higher levels of LINE-1 methylation appear to be positively associated with RCC risk, particularly among current smokers. Further investigations using both post- and pre-diagnostic genomic DNA is warranted to confirm findings and will be necessary to determine whether the observed differences occur prior to, or as a result of carcinogenesis.
PLoS ONE 01/2011; 6(11):e27361. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Trichloroethylene (TCE) is a suspected renal carcinogen. TCE-associated renal genotoxicity occurs predominantly through glutathione S-transferase (GST) conjugation and bioactivation by renal cysteine beta-lyase (CCBL1). We conducted a case-control study in Central Europe (1,097 cases and 1,476 controls) specifically designed to assess risk associated with occupational exposure to TCE through analysis of detailed job histories. All jobs were coded for organic/chlorinated solvent and TCE exposure (ever/never) as well as the frequency and intensity of exposure based on detailed occupational questionnaires, specialized questionnaires, and expert assessments. Increased risk was observed among subjects ever TCE exposed [odds ratio (OR) = 1.63; 95% confidence interval (95% CI), 1.04-2.54]. Exposure-response trends were observed among subjects above and below the median exposure [average intensity (OR = 1.38; 95% CI, 0.81-2.35; OR = 2.34; 95% CI, 1.05-5.21; P(trend) = 0.02)]. A significant association was found among TCE-exposed subjects with at least one intact GSTT1 allele (active genotype; OR = 1.88; 95% CI, 1.06-3.33) but not among subjects with two deleted alleles (null genotype; OR = 0.93; 95% CI, 0.35-2.44; P(interaction) = 0.18). Similar associations for all exposure metrics including average intensity were observed among GSTT1-active subjects (OR = 1.56; 95% CI, 0.79-3.10; OR = 2.77; 95% CI, 1.01-7.58; P(trend) = 0.02) but not among GSTT1 nulls (OR = 0.81; 95% CI, 0.24-2.72; OR = 1.16; 95% CI, 0.27-5.04; P(trend) = 1.00; P(interaction) = 0.34). Further evidence of heterogeneity was seen among TCE-exposed subjects with >or=1 minor allele of several CCBL1-tagging single nucleotide polymorphisms: rs2293968, rs2280841, rs2259043, and rs941960. These findings provide the strongest evidence to date that TCE exposure is associated with increased renal cancer risk, particularly among individuals carrying polymorphisms in genes that are important in the reductive metabolism of this chemical, and provides biological plausibility of the association in humans.
Cancer Research 08/2010; 70(16):6527-36. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hypertension is a known risk factor for renal cell carcinoma (RCC), although the underlying biological mechanisms of its action are unknown. To clarify the role of hypertension in RCC, we examined the risk of RCC in relation to 142 single-nucleotide polymorphisms (SNPs) in eight genes having a role in blood pressure control. We analyzed 777 incident and histologically confirmed RCC cases and 1035 controls who completed an in-person interview as part of a multi-center, hospital-based case-control study in Central Europe. Genotyping was conducted with an Illumina GoldenGate Oligo Pool All assay using germ line DNA. Of the eight genes examined, AGT (angiotensinogen) was most strongly associated with RCC (minimum P-value permutation test = 0.02). Of the 17 AGT tagging SNPs considered, associations were strongest for rs1326889 [odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.15-1.58] and rs2493137 (OR = 1.31, 95% CI = 1.12-1.54), which are located in the promoter. Stratified analysis revealed that the effects of the AGT SNPs were statistically significant in participants with hypertension or high body mass index (BMI) (> or =25 kg/m(2)), but not in subjects without hypertension and with a normal BMI (<25 kg/m(2)). Also, haplotypes with risk-conferring alleles of markers located in the promoter and intron 1 regions of AGT were significantly associated with RCC compared with the common haplotype in subjects with hypertension or high BMI (global P = 0.003). Our findings suggest that common genetic variants of AGT, particularly those in the promoter, increase RCC risk among subjects who are hypertensive or overweight.
[show abstract][hide abstract] ABSTRACT: Renal-cell carcinomas (RCC) are frequent in central and eastern Europe and the reasons remain unclear. Molecular mechanisms, except for VHL, have not been much investigated. We analysed 361 RCCs (334 clear-cell carcinomas) from a multi-centre case-control study for mutations in TP53 (exons 5-9 in the whole series and exons 4 and 10 in a pilot subset of 60 tumours) and a pilot 50 tumours for mutations in EGFR (exons 18-21) or KRAS (codon 12) in relation to VHL status. TP53 mutations were detected in 4% of clear-cell cases, independently of VHL mutations. In non-clear-cell carcinomas, they were detected in 11% of VHL-wild-type tumours and in 0% of tumours with VHL functional mutations. No mutations were found in EGFR or KRAS. We conclude that mutations in TP53, KRAS, or EGFR are not major contributors to the RCC development even in the absence of VHL inactivation. The prevalence of TP53 mutations in relation to VHL status may differ between clear-cell and other renal carcinomas.
Cancer letters 02/2010; 293(1):92-8. · 4.86 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hereditary cancer syndromes are frequently seen in young cancer patients and patients with a positive family history. Genetic testing is important for the identification of high-risk individuals, and for the early introduction of specialized preventive care or prophylactic surgeries. High-risk tumour suppressor genes (BRCA1 and BRCA2) and DNA repair genes (MLH1, MSH2 and MSH6) are responsible for a substantial part of hereditary breast, ovarian and colorectal cancer. Other hereditary cancers are seen less frequently, but genetic testing has increased for many other site-specific cancers and complex syndromes. Genetic centres and molecular genetic laboratories are located mostly within university or regional hospitals. Some genetic centres are private. It is highly recommended (Czech Society for Medical Genetics) that all laboratories are accredited according to ISO 15,189 and that genetic testing of hereditary cancer syndromes is indicated by medical geneticists. The indication criteria and prevention strategies were published in Supplement 22 of Clinical Oncology 2009 (in Czech). Preventive care for high-risk individuals is organized by thirteen Oncology Centres, which provide most of the oncology care in the Czech Republic. Genetic testing and preventive care for high-risk individuals and mutation carriers is covered by health insurance. The molecular genetic laboratory at the MMCI provides molecular genetic testing of BRCA1, BRCA2, CHEK2 for hereditary breast/ovarian cancer, MLH1, MSH2, MSH6 for Lynch syndrome,TP53 for Li-Fraumeni syndrome, CDKN2A for familial malignant melanoma syndrome and CDH1 gene for hereditary diffuse gastric cancer. Other syndromes are tested in specialized laboratories elsewhere.The use of genetic testing is increasing because of more frequent referrals from oncologists and other specialists and the increasing variety of genes tested. However, in some patients the testing is not recommended and other family members are dying because of the late diagnosis of hereditary syndrome. Greater awareness of the importance of genetic testing in oncology is needed.
Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti 01/2010; 23(6):388-400.
[show abstract][hide abstract] ABSTRACT: Mediated by binding to the high-affinity vitamin D receptor (VDR), vitamin D forms a heterodimer complex with the retinoid-X-receptor (RXR). Variation in both genes has been shown to modify renal cell carcinoma (RCC) risk. Therefore, we investigated whether VDR and RXRA polymorphisms modify associations between RCC risk and frequency of dietary intake of vitamin D and calcium rich foods, and occupational ultraviolet exposure among 777 RCC case and 1035 controls from Central and Eastern Europe. A positive association was observed in this population between increasing dietary intake frequency of yogurt, while an inverse association was observed with egg intake frequency. RXRA polymorphisms, located 3' of the coding sequence, modified associations between specific vitamin D rich foods and RCC risk, while RXRA polymorphisms, located in introns 1 and 4, modified associations with specific calcium rich foods. Results suggest that variants in the RXRA gene modified the associations observed between RCC risk and calcium and vitamin D intake.
International Journal of Endocrinology 01/2010; 2010:879362. · 2.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Lipid peroxidation is considered a unifying mechanistic pathway through which known risk factors induce renal cell carcinoma (RCC). We hypothesized that genes selected a priori for their role in lipid peroxidation would modify cancer risk. We genotyped 635 single nucleotide polymorphisms (SNP) in 38candidate genes in 777 Caucasian RCC cases and 1,035 controls enrolled in a large European case-control study. Top candidate SNPs were confirmed among 718 Caucasian cases and 615 controls in a second study in the United States. Two of the three SNPs (rs8106822 and rs405509) that replicated in the U.S. study were within a regulatory region of the APOE promoter. The OR for rs8106822 A>G variant was 1.22(AG) and 1.41(GG) (P(trend) = 0.01) in the European study, 1.05(AG) and 1.51(GG) (P(trend) = 0.03) in the U.S. study, and 1.15(AG) and 1.44(GG) (P(trend) = 0.001) among 1,485 cases and 1,639 controls combined. The rs405509 G>T variant was associated with risk in the European (OR, 0.87(TG); OR, 0.71(TT); P(trend) = 0.02), the U.S. (OR, 0.68(TG); OR, 0.71(TT); P(trend) = 0.02), and both studies combined (OR(TG), 0.79; OR(TT), 0.71; P(trend) = 0.001), as was the G-G haplotype (r(2) = 0.64; P= 4.7 x 10(-4)). This association is biologically plausible as SNP rs405509 was shown to modify protein binding and transcriptional activity of the APOE protein in vitro and is in linkage disequilibrium with key known variants defining the e2, e3, and e4 alleles that modify risk of atherosclerosis, Alzheimer's disease risk, and progression to AIDS. In two large case-control studies, our findings further define a functional region of interest at the APOE locus that increases RCC susceptibility.
Cancer Research 10/2009; 69(20):8001-8. · 8.65 Impact Factor