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The recent revolution in genomics is already having a profound impact on the practice of epidemiology. The purpose of this commentary is to demonstrate how genomics and epidemiology will continue to rely heavily on each other, now and in the future, by illustrating a number of interaction points between these 2 disciplines: (1) the use of genomics to estimate disease heritability; (2) the impact of genomics on analytical study design; (3) how genome-wide data can be employed to effectively overcome residual population stratification arising from selection bias; (4) the importance of genomics as a tool in epidemiological investigation; (5) the importance of epidemiology in the collection of adequately phenotyped samples for genomics studies, and (6) for unraveling the clinical and therapeutic relevance of genetic variants once they are discovered. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Advances in genomics promise to deliver personalized medicine both for prevention and treatment of disease. Considerable effort is being directed towards translating observed associations between various genetic variants, such as single nucleotide polymorphisms (SNPs), and disease or drug response into clinically useful genetic tests. Unfortunately, because reported associations are usually weak or moderate, tests based on them are generally not accurate enough for use in routine clinical practice, and therefore, ensuring the appropriate use of genetic tests is important. In a recent report, a combination of 5 SNPs was claimed to improve the predictive value of the test for prostate cancer, compared with the individual SNPs. This led the authors to suggest that a 5-SNP-test could be used to predict the risk of prostate cancer. We evaluate the characteristics of the proposed test, comment on it, and summarize the views of others on its potential clinical utility. We hope that this may serve as a case-example for the evaluation of the many new genetic tests being suggested for adoption. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

OBJECTIVE--We investigated the effects of 18 confirmed type 2 diabetes risk single nucleotide polymorphisms (SNPs) on insulin sensitivity, insulin secretion, and conversion of proinsulin to insulin. RESEARCH DESIGN AND METHODS--A total of 5,327 nondiabetic men (age 58 ± 7 years, BMI 27.0 ± 3.8 kg/m²) from a large population-based cohort were included. Oral glucose tolerance tests and genotyping of SNPs in or near PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, LOC387761, CDKN2B, IGF2BP2, CDKAL1, HNF1B, WFS1, JAZF1, CDC123, TSPANS, THADA, ADAMTS9, NOTCH2, KCNQ1, and MTNR1B were performed. HNF1B rs757210 was excluded because of failure to achieve Hardy-Weinberg equilibrium. RESULTS--Six SNPs (TCF7L2, SLC30A8, HHEX, CDKN2B, CDKAL1, and MTNR1B) were significantly (P < 6.9 x 10[sup -4]) and two SNPs (KCNJ11 and IGF2BP2) were nominally (P < 0.05) associated with early-phase insulin release (InsAUC0-30/GluAUC0-30), adjusted for age, BMI, and insulin sensitivity (Matsuda ISI). Combined effects of these eight SNPs reached -32% reduction in InsAUC0-30/GluAUC0-30 in carriers of ≥11 vs. ≤3 weighted risk alleles. Four SNPs (SLC30A8, HHEX, CDKAL1, and TCF7L2) were significantly or nominally associated with indexes of proinsulin conversion. Three SNPs (KCNJ11, HHEX, and TSPAN8) were nominally associated with Matsuda ISI (adjusted for age and BMI). The effect of HHEX on Matsuda ISI became significant after additional adjustment for InsAUC0-30/ GluAUC0-30. Nine SNPs did not show any associations with examined traits. CONCLUSIONS--Eight type 2 diabetes-related loci were significantly or nominally associated with impaired early-phase insulin release. Effects of SLC30A8, HHEX, CDKAL1, and TCF7L2 on insulin release could be partially explained by impaired proinsulin conversion. HHEX might influence both insulin release and insulin sensitivity. Diabetes 58:2129-2136, 2009 [ABSTRACT FROM AUTHOR]

Human height (stature) is a strongly genetic trait, with up to 90% of the variation in height within a population determined by a combination of multiple inherited factors. Recent advances in genetics and genomics now permit comprehensive genome-wide surveys of common genetic variations in those variants that are associated with stature. The first such studies have borne fruit, identifying over 40 genetic loci that can be reproducibly shown to have an influence on adult height. These unbiased searches throughout the genome identified several loci that also harbour rare mutations responsible for more severe alterations in height or skeletal growth. Although the predictive value of the common variants thus far discovered remains low, the identification of these loci has led to new insights into the biology of human growth, and may help identify genes that underlie previously uncharacterized syndromes of abnormal skeletal growth. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

OBJECTIVE--Hepatocyte nuclear factor 1β (HNF1β) is a transcription factor that is critical for pancreatic cell formation and glucose homeostasis. Previous studies have reported that common variants of HNF1β were associated with type 2 diabetes in Caucasians and West Africans. However, analysis in the subjects from the Botnia study and Malmö Preventive Project produced conflicting results, and the role for HNF1β in type 2 diabetes susceptibility remains unclear. We therefore investigated common variants across the HNF1β gene in a Chinese population. RESEARCH DESIGN AND METHODS--Fifteen tagging single nucleotide polymorphisms (SNPs) were analyzed for association with type 2 diabetes in subjects with type 2 diabetes (n = 1,859) and normal glucose regulation (n = 1,785). RESULTS--Consistent with the initial study, we observed evidence that the risk G allele of rs4430796 in intron 2 was significantly associated with type 2 diabetes (odds ratio 1.16 [95% CI 1.05-1.29], P = 0.0035, empirical P = 0.0475). Furthermore, the at-risk G allele was associated with earlier age at diagnosis in the type 2 diabetic subjects (P = 0.0228). CONCLUSIONS--The result of this study provides evidence that variants in the HNF1β region contribute to susceptibility to type 2 diabetes in the Chinese population. Diabetes 58:1023-1027, 2009 [ABSTRACT FROM AUTHOR]

Background/Aims: Genetic factors influencing common complex conditions have proven difficult to identify, and data from numerous investigations have provided incomplete conclusions as to the identity of these genes. Here we aimed to identify susceptibility genes for late-onset Alzheimer’s disease (AD). Methods: The case-control analysis included samples from 86 AD patients and 404 cognitively healthy controls selected from the Uppsala Longitudinal Study of Adult Men (ULSAM). In the incidence analysis, all 1,088 genotyped ULSAM participants were included. DNA samples from ULSAM participants were analyzed for 2,578 single nucleotide polymorphisms (SNP) within 368 genes. The selection of genes tested for association to AD within this cohort was based on genes previously implicated in conditions with relevance to ULSAM, such as dementia, cardiovascular disease, diabetes and metabolic syndrome, osteoporosis, and cancer. Results/Conclusion: Association analysis revealed 82 genes containing at least 1 significant SNP at p < 0.05 with association to AD. Only 20 genes remained significant after a permutation test to correct for multiple comparisons within individual genes. Using publicly available data from 2 genome-wide association (GWA) studies and linkage disequilibrium data from HapMap, we attempted to replicate the AD association identified in ULSAM. In addition to apolipoprotein E, we were able to replicate 5 other genes in both GWA studies at p < 0.05. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

OBJECTIVE--Type 2 diabetes is a common complex disorder with environmental and genetic components. We used a candidate gene-based approach to identify single nucleotide polymorphism (SNP) variants in 222 candidate genes that influence susceptibility to type 2 diabetes. RESEARCH DESIGN AND METHODS--In a case-control study of 1,101 type 2 diabetic subjects and 1,174 control Finns who are normal glucose tolerant, we genotyped 3,531 tagSNPs and annotation-based SNPs and imputed an additional 7,498 SNPs, providing 99.9% coverage of common HapMap variants in the 222 candidate genes. Selected SNPs were genotyped in an additional 1,211 type 2 diabetic case subjects and 1,259 control subjects who are normal glucose tolerant, also From Finland. RESULTS--Using SNP- and gene-based analysis methods, we replicated previously reported SNP-type 2 diabetes associations in PPARG, KCNJ11, and SLC2A2; identified significant SNPs in genes with previously reported associations (ENPP1 [rs2021966, P = 0.00026] and NRF1 [rs1882095, P = 0.00096]); and implicated novel genes, including RAPGEF1 (rs4740283, P = 0.00013) and TP53 (rs1042522, Arg72Pro, P = 0.00086), in type 2 diabetes susceptibility. CONCLUSIONS--Our study provides an effective gene-based approach to association study design and analysis. One or more of the newly implicated genes may contribute to type 2 diabetes pathogenesis. Analysis of additional samples will be necessary to determine their effect on susceptibility. Diabetes 57:3136-3144, 2008 [ABSTRACT FROM AUTHOR]

The article examines new developments in diabetes resulting from the definition of etiological genes in monogenic diabetes and of predisposing polymorphisms in type 2 diabetes. It notes that monogenic genes have been successfully defined through the use of the candidate gene approach. It adds that the positional cloning of novel monogenic diabetes genes have resulted to the discovery of critical pathways for insulin secretion and action such as the hepatic nuclear factor (HNF)-1A. It mentions that new phenotypes can emerge from gene discoveries.

Genome-wide association (GWA) studies identified novel gene variants that are associated with type 2 diabetes. However, results were not always consistent across different populations. Thus, the aims of this study were (i) to replicate findings from previous GWA studies in mainly Northern European populations using data from the German KORA 500?K diabetes project and (ii) to assess the impact of BMI on associations between single nucleotide polymorphisms (SNPs) and type 2 diabetes. The KORA 500?K diabetes project includes 433 cases with validated type 2 diabetes and 1?438 nondiabetic controls from two population-based KORA surveys. Genotyping was performed using the Affymetrix GeneChip Human Mapping 500?K Array Set. We investigated associations between SNPs and type 2 diabetes in 10 genes that have been reported to increase the risk of type 2 diabetes or were in complete or near-complete linkage disequilibrium with these variants. SNPs in the CDKAL1 gene showed the strongest association with type 2 diabetes [range of age and sex-adjusted odds ratios (OR): 1.30-1.39, p-values 0.0008-0.0004]. In addition, we found evidence for association of SNPs in the genes PPARG, IGF2BP2, HHEX, TCF7L2, and FTO with type 2 diabetes in the same directions as previously described (p<0.05), but not for WFS1, CDKN2A/B, KCNJ11, or EXT2. Adjustment for BMI slightly strengthened the link between CDKAL1 and type 2 diabetes, but had almost no impact on the other associations. We conclude that gene variants of CDKAL1, PPARG, IGF2BP2, HHEX, TCF7L2, and FTO predispose to type 2 diabetes in the German KORA 500?K study population. These associations appear to be independent of BMI. [ABSTRACT FROM AUTHOR]

The article discusses various reports published within the issue including one on the controversial guidelines on prostate specific antigen (PSA)-based screening for prostate cancer and another on prostate screening initiated by the "International Journal of Urology."

Recently, genome-wide association studies have identified loci across a segment of chromosome 8q24 (128,100,000–128,700,000) associated with the risk of breast, colon and prostate cancers. At least three regions of 8q24 have been independently associated with prostate cancer risk; the most centromeric of which appears to be population specific. Haplotypes in two contiguous but independent loci, marked by rs6983267 and rs1447295, have been identified in the Cancer Genetic Markers of Susceptibility project (), which genotyped more than 5,000 prostate cancer cases and 5,000 controls of European origin. The rs6983267 locus is also strongly associated with colorectal cancer. To ascertain a comprehensive catalog of common single-nucleotide polymorphisms (SNPs) across the two regions, we conducted a resequence analysis of 136 kb (chr8: 128,473,000–128,609,802) using the Roche/454 next-generation sequencing technology in 39 prostate cancer cases and 40 controls of European origin. We have characterized a comprehensive catalog of common (MAF > 1%) SNPs within this region, including 442 novel SNPs and have determined the pattern of linkage disequilibrium across the region. Our study has generated a detailed map of genetic variation across the region, which should be useful for choosing SNPs for fine mapping of association signals in 8q24 and investigations of the functional consequences of select common variants. [ABSTRACT FROM AUTHOR]

The effects of printed educational material on cancer screening in women (Pap test and mammography) are well documented and confirmed by several studies. The aim of our study was to evaluate the impact of similar printed educational material on prostate cancer screening by PSA and DRE. Thousand five hundred men aged between 50 and 86 years of age, who attended our institutions for various medical conditions except prostate-related conditions, were randomly assigned to two study groups. Men in the informed group, received an educational leaflet with simple, general information on prostate cancer screening methods given by their physician along with treatment and other regular recommendations, while men in the non-informed group, were only informed by their physician in the examination room during an interview. After 24 months, there was no statistically significant difference between the two groups in terms of DRE screening. The percentages of men who were actually screened by DRE were 4 and 5% in the informed and non-informed groups, respectively, while the difference in the percentages of PSA screening was of statistical significance, with 31% of men screened in the non-informed group as compared to 93% of men screened in the informational leaflet group. A single, one-shift distribution of printed educational material on prostate cancer screening, changed their attitude regarding prostate cancer screening only in favour of PSA testing, while did not manage to change the DRE acceptance behavior. However, since the combination of the two tests is more sensitive for diagnosis than either one alone, there is a need of introducing intervention strategies, in the efforts of ameliorating the prostate cancer screening behavior. [ABSTRACT FROM AUTHOR]

OBJECTIVE To evaluate the clinical and pathological characteristics of screen vs non-screen-detected prostate cancers, to determine if there is a difference in the same prostate-specific antigen (PSA) range. PATIENTS AND METHODS In all, 997 patients who had had a radical prostatectomy were evaluated; 806 were Tyrolean screening volunteers, and 191 were from outside Tyrol, representing the ‘referred prostate cancer’ group. PSA level, age, prostate volume and pathological characteristics were assessed, as was the amount of over- and under-diagnosis. RESULTS There were no statistically significant differences in patient age or PSA levels in the two groups. Even in the same PSA range there were statistically significantly more extraprostatic cancers in the referral group, at 31.7% and 17.4%, respectively. In the referred and screening groups there was over-diagnosis in 7.9% and 16.8%, and under-diagnosis in 40.8% and 27.8%, respectively. CONCLUSION This study suggests that screening volunteers have a statistically significantly higher rate of organ-confined prostate cancers, and a statistically significantly lower rate of extracapsular extension and positive surgical margins than their counterparts in the referral group even in the same PSA range. As the pathological stage and surgical margin status are significant predictors of recurrence, these findings support the concept of PSA screening. [ABSTRACT FROM AUTHOR]

While the number of success stories for mapping genes associated with complex diseases using genome-wide association approaches is growing, there is still much work to be done in developing methods for such studies when the samples are collected from a population, which may not be homogeneous. Here we report the first genome-wide association study to identify genes associated with asthma in an admixed population. We genotyped 96 Puerto Rican moderate to severe asthma cases and 88 controls as well as 109 samples representing Puerto Rico’s founding populations using the Affymetrix GeneChip Human Mapping 100K array sets. The data from samples representing Puerto Rico’s founding populations was used to identify ancestry informative markers for admixture mapping analyses. In addition, a genome-wide association analysis using logistic regression was performed on the data. Although neither admixture mapping nor regression analysis gave any significant association with asthma after correction for multiple testing, an overlap analysis using the top scoring SNPs from different methods suggested chromosomal regions 5q23.3 and 13q13.3 as potential regions harboring genes for asthma in Puerto Ricans. The validation analysis of these two regions in 284 Puerto Rican asthma trios gave significant association for the 5q23.3 region. Our results provide strong evidence that the previously linked 5q23 region is associated with asthma in Puerto Ricans. The detection of causative variants in this region will require fine mapping and functional validation. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Mutations in the hepatocyte nuclear factor (HNF)-1a, HNF-4α, glucokinase (GCK), and HNF-1β genes cause maturity-onset diabetes of the young (MODY), but it is not known whether common variants in these genes predict future type 2 diabetes. RESEARCH DESIGN AND METHODS--We tested 14 previously associated polymorphisms in HNF-1α, HNF-4α, GCK, and HNF-1β for association with type 2 diabetes-related traits and future risk of type 2 diabetes in 2,293 individuals from the Botnia study (Finland) and in 15,538 individuals from the Malmö Preventive Project (Sweden) with a total follow-up >360,000 years. RESULTS--The polymorphism rs1169288 in HNF-1α strongly predicted future type 2 diabetes (hazard ratio [HR] 1.2, P = 0.0002). Also, SNPs rs4810424 and rs3212198 in HNF-4α nominally predicted future type 2 diabetes (HR 1.3 [95% CI 1.0-1.6], P = 0.03; and 1.1 [1.0-1.2], P = 0.04). The rs2144908 polymorphism in HNF-4α was associated with elevated rate of hepatic glucose production during a hyperinsulinemic-euglycemic clamp (P = 0.03) but not with deterioration of insulin secretion over time. The SNP rs1799884 in the GCK promoter was associated with elevated fasting plasma glucose (fPG) concentrations that remained unchanged during the follow-up period (P = 0.4; SE 0.004 [-0.003-0.007]) but did not predict future type 2 diabetes (HR 0.9 [0.8-4.0], P = 0.1). Polymorphisms in HNF-1β (transcription factor 2 [TCF2]) did not significantly influence insulin or glucose values nor did they predict future type 2 diabetes. CONCLUSIONS--In conclusion, genetic variation in both HNF-1α and HNF-4α predict future type 2 diabetes, whereas variation in the GCK promoter results in a sustained but subtle elevation of fPG that is not sufficient to increase risk for future type 2 diabetes. Diabetes 57:1738-1744, 2008 [ABSTRACT FROM AUTHOR]

OBJECTIVES To evaluate possible over- and under-diagnosis of prostate cancer in a screened vs a referral population in the same range of prostate-specific antigen (PSA). PATIENTS AND METHODS In all, 1445 patients undergoing radical prostatectomy and with a PSA level of <10 ng/mL were evaluated; 237 were from outside Tyrol (Austria) and represented the unscreened group, and 1208 were Tyrolean screening volunteers. Over-diagnosis was defined as a pathological stage of pT2a and a Gleason score of <7 with no positive surgical margins. Under-diagnosis was defined as a pathological stage of ≥pT3a or positive surgical margins. The chi-square test was used to assess the differences, with P < 0.05 considered to indicate statistical significance. RESULTS There were no significant differences in patient age or PSA levels between the study groups. There was over-diagnosis in the screening and referral groups in 17.4% and 8.9%, respectively, and under-diagnosis in 18.6% and 42.2%, respectively. CONCLUSION This study suggests that patients with prostate cancer participating in a screening programme are less likely to be under-diagnosed or have extracapsular disease than their counterparts in a referral population, even in the same PSA range, after radical prostatectomy. Furthermore, there was more under-diagnosis in the referral group than over-diagnosis in the screened group. [ABSTRACT FROM AUTHOR]

Much evidence supports the premise that population genetic variation contributes significantly to the risk of testicular germ-cell tumor (TGCT). However, investigations of the association between genomic markers and TGCT susceptibility are scarce. Single nucleotide polymorphisms (SNPs) at the locus 8q24 have recently been found to be associated with prostate, colorectal and breast cancer. The US Servicemen’s testicular tumor environmental and endocrine determinants (STEED) study was used to investigate the association of 15 specific 8q24 SNPs with TGCT and its two main histologic groups of seminoma and nonseminoma. Conditional and unconditional logistic regression models, adjusted for the matching variables of year of birth, race/ethnicity and serum date, were utilized to produce odds ratios (OR) and 95% confidence intervals (95%CI). The analysis included 680 controls and 568 TGCT cases. In the TGCT analysis, no SNP was associated with risk in both heterozygotes and variant homozygotes. When stratified by histology the seminoma analysis also showed no association with the 8q24 SNPs. Conversely, the analysis of nonseminomas had three tentative associations (rs6470494, ORgenotype AG = 1.15, 95%CI: 0.86–1.54; ORgenotype GG = 1.68, 95%CI: 1.04–2.73; p for trend = 0.04) (rs13254738, ORgenotype GT = 1.04, 95%CI: 0.77–1.40; ORgenotype TT = 1.62, 95%CI: 1.06–2.49; p for trend = 0.07) (rs10505476, ORgenotype CT = 0.67, 95%CI: 0.50, 0.91; ORgenotype TT = 0.81, 95%CI: 0.47–1.39; p for trend = 0.04). There was no linkage disequilibrium between any of the 8q24 SNPs analyzed in this population. In conclusion, this study has found little evidence for an association between the reported 8q24 SNPs and TGCTs, although the findings for nonseminoma may be worth further investigation. [ABSTRACT FROM AUTHOR]

A brief history of human genetics and genomics is provided, comparing recent progress in those fields with that in pharmacogenetics and pharmacogenomics, which are subsets of genetics and genomics, respectively. Sequencing of the entire human genome, the mapping of common haplotypes of single-nucleotide polymorphisms (SNPs), and cost-effective genotyping technologies leading to genome-wide association (GWA) studies - have combined convincingly in the past several years to demonstrate the requirements needed to separate true associations from the plethora of false positives. While research in human genetics has moved from monogenic to oligogenic to complex diseases, its pharmacogenetics branch has followed, usually a few years behind. The continuous discoveries, even today, of new surprises about our genome cause us to question reviews declaring that "personalized medicine is almost here" or that "individualized drug therapy will soon be a reality." As summarized herein, numerous reasons exist to show that an "unequivocal genotype" or even an "unequivocal phenotype" is virtually impossible to achieve in current limited-size studies of human populations. This problem (of insufficiently stringent criteria) leads to a decrease in statistical power and, consequently, equivocal interpretation of most genotype-phenotype association studies. It remains unclear whether personalized medicine or individualized drug therapy will ever be achievable by means of DNA testing alone. [ABSTRACT FROM AUTHOR]

OBJECTIVE To evaluate the effectiveness of a well-controlled programme of early detection and treatment of prostate cancer in the population of Tyrol, Austria, where such a programme of early detection and treatment was initiated in 1988 and where prostate-specific antigen (PSA) testing was offered for free to all men aged 45–75 years from 1993. SUBJECTS AND METHODS Comparison of prostate cancer mortality rates in Tyrol and the rest of Austria was accomplished through a generalized additive model. A piecewise linear change-point Poisson regression model was used to compare mortality rates in Tyrol and the rest of Austria. Standardized mortality ratios were calculated with reference to the mortality rates in 1986–1990. RESULTS In all, 86.6% of eligible men have been tested at least once since 1993. Cancer deaths in Tyrol in 2005 were 54% (95% confidence interval [CI] 34–69%) lower than expected compared with 29% (95% CI 22–35%) in the rest of Austria. The decreasing trend in prostate cancer mortality was significantly greater in Tyrol compared with the rest of Austria ( P = 0.001). A significant migration to lower stage disease occurred and radical prostatectomy was associated with low morbidity. CONCLUSIONS In the Tyrol region where treatment is freely available to all patients, where widespread PSA testing and treatment with curative intent occurs, there was a reduction in prostate cancer mortality rates which was significantly greater than the reduction in the rest of Austria. This reduction in prostate cancer mortality is most probably due to early detection, consequent down-staging and effective treatment of prostate cancer. [ABSTRACT FROM AUTHOR]

Objective: The authors carried out a genetic association study of 14 schizophrenia candidate genes (RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF). This study tested the hypothesis of association of schizophrenia with common single nucleotide polymorphisms (SNPs) in these genes using the largest sample to date that has been collected with uniform clinical methods and the most comprehensive set of SNPs in each gene. Method: The sample included 1870 cases (schizophrenia and schizoaffective disorder) and 2,002 screened comparison subjects (i.e. controls), all of European ancestry, with ancestral outliers excluded based on analysis of ancestry-informative markers. The authors genotyped 789 SNPs, including tags for most common SNPs in each gene, SNPs previously reported as associated, and SNPs located in functional domains of genes such as promoters, coding exons (including nonsynonymous SNPs), 3′ untranslated regions, and conserved noncoding sequences. After extensive data cleaning, 648 SNPs were analyzed for association of single SNPs and of haplotypes. Results: Neither experiment-wide nor gene-wide statistical significance was observed in the primary single-SNP analyses or in secondary analyses of haplotypes or of imputed genotypes for additional common HapMap SNPs. Results in SNPs previously reported as associated with schizophrenia were consistent with chance expectation, and four functional polymorphisms in COMT, DRD2, and HTR2A did not produce nominally significant evidence to support previous evidence for association. Conclusions: It is unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects cannot be ruled out. [ABSTRACT FROM AUTHOR]

For more than a decade, prostate-specific antigen (PSA) has been used for prostate cancer screening. Over the years, this screening has been continually refined, including investigation into the use of lower total PSA thresholds, PSA isoforms, and PSA kinetics. This review describes the evolution of prostate cancer screening and provides clinical insights into the informed use of PSA and its adjunctive measurements. [ABSTRACT FROM AUTHOR]

Background: Statistical power calculations inform the design and interpretation of genetic association studies, but few programs are tailored to case-control studies of single nucleotide polymorphisms (SNPs) in unrelated subjects. Results: We have developed the "Power for Genetic Association analyses" (PGA) package which comprises algorithms and graphical user interfaces for sample size and minimum detectable risk calculations using SNP or haplotype effects under different genetic models and study constrains. The software accounts for linkage disequilibrium and statistical multiple comparisons. The results are presented in graphs or tables and can be printed or exported in standard file formats. Conclusion: PGA is user friendly software that can facilitate decision making for association studies of candidate genes, fine-mapping studies, and whole-genome scans. Stand-alone executable files and a Matlab toolbox are available for download at: http://dceg.cancer.gov/bb/tools/pga [ABSTRACT FROM AUTHOR]

Background: Identification of disease-related genes in association studies is challenged by the large number of SNPs typed. To address the dilution of power caused by high dimensionality, and to generate results that are biologically interpretable, it is critical to take into consideration spatial correlation of SNPs along the genome. With the goal of identifying true genetic associations, partitioning the genome according to spatial correlation can be a powerful and meaningful way to address this dimensionality problem. Results: We developed and validated an MCMC Algorithm To Identify blocks of Linkage DisEquilibrium (MATILDE) for clustering contiguous SNPs, and a statistical testing framework to detect association using partitions as units of analysis. We compared its ability to detect true SNP associations to that of the most commonly used algorithm for block partitioning, as implemented in the Haploview and HapBlock software. Simulations were based on artificially assigning phenotypes to individuals with SNPs corresponding to region 14q11 of the HapMap database. When block partitioning is performed using MATILDE, the ability to correctly identify a disease SNP is higher, especially for small effects, than it is with the alternatives considered. Advantages can be both in terms of true positive findings and limiting the number of false discoveries. Finer partitions provided by LD-based methods or by marker-by-marker analysis are efficient only for detecting big effects, or in presence of large sample sizes. The probabilistic approach we propose offers several additional advantages, including: a) adapting the estimation of blocks to the population, technology, and sample size of the study; b) probabilistic assessment of uncertainty about block boundaries and about whether any two SNPs are in the same block; c) user selection of the probability threshold for assigning SNPs to the same block. Conclusion: We demonstrate that, in realistic scenarios, our adaptive, study-specific block partitioning approach is as or more efficient than currently available LD-based approaches in guiding the search for disease loci. [ABSTRACT FROM AUTHOR]

Although the familial aspect of chronic lymphocytic leukaemia (CLL) has been appreciated for decades, it is only with the recent confluence of improved molecular and gene technologies and world-wide collaborative networks that accelerated progress has become apparent. In this summary we highlight selected themes in the genetics of CLL emphasizing the opportunities and challenges of this malignancy. [ABSTRACT FROM AUTHOR]

The article highlights research done on prostate cancer. A study is said to have investigated the natural history of patients whose radical prostatectomy treatment was not successful prior to onset hormonal therapy. It says that in another study, the frequent discrepancy between preoperative clinical traits and pathological tumor features, concerning the management of low-risk prostate cancer, was the focus.

Approximately, a third of all colorectal cancer (CRC) is due to inherited susceptibility. However, high-risk mutations in APC, the mismatch repair (MMR) genes, MUTYH/MYH, SMAD4, ALK3 and STK11/LKB1 are rare and account for <5% of cases. Much of the remaining variation in genetic risk is likely to be explained by combinations of more common gene variants that modestly increase risk. Reliable identification of such 'low penetrance' alleles would provide insight into the aetiology of CRC and might highlight potential therapeutic and preventative interventions. In 2003, the National Study of Colorectal Cancer Genetics (NSCCG) was established with the aim of collecting DNA and clinicopathological data from 20,000 CRC cases and a series of spouse/partner controls, thereby creating a unique resource for identifying low-penetrance CRC susceptibility alleles. The National Cancer Research Network (NCRN) adopted NSCCG onto its portfolio of trials and 148 centres in the United Kingdom (UK) are now actively participating. Over 8,700 cases and 2,185 controls have so far been entered into NSCCG. Our experience in developing NSCCG serves to illustrate how world-class DNA databases for genetic analyses can be rapidly developed in the United Kingdom. [ABSTRACT FROM AUTHOR]

Simple Summary: In prostate cancer, overdiagnosis and overtreatment is a common problem for clinicians. Accurate diagnosis and prognosis are essential to avoid unnecessary biopsy and to increases the effectiveness of treatment. A new, easy-to-use and non-invasive test based on liquid biopsy biomarkers such as Progensa PCA3, MyProstateScore, ExoDx, SelectMDx, PHI, 4K, Stockholm3 and ConfirmMDx have been developed to improve diagnosis, prognosis and to help guide the decision-making process. This article provides an overview of the above-mentioned commercial tests. The performance and financial aspects of the tests have been compared using available studies. Then the application of biomarker tests as an adjunct to multiparametric MRI in the diagnosis, prognosis and monitoring of prostate cancer has been discussed. Prostate cancer (PCa) is the most common cancer in men worldwide. The current gold standard for diagnosing PCa relies on a transrectal ultrasound-guided systematic core needle biopsy indicated after detection changes in a digital rectal examination (DRE) and elevated prostate-specific antigen (PSA) level in the blood serum. PSA is a marker produced by prostate cells, not just cancer cells. Therefore, an elevated PSA level may be associated with other symptoms such as benign prostatic hyperplasia or inflammation of the prostate gland. Due to this marker's low specificity, a common problem is overdiagnosis, which leads to unnecessary biopsies and overtreatment. This is associated with various treatment complications (such as bleeding or infection) and generates unnecessary costs. Therefore, there is no doubt that the improvement of the current procedure by applying effective, sensitive and specific markers is an urgent need. Several non-invasive, cost-effective, high-accuracy liquid biopsy diagnostic biomarkers such as Progensa PCA3, MyProstateScore ExoDx, SelectMDx, PHI, 4K, Stockholm3 and ConfirmMDx have been developed in recent years. This article compares current knowledge about them and their potential application in clinical practice. [ABSTRACT FROM AUTHOR]

Cell cycle regulators play crucial roles in the preadipocyte proliferation and adipocyte differentiation. Cyclin-dependent kinase 4 (CDK4) mediates with D-type cyclins entry of cells into cell cycle in response to external stimuli. CDK4 plays a role in body weight, adipogenesis, and beta cell proliferation. CDK4 null mice develop type 2 diabetes (T2D). Furthermore, CDK4 variants are associated with obesity-associated tumors/cancer. We aimed at identifying a role of CDK4 IVS4-nt40G → A variant in T2D-associated obesity (body mass index, BMI ≥ 30) by association tests in an Italian T2D subjects dataset. We recruited from Italy 128 unrelated T2D subjects with BMI <30 kg/m2 and 54 unrelated T2D subjects with BMI ≥ 30 kg/m2. We performed statistical power calculations in our dataset. DNA samples were directly sequenced with specific primers for CDK4 IVS4-nt40G → A variant. We identified a significant association of the G allele with T2D-associated obesity and of the A allele with T2D-associated BMI < 30. In our study, we found that the CDK4 IVS4-nt40GG genotype is a risk variant for T2D-associated obesity and that the AA genotype is associated with BMI < 30 in T2D. Hence, CDK4 IVS4-nt40A allele is protective and G allele confers risk for obesity in T2D patients. This study should prompt further work aiming at establishing CDK4 role in contributing to human obesity and T2D-associated obesity. J. Cell. Physiol. 221: 273–275, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

In 2020, approximately 191,930 new prostate cancer (PCa) cases are estimated in the United States (US). Hispanic/Latinos (H/L) are the second largest racial/ethnic group in the US. This study aims to assess methylation patterns between aggressive and indolent PCa including DNA repair genes along with ancestry proportions. Prostate tumors classified as aggressive (n = 11) and indolent (n = 13) on the basis of the Gleason score were collected. Tumor and adjacent normal tissue were annotated on H&E (Haemotoxylin and Eosin) slides and extracted by macro-dissection. Methylation patterns were assessed using the Illumina 850K DNA methylation platform. Raw data were processed using the Bioconductor package. Global ancestry proportions were estimated using ADMIXTURE (k = 3). One hundred eight genes including AOX1 were differentially methylated in tumor samples. Regarding the PCa aggressiveness, six hypermethylated genes (RREB1, FAM71F2, JMJD1C, COL5A3, RAE1, and GABRQ) and 11 hypomethylated genes (COL9A2, FAM179A, SLC17A2, PDE10A, PLEKHS1, TNNI2, OR51A4, RNF169, SPNS2, ADAMTSL5, and CYP4F12) were identified. Two significant differentially methylated DNA repair genes, JMJD1C and RNF169, were found. Ancestry proportion results for African, European, and Indigenous American were 24.1%, 64.2%, and 11.7%, respectively. The identification of DNA methylation patterns related to PCa in H/L men along with specific patterns related to aggressiveness and DNA repair constitutes a pivotal effort for the understanding of PCa in this population. [ABSTRACT FROM AUTHOR]

There is clinically relevant molecular heterogeneity in prostate cancer (PCa), but this biological diversity has had only a minimal impact on clinical practice. Treatment outcomes in patients with localised PCa are often highly variable, even among patients stratified to the same risk group or disease state based on standard clinical and pathological parameters. In recent years, the development of gene panels has provided valuable data on the differential expression of genes in patients with PCa. Nevertheless, there is an urgent need to identify and validate prognostic and predictive biomarkers that can be applied across clinical scenarios, ranging from localised disease to metastatic castration-resistant PCa. The availability of such tools would allow for precision medicine to finally reach PCa patients. In this review, we evaluate current data on molecular biomarkers for PCa, with an emphasis on the biomarkers and gene panels with the most robust evidence to support their application in routine clinical practice. [ABSTRACT FROM AUTHOR]

A case study is presented on a 70-year-old man who was confined to the hospital due to pyrexia, along with pain and inflammation in his right arm. The magnetic resonance imaging (MRI) reveals a pathological fracture on the right humerus while the biospy showed abnormal plasma cells. Based on these findings, the patient was diagnosed with a non-secretory plasmablastic solitary plasmacytoma of bone (SPB), stage III. He was treated with a chemotherapy, prednisone, and bortezomid plus melphalan.