An Association Study of Germline Variants in Bladder Cancer-Related Genes with the Prognosis of Non-Muscle Invasive Bladder Cancer.

BACKGROUND: Various germline genetic variants are associated with the prognosis of non-muscle invasive bladder cancer (NMIBC). Germline variants in genes frequently somatically mutated in bladder cancer have not been studied thoroughly in relation to risk of recurrence or progression in NMIBC. OBJECTIVE: To identify germline DNA variants in bladder carcinogenesis-related genes associated with recurrence or progression in NMIBC. METHODS: We analysed associations between single-nucleotide polymorphisms (SNPs) and NMIBC recurrence and progression using data from the Nijmegen Bladder Cancer Study (NBCS, 1,443 patients). We included 5,053 SNPs within 46 genes known to have mutation, overexpression or amplification in bladder cancer. We included all recurrences in the statistical analysis and performed both single variant analysis and gene-based analysis. SNPs and genes that showed significant or suggestive association (false discovery rate P value < 20%) were followed-up in independent cohorts for replication analysis, through eQTL analysis and tests for association of tumour expression levels with NMIBC recurrence and progression. RESULTS: Single variant analysis showed no statistically significant associations with recurrence or progression. In gene-based analysis, the aggregate effect of the 25 SNPs in the Cyclin D1 gene (CCND1) was statistically significantly associated with NMIBC recurrence (Punadj = 0.001, PFDR = 0.046), but not with progression (Punadj = 0.17, PFDR = 0.54). Validation analysis in independent cohorts did not confirm the association of CCND1 with NMIBC recurrence. CONCLUSIONS: We could not identify reproducible associations between common germline variants in bladder carcinogenesis-related genes and NMIBC recurrence or progression.

Transcriptomics Integrated with Metabolomics Unveil Carotenoids Accumulation and Correlated Gene Regulation in White and Yellow-Fleshed Turnip (Brassica rapa ssp. rapa).

Turnip (Brassica rapa ssp. rapa) is considered to be a highly nutritious and health-promoting vegetable crop, whose flesh color can be divided into yellow and white. It is widely accepted that yellow-fleshed turnips have higher nutritional value. However, reports about flesh color formation is lacking. Here, the white-fleshed inbred line, W21, and yellow-fleshed inbred line, W25, were profiled from the swollen root of the turnip at three developmental periods to elucidate the yellow color formation. Transcriptomics integrated with metabolomics analysis showed that the PSY gene was the key gene affecting the carotenoids formation in W25. The coding sequence of BrrPSY-W25 was 1278 bp and that of BrrPSY-W21 was 1275 bp, and BrrPSY was more highly expressed in swollen roots in W25 than in W21. Transient transgenic tobacco leaf over-expressing BrrPSY-W and BrrPSY-Y showed higher transcript levels and carotenoids contents. Results revealed that yellow turnip formation is due to high expression of the PSY gene rather than mutations in the PSY gene, indicating that a post-transcriptional regulatory mechanism may affect carotenoids formation. Results obtained in this study will be helpful for explaining the carotenoids accumulation of turnips.

Genetic Predictors for Sinusoidal Obstruction Syndrome-A Systematic Review.

Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication after hematopoietic stem cell transplantation (HSCT) or antineoplastic treatment without HSCT. Genetic variants were investigated for their association with SOS, but the evidence is inconclusive. We performed a systematic literature review to identify genes, gene variants, and methods of association analyses of genetic markers with SOS. We identified 23 studies after HSCT and 4 studies after antineoplastic treatment without HSCT. One study (4%) performed whole-exome sequencing (WES) and replicated the analysis in an independent cohort, 26 used a candidate-gene approach. Three studies included >200 participants (11%), and six were of high quality (22%). Variants in 34 genes were tested in candidate gene studies after HSCT. Variants in GSTA1 were associated with SOS in three studies, MTHFR in two, and CPS1, CTH, CYP2B6, GSTM1, GSTP1, HFE, and HPSE in one study each. UGT2B10 and LNPK variants were identified in a WES analysis. After exposure to antineoplastic agents without HSCT, variants in six genes were tested and only GSTM1 was associated with SOS. There was a substantial heterogeneity of populations within and between studies. Future research should be based on sufficiently large homogenous samples, adjust for covariates, and replicate findings in independent cohorts.

QTL Mapping of Heat Tolerance in Cucumber (Cucumis sativus L.) at Adult Stage.

Heat stress during cucumber production often leads to sunburn of leaves, growth retardation of stems and roots, fruit malformation, and even plant death, which have a great impact on the fruit quality and yield. However, no studies on the genetic inheritance and quantitative trait locus mapping of heat tolerance in cucumber at the adult stage have been reported yet. In this study, a set of 86 recombinant inbred lines (RILs) derived from "99281" (heat-tolerant) and "931" (heat-sensitive) were used to identify the heat tolerance QTL in summer 2018, 2019, and 2020. Eight-week-old plants were exposed to a natural high temperature environment in the field, and the heat injury index was used to indicate the heat tolerance performance. Genetic analysis showed that the heat tolerance of adult cucumber is quantitatively inherited. One QTL named qHT1.1 on chromosome 1 was identified. It was delimited by Indel 3-3 and Indel 1-15 and explained 59.6%, 58.1%, and 40.1% of the phenotypic variation in 2018, 2019, and 2020, respectively. The efficiency of marker HT-1, which is closely linked to the locus, was tested using 62 cucumber germplasm accessions and was found to have an accuracy of 97.8% in heat sensitive plants. The qHT1.1 was delimited to a 694.5-kb region, containing 98 genes, nine of which may be involved in heat tolerance. Further sequence analysis showed that there are three single-base substitutions within the coding sequences of Csa1G004990. Gene expression analyses suggested that the expression of Csa1G004990 was significantly higher in "99281" than "931" at 14d, 35d, 42d, and 49d after transplanting. This study provides practically useful markers for heat tolerance breeding in cucumber and provides a basis for further identifying heat tolerant genes.

Genetics of systemic sclerosis.

Systemic sclerosis is an autoimmune disease characterized by generalized fibrosis in connective tissues and internal organs as consequences of microvascular dysfunction and immune dysfunctions, which leads to premature death in affected individuals. The etiology of systemic sclerosis is complex and poorly understood, but as with most autoimmune diseases, it is widely accepted that both environmental and genetic factors contribute to disease risk. During the last decade, the number of genetic markers convincingly associated with systemic sclerosis has exponentially increased. In this article, we briefly mention the genetic components of systemic sclerosis. Then, we review the classical and novel genetic associations with systemic sclerosis, analyzing the firmest and replicated signals within non-human leukocyte antigen genes, identified by both candidate gene approach and genome-wide association studies. We also provide an insight into the future perspectives that will shed more light into the complex genetic background of the disease. Despite the remarkable advance of systemic sclerosis genetics during the last decade, the use of the new genetic technologies such as next-generation sequencing, as well as the deep phenotyping of the study cohorts, to fully characterize the genetic component of this disease is imperative to identify causal variants, which leads to more targeted and effective treatment of systemic sclerosis.

Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma: Results from two independent African cohorts.

The risk of developing posttraumatic stress disorder (PTSD) increases with the number of traumatic event types experienced (trauma load) in interaction with other psychobiological risk factors. The NOTCH (neurogenic locus notch homolog proteins) signaling pathway, consisting of four different trans-membrane receptor proteins (NOTCH1-4), constitutes an evolutionarily well-conserved intercellular communication pathway (involved, e.g., in cell-cell interaction, inflammatory signaling, and learning processes). Its association with fear memory consolidation makes it an interesting candidate for PTSD research. We tested for significant associations of common genetic variants of NOTCH1-4 (investigated by microarray) and genomic methylation of saliva-derived DNA with lifetime PTSD risk in independent cohorts from Northern Uganda (N1 = 924) and Rwanda (N2 = 371), and investigated whether NOTCH-related gene sets were enriched for associations with lifetime PTSD risk. We found associations of lifetime PTSD risk with single nucleotide polymorphism (SNP) rs2074621 (NOTCH3) (puncorrected = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (puncorrected = 0.05) in Rwandans. Yet, none of the (epi-)genetic associations survived multiple testing correction. Gene set enrichment analyses revealed enrichment for associations of two NOTCH pathways with lifetime PTSD risk in Ugandans: NOTCH binding (pcorrected = 0.003) and NOTCH receptor processing (pcorrected = 0.01). The environmental factor trauma load was significant in all analyses (all p < 0.001). Our integrated methodological approach suggests NOTCH as a possible mediator of PTSD risk after trauma. The results require replication, and the precise underlying pathophysiological mechanisms should be illuminated in future studies.

The JAX Synteny Browser for mouse-human comparative genomics.

Visualizing regions of conserved synteny between two genomes is supported by numerous software applications. However, none of the current applications allow researchers to select genome features to display or highlight in blocks of synteny based on the annotated biological properties of the features (e.g., type, function, and/or phenotype association). To address this usability gap, we developed an interactive web-based conserved synteny browser, The Jackson Laboratory (JAX) Synteny Browser. The browser allows researchers to highlight or selectively display genome features in the reference and/or the comparison genome according to the biological attributes of the features. Although the current implementation for the browser is limited to the reference genomes for the laboratory mouse and human, the software platform is intentionally genome agnostic. The JAX Synteny Browser software can be deployed for any two genomes where genome coordinates for syntenic blocks are defined and for which biological attributes of the features in one or both genomes are available in widely used standard bioinformatics file formats. The JAX Synteny Browser is available at: http://syntenybrowser.jax.org/. The code base is available from GitHub: https://github.com/TheJacksonLaboratory/syntenybrowser and is distributed under the Creative Commons Attribution license (CC BY).

Genome-Wide Association Study Reveals Candidate Genes for Flowering Time Variation in Common Bean (Phaseolus vulgaris L.).

The common bean is one of the most important staples in many areas of the world. Extensive phenotypic and genetic characterization of unexplored bean germplasm are still needed to unlock the breeding potential of this crop. Dissecting genetic control of flowering time is of pivotal importance to foster common bean breeding and to develop new varieties able to adapt to changing climatic conditions. Indeed, flowering time strongly affects yield and plant adaptation ability. The aim of this study was to investigate the genetic control of days to flowering using a whole genome association approach on a panel of 192 highly homozygous common bean genotypes purposely developed from landraces using Single Seed Descent. The phenotypic characterization was carried out at two experimental sites throughout two growing seasons, using a randomized partially replicated experimental design. The same plant material was genotyped using double digest Restriction-site Associated DNA sequencing producing, after a strict quality control, a dataset of about 50 k Single Nucleotide Polymorphisms (SNPs). The Genome-Wide Association Study revealed significant and meaningful associations between days to flowering and several SNP markers; seven genes are proposed as the best candidates to explain the detected associations.

Quantitative Trait Loci Mapping and Candidate Gene Analysis of Low Temperature Tolerance in Cucumber Seedlings.

Cucumber (Cucumis sativus L.) is an economically important vegetable crop worldwide, but it is sensitive to low temperatures. Cucumber seedlings exposed to long-term low temperature stress (LT), i.e., below 20°C during the day, and 8°C at night, exhibit leaf yellowing, accelerated senescence, and reduced yield, therefore posing a threat to cucumber production. Studying the underlying mechanisms involved in LT tolerance in cucumber seedlings, and developing germplasm with improved LT-tolerance could provide fundamental solutions to the problem. In this study, an F2 population was generated from two parental lines, "CG104" (LT-tolerant inbred line) and "CG37" (LT-sensitive inbred line), to identify loci that are responsible for LT tolerance in cucumber seedlings. Replicated phenotypic analysis of the F2-derived F3 family using a low-temperature injury index (LTII) suggested that the LT tolerance of cucumber seedlings is controlled by multiple genes. A genetic map of 990.8 cM was constructed, with an average interval between markers of 5.2 cM. One quantitative trait loci (QTL) named qLTT5.1 on chromosome 5, and two QTLs named qLTT6.1 and qLTT6.2 on chromosome 6 were detected. Among them, qLTT6.2 accounted for 26.8 and 24.1% of the phenotypic variation in two different experiments. Single-nucleotide polymorphism (SNP) variations within the region of qLTT6.2 were analyzed using two contrasting in silico bulks generated from the cucumber core germplasm. Result showed that 214 SNPs were distributed within the 42-kb interval, containing three candidate genes. Real-time quantitative reverse transcription PCR and sequence analysis suggested that two genes Csa6G445210, an auxin response factor, and Csa6G445230, an ethylene-responsive transmembrane protein, might be candidate genes responsible for LT tolerance in cucumber seedlings. This study furthers the understanding of the molecular mechanism underlying LT tolerance in cucumber seedlings, and provides new markers for molecular breeding.

Effect of Ovar-DRA and Ovar-DRB1 genotype in small ruminants with haemonchosis.

The effect of Ovar-DRA and Ovar-DRB1 genotypes on faecal egg count (FEC) was determined in sheep and goats infected with Haemonchus contortus. One hundred and forty-three sheep from 3 different breeds (St. Croix, Katahdin and Dorper) and 150 goats from three different breeds (Spanish, Boer and Kiko) were used. Parasitological (FEC), haematological (packed cell volume) and immunological (IgA, IgG and IgM) parameters were measured. Sheep populations showed a higher FEC and humoural response than goat breeds. Genotypes were determined by high-resolution melting assays and by conventional PCR. For Ovar-DRA, sheep and goats carrying the AA genotype showed significant lower FEC than AG and GG genotypes. The additive effect was found to be 115.35 less eggs per gram of faeces for the A allele for goats. For Ovar-DRB1, only in sheep, the GC genotype was associated with low FEC. The additive effect was 316.48 less eggs per gram of faeces for the G allele, and the dominance effect was 538.70 less eggs per gram of faeces. The results indicate that single nucleotide polymorphisms within Ovar-DRA and Ovar-DRB1 could be potential markers to be used in selection programmes for improving resistance to Haemonchus contortus infection.

Structural Equation Modeling.

Structural equation modeling (SEM) is a multivariate statistical framework that is used to model complex relationships between directly observed and indirectly observed (latent) variables. SEM is a general framework that involves simultaneously solving systems of linear equations and encompasses other techniques such as regression, factor analysis, path analysis, and latent growth curve modeling. Recently, SEM has gained popularity in the analysis of complex genetic traits because it can be used to better analyze the relationships between correlated variables (traits), to model genes as latent variables as a function of multiple observed genetic variants, and to assess the association between multiple genetic variants and multiple correlated phenotypes of interest. Though the general SEM framework only allows for the analysis of independent observations, recent work has extended SEM for the analysis of data on general pedigrees. Here, we review the theory of SEM for both unrelated and family data, describe the available software for SEM, and provide examples of SEM analysis.

Genome-wide association study for carcass traits, fatty acid composition, chemical composition, sugar, and the effects of related candidate genes in Japanese Black cattle.

We performed a genome-wide association study (GWAS) and candidate gene analysis to: (i) evaluate the effectiveness of the GWAS in our small population by performing GWAS for carcass weight (CW) and fatty acid composition; (ii) detect novel candidate regions affecting non-CW carcass traits, chemical composition and sugar; and (iii) evaluate the association of the candidate genes previously detected in CW and fatty acid composition with other economically important traits. A total of 574 Japanese Black cattle and 40 657 Single nucleotide polymorphisms were used. In addition, candidate gene analyses were performed to evaluate the association of three CW-related genes and two fatty acid-related genes with carcass traits, fatty acid composition, chemical composition and sugar. The significant regions with the candidate genes were detected for CW and fatty acid composition, and these results showed that a significant region would be detectable despite the small sample size. The novel candidate regions were detected on BTA23 for crude protein and on BTA19 for fructose. CW-related genes associated with the rib-eye area and fatty acid composition were identified, and fatty acid-related genes had no relationship with other traits. Moreover, the favorable allele of CW-related genes had an unfavorable effect on fatty acid composition.

Human ULK1 Variation and Susceptibility to Mycobacterium tuberculosis Infection.

BACKGROUND: Unlike tuberculosis, few studies have evaluated a host genetic basis for variability in susceptibility to latent Mycobacterium tuberculosis infection (LTBI). We performed a candidate gene association study of autophagy-related genes and LTBI. METHODS: We enrolled close contacts of individuals with pulmonary tuberculosis, assessed LTBI status, and determined clinical and sociodemographic risk factors for LTBI. In participants who self-identified as Asian or black, we compared haplotype-tagging single-nucleotide polymorphisms (SNPs) in ULK1 and GABARAP between cases (n = 143) and controls (n = 106). Using CRISPR/Cas9 in U937 monocytes, we investigated the effect of ULK1 deficiency on cytokine expression, autophagy, and M. tuberculosis replication. RESULTS: In Asian participants, we identified 2 ULK1 SNPs (rs12297124 and rs7300908) associated with LTBI. After adjustment for population admixture and clinical risk for LTBI, each rs12297124 minor allele conferred 80% reduction in LTBI risk (odds ratio, 0.18; 95% confidence interval, .07-.46). Compared with controls, ULK1-deficient cells exhibited decreased tumor necrosis factor secretion after stimulation with Toll-like receptor ligands and M. tuberculosis whole-cell lysate, increased M. tuberculosis replication, and decreased selective autophagy. CONCLUSIONS: These results demonstrate a strong association of rs12297124, a noncoding ULK1 SNP, with LTBI and a role for ULK1 regulation of TNF secretion, nonspecific and M. tuberculosis-induced autophagy, and M. tuberculosis replication in monocytes.

Autosomal dominant hereditary spastic paraplegia with axonal sensory motor polyneuropathy maps to chromosome 21q 22.3.

AIM: Hereditary spastic paraplegia (HSP) are a genetically and clinically heterogeneous group of disorders. At present, 19 autosomal dominant loci for HSP have been mapped. We ascertained an American family of European descent segregating an autosomal dominant HSP associated with peripheral neuropathy. METHODS: A genome wide scan was performed with 410 microsatellite repeat marker (Weber lab screening set 16) and following linkage and haplotype analysis, fine mapping was performed. Established genes or loci for HSP were excluded by direct sequencing or haplotype analysis. RESULTS: All established loci for HSP were excluded. Fine mapping suggested a locus on chromosome 21q22.3 flanked by markers D21S1411 and D21S1446 with a maximum logarithm of odds score of 2.05 and was supported by haplotype analysis. A number of candidate genes in this region were analyzed and no disease-producing mutations were detected. CONCLUSION: We present the clinical and genetic analysis of an American family with autosomal dominant HSP with axonal sensory motor polyneuropathy mapping to a novel locus on chromosome 21q22.3 designated SPG56.

Study of IRF6 and 8q24 region in non-syndromic oral clefts in the Brazilian population.

OBJECTIVES: We investigated the association between non-syndromic oral cleft and variants in IRF6 (rs2235371 and rs642961) and 8q24 region (rs987525) according to the ancestry contribution of the Brazilian population. SUBJECTS AND METHODS: Subjects with oral cleft (CL, CLP, or CP) and their parents were selected from different geographic regions of Brazil. Polymorphisms were genotyped using a TaqMan assay and genomic ancestry was estimated using a panel of 48 INDEL polymorphisms. RESULTS: A total of 259 probands were analyzed. A TDT detected overtransmission of the rs2235371 G allele (P = 0.0008) in the total sample. A significant association of this allele was also observed in CLP (P = 0.0343) and CLP + CL (P = 0.0027). IRF6 haplotype analysis showed that the G/A haplotype increased the risk for cleft in children (single dose: P = 0.0038, double dose: P = 0.0022) and in mothers (single dose: P = 0.0016). The rs987525 (8q24) also exhibited an association between the A allele and the CLP + CL group (P = 0.0462). These results were confirmed in the probands with European ancestry. CONCLUSIONS: The 8q24 region plays a role in CL/P and the IRF6 G/A haplotype (rs2235371/rs642961) increases the risk for oral cleft in the Brazilian population.

Genetic analysis of the bicarbonate secreting anion exchanger SLC26A6 in chronic pancreatitis.

BACKGROUND: Pancreatic ductal HCO3(-) secretion is critically dependent on the cystic fibrosis transmembrane conductance regulator chloride channel (CFTR) and the solute-linked carrier 26 member 6 anion transporter (SLC26A6). Deterioration of HCO3(-) secretion is observed in chronic pancreatitis (CP), and CFTR mutations increase CP risk. Therefore, SLC26A6 is a reasonable candidate for a CP susceptibility gene, which has not been investigated in CP patients so far. METHODS: As a first screening cohort, 106 subjects with CP and 99 control subjects with no pancreatic disease were recruited from the Hungarian National Pancreas Registry. In 60 non-alcoholic CP cases the entire SLC26A6 coding region was sequenced. In the Hungarian cohort variants c.616G > A (p.V206M) and c.1191C > A (p.P397=) were further genotyped by restriction fragment length polymorphism analysis. In a German replication cohort all exons were sequenced in 40 non-alcoholic CP cases and variant c.616G > A (p.V206M) was further analyzed by sequencing in 321 CP cases and 171 controls. RESULTS: Sequencing of the entire coding region revealed four common variants: intronic variants c.23 + 78_110del, c.183-4C > A, c.1134 + 32C > A, and missense variant c.616G > A (p.V206M) which were found in linkage disequilibrium indicating a conserved haplotype. The distribution of the haplotype did not show a significant difference between patients and controls in the two cohorts. A synonymous variant c.1191C > A (p.P397=) and two intronic variants c.1248 + 9_20del and c.-10C > T were detected in single cases. CONCLUSION: Our data show that SLC26A6 variants do not alter the risk for the development of CP.

Beta-catenin in schizophrenia: Possibly deleterious novel mutation.

Schizophrenia is a debilitating psychiatric disorder, affecting approximately 1% of the human population. Mostly genetic factors contribute to schizophrenia, but the genetics are complex and various aspects of brain functioning and structure, from development to synapse plasticity, seem to be involved in the pathogenesis. The goal of the study was to look for novel mutations in genes, implicated in molecular networks, important in schizophrenia. In the study four candidate genes taking part in the WNT signaling pathway were analyzed by sequencing in a cohort of 87 schizophrenia patients from Saint Petersburg, Russia. The gene list included CTNNB1 (beta-catenin), GSK3B, WNT2B and WNT7B. The impact of discovered variants on the protein function was analyzed in silico. We found three variants in the genes CTNNB1 and WNT7B, absent in healthy controls, including 212 controls from the same geographic area. The novel mutation c.1943A>G (p.N648S) in CTNNB1 seems to be the best candidate for disease-associated mutation in this study, as it damages the protein product in silico. This is the first study reporting mutations in CTNNB1 in schizophrenia.

Dental caries and enamelin haplotype.

In the literature, the enamelin gene ENAM has been repeatedly designated as a possible candidate for caries susceptibility. Here, we checked whether ENAM variants could increase caries susceptibility. To this aim, we sequenced coding exons and exon-intron boundaries of ENAM in 250 children with a severe caries phenotype and in 149 caries-free patients from 9 French hospital groups. In total, 23 single-nucleotide polymorphisms (SNPs) were found, but none appeared to be responsible for a direct change of ENAM function. Six SNPs had a high minor allele frequency (MAF) and 6 others were identified for the first time. Statistical and evolutionary analyses showed that none of these SNPs was associated with caries susceptibility or caries protection when studied separately and challenged with environmental factors. However, haplotype interaction analysis showed that the presence, in a same variant, of 2 exonic SNPs (rs7671281 and rs3796704; MAF 0.12 and 0.10, respectively), both changing an amino acid in the protein region encoded by exon 10 (p.I648T and p.R763Q, respectively), increased caries susceptibility 2.66-fold independent of the environmental risk factors. These findings support ENAM as a gene candidate for caries susceptibility in the studied population.

Expression patterns of candidate susceptibility genes HNF1ß and CtBP2 in prostate cancer: association with tumor progression.

OBJECTIVES: Genome-wide association studies have identified variants at multiple loci associated with prostate cancer (PCa) risk. Some of these loci include candidate susceptibility genes, such as MSMB, HNF1ß, and C-terminal-binding protein (CtBP2). Except for MSMB, the clinicopathological significance of these genes has not been investigated. We therefore aimed to analyze their expression in PCa tissues, in relation with tumor progression and aggressiveness. METHODS AND MATERIALS: Protein expression was evaluated by immunohistochemistry on tissue microarrays containing samples from normal prostate (NL, n = 91), high-grade prostatic intraepithelial neoplasia (PIN, n = 61), clinically localized PCa (CLC, n = 434), PCa metastases (M, n = 28), and castration-resistant PCa (CRC, n = 49). Moreover, mRNA expression for each marker was assessed by quantitative real-time polymerase chain reaction, on 53 frozen samples of NL, CLC, and CRC. RESULTS: These genes were differentially expressed at the different stages of PCa natural history. MSMB expression decreased with disease development and progression. In contrast, nuclear HNF1ß and CtBP2 staining significantly increased in the CRC and M groups when compared with CLC, together with the transcripts levels. In patients with CLC, HNF1ß and CtBP2 nuclear expressions were strongly associated with cancer cell proliferation. After adjusting for the Gleason score and the pathological stage, none of the candidate genes was significantly predictive of recurrence after radical prostatectomy. In patients with CRC, CtBP2 nuclear staining was associated with shorter overall survival. CONCLUSIONS: The decrease of MSMB expression during tumor progression strongly supports its role as a tumor-suppressor gene. Although its functions remain to be clarified in PCa cells, HNF1ß and CtBP2 are associated with cancer cell proliferation, tumor progression, and castration-resistant disease.