The phase 3 CAIRO3 study showed that capecitabine plus bevacizumab (CAP-B) maintenance treatment after six cycles capecitabine, oxaliplatin, and bevacizumab (CAPOX-B) in metastatic colorectal cancer ...(mCRC) patients is effective, without compromising quality of life. In this post hoc analysis with updated follow-up and data regarding sidedness, we defined subgroups according to RAS/BRAF mutation status and mismatch repair (MMR) status, and investigated their influence on treatment efficacy.
A total of 558 patients with previously untreated mCRC and stable disease or better after six cycles CAPOX-B induction treatment were randomised to either CAP-B maintenance treatment (n = 279) or observation (n = 279). Upon first progression, patients were to receive CAPOX-B reintroduction until second progression (PFS2, primary end point). We centrally assessed RAS/BRAF mutation status and MMR status, or used local results if central assessment was not possible. Intention-to-treat stratified Cox models adjusted for baseline covariables were used to examine whether treatment efficacy was modified by RAS/BRAF mutation status.
RAS, BRAF mutations, and MMR deficiency were detected in 240/420 (58%), 36/381 (9%), and 4/279 (1%) patients, respectively. At a median follow-up of 87 months (IQR 69–97), all mutational subgroups showed significant improvement from maintenance treatment for the primary end point PFS2 RAS/BRAF wild-type: hazard ratio (HR) 0.57 (95% CI 0.39–0.84); RAS-mutant: HR 0.74 (0.55–0.98); V600EBRAF-mutant: HR 0.28 (0.12–0.64) and secondary end points, except for the RAS-mutant subgroup regarding overall survival. Adjustment for sidedness instead of primary tumour location yielded comparable results. Although right-sided tumours were associated with inferior prognosis, both patients with right- and left-sided tumours showed significant benefit from maintenance treatment.
CAP-B maintenance treatment after six cycles CAPOX-B is effective in first-line treatment of mCRC across all mutational subgroups. The benefit of maintenance treatment was most pronounced in patients with RAS/BRAF wild-type and V600EBRAF-mutant tumours.
NCT00442637.
The N-methyl-D-aspartate receptor (NMDAR) coagonists glycine, D-serine and L-proline play crucial roles in NMDAR-dependent neurotransmission and are associated with a range of neuropsychiatric ...disorders. We conducted the first genome-wide association study of concentrations of these coagonists and their enantiomers in plasma and cerebrospinal fluid (CSF) of human subjects from the general population (N=414). Genetic variants at chromosome 22q11.2, located in and near PRODH (proline dehydrogenase), were associated with L-proline in plasma (β=0.29; P=6.38 × 10(-10)). The missense variant rs17279437 in the proline transporter SLC6A20 was associated with L-proline in CSF (β=0.28; P=9.68 × 10(-9)). Suggestive evidence of association was found for the D-serine plasma-CSF ratio at the D-amino-acid oxidase (DAO) gene (β=-0.28; P=9.08 × 10(-8)), whereas a variant in SRR (that encodes serine racemase and is associated with schizophrenia) constituted the most strongly associated locus for the L-serine to D-serine ratio in CSF. All these genes are highly expressed in rodent meninges and choroid plexus, anatomical regions relevant to CSF physiology. The enzymes and transporters they encode may be targeted to further construe the nature of NMDAR coagonist involvement in NMDAR gating. Furthermore, the highlighted genetic variants may be followed up in clinical populations, for example, schizophrenia and 22q11 deletion syndrome. Overall, this targeted metabolomics approach furthers the understanding of NMDAR coagonist concentration variability and sets the stage for non-targeted CSF metabolomics projects.
A strong association between susceptibility to type 2 diabetes and common variants of transcription factor 7-like 2 (TCF7L2), encoding an enteroendocrine transcription factor involved in glucose ...homeostasis, has been reported in three different populations (Iceland, Denmark and USA) by Grant et al. We aimed to replicate these findings in a Dutch cohort.
We analysed the genotypes of two intronic single nucleotide polymorphisms (SNPs) in TCF7L2 gene in 502 unrelated type 2 diabetes patients and in a set of healthy controls (n = 920). The two SNPs showed almost complete linkage disequilibrium (D' = 0.91).
We were able to replicate the previously reported association in our Breda cohort. The minor alleles of both variants were significantly over-represented in cases (odds ratio OR 1.29, 95% CI 1.09-1.52, Formula: see text for rs12255372; OR 1.41, 95% CI 1.19-1.66, Formula: see text for rs7903146). In addition, TCF7L2 haplotypes were analysed for association with the disease. The analysis of haplotypes did not reveal any strong association beyond that expected from analysing individual SNPs. The TT haplotype carrying the minor alleles was more frequent among cases (OR 1.38, Formula: see text).
Our data strongly confirm that variants of the TCF7L2 gene contribute to the risk of type 2 diabetes. The population-attributable risk from this factor in the Dutch type 2 diabetes population is 10%.
Studying monoaminergic seasonality is likely to improve our understanding of neurobiological mechanisms underlying season-associated physiological and pathophysiological behavior. Studies of ...monoaminergic seasonality and the influence of the serotonin-transporter-linked polymorphic region (5-HTTLPR) on serotonin seasonality have yielded conflicting results, possibly due to lack of power and absence of multi-year analyses. We aimed to assess the extent of seasonal monoamine turnover and examined the possible involvement of the 5-HTTLPR. To determine the influence of seasonality on monoamine turnover, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid of 479 human subjects collected during a 3-year period. Cosine and non-parametric seasonal modeling were applied to both metabolites. We computed serotonin (5-HT) seasonality values and performed an association analysis with the s/l alleles of the 5-HTTLPR. Depressive symptomatology was assessed using the Beck Depression Inventory-II. Circannual variation in 5-HIAA fitted a spring-peak cosine model that was significantly associated with sampling month (P=0.0074). Season of sampling explained 5.4% (P=1.57 × 10(-7)) of the variance in 5-HIAA concentrations. The 5-HTTLPR s-allele was associated with increased 5-HIAA seasonality (standardized regression coefficient=0.12, P=0.020, N=393). 5-HIAA seasonality correlated with depressive symptoms (Spearman's rho=0.13, P=0.018, N=345). In conclusion, we highlight a dose-dependent association of the 5-HTTLPR with 5-HIAA seasonality and a positive correlation between 5-HIAA seasonality and depressive symptomatology. The presented data set the stage for follow-up in clinical populations with a role for seasonality, such as affective disorders.
Summary
Survival of patients with esophageal adenocarcinoma remains poor and individual differences in prognosis remain unexplained. This study investigated whether gene mutations can explain why ...patients with high-risk (pT3-4, pN+) esophageal adenocarcinoma survive past 5 years after esophagectomy. Six long-term survivors (LTS) (≥5 years survival without recurrence) and six short-term survivors (STS) (<2 years survival due to recurrence) who underwent resection without neoadjuvant therapy for high-risk esophageal adenocarcinoma were included. Targeted next-generation sequencing of 16 genes related to esophageal adenocarcinoma was performed. Mutations were compared between the LTS and STS and described in comparison with literature. A total of 48 mutations in 10 genes were identified. In the LTS, the median number of mutated genes per sample was 5 (range: 0–5) and the samples together harbored 22 mutations in 8 genes: APC (n = 1), CDH11 (n = 2), CDKN2A (n = 2), FAT4 (n = 5), KRAS (n = 1), PTPRD (n = 1), TLR4 (n = 8), and TP53 (n = 2). The median number of mutated genes per sample in the STS was 4 (range: 1–8) and in total 26 mutations were found in six genes: CDH11 (n = 5), FAT4 (n = 7), SMAD4 (n = 1), SMARCA4 (n = 1), TLR4 (n = 7), and TP53 (n = 5). CDH11, CDKN2A, FAT4, TLR4, and TP53 were mutated in at least 2 LTS or STS, exceeding mutation rates in literature. Mutations across the LTS and STS were found in 10 of the 16 genes. The results warrant future studies to investigate a larger range of genes in a larger sample size. This may result in a panel with prognostic genes, to predict individual prognosis and to select effective individualized therapy for patients with esophageal adenocarcinoma.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The blood-brain barrier separates circulating blood from the central nervous system (CNS). The scope of this barrier is not fully understood which limits our ability to relate biological measurements ...from peripheral to central phenotypes. For example, it is unknown to what extent gene expression levels in peripheral blood are reflective of CNS metabolism. In this study, we examine links between central monoamine metabolite levels and whole-blood gene expression to better understand the connection between peripheral systems and the CNS. To that end, we correlated the prime monoamine metabolites in cerebrospinal fluid (CSF) with whole-genome gene expression microarray data from blood (N=240 human subjects). We additionally applied gene-enrichment analysis and weighted gene co-expression network analyses (WGCNA) to identify modules of co-expressed genes in blood that may be involved with monoamine metabolite levels in CSF. Transcript levels of two genes were significantly associated with CSF serotonin metabolite levels after Bonferroni correction for multiple testing: THAP7 (P=2.8 × 10
, β=0.08) and DDX6 (P=2.9 × 10
, β=0.07). Differentially expressed genes were significantly enriched for genes expressed in the brain tissue (P=6.0 × 10
). WGCNA revealed significant correlations between serotonin metabolism and hub genes with known functions in serotonin metabolism, for example, HTR2A and COMT. We conclude that gene expression levels in whole blood are associated with monoamine metabolite levels in the human CSF. Our results, including the strong enrichment of brain-expressed genes, illustrate that gene expression profiles in peripheral blood can be relevant for quantitative metabolic phenotypes in the CNS.
Schizophrenia is a severe psychiatric disease with complex etiology, affecting approximately 1% of the general population. Most genetics studies so far have focused on disease association with common ...genetic variation, such as single-nucleotide polymorphisms (SNPs), but it has recently become apparent that large-scale genomic copy-number variants (CNVs) are involved in disease development as well. To assess the role of rare CNVs in schizophrenia, we screened 54 patients with deficit schizophrenia using Affymetrix's GeneChip 250K SNP arrays. We identified 90 CNVs in total, 77 of which have been reported previously in unaffected control cohorts. Among the genes disrupted by the remaining rare CNVs are
MYT1L,
CTNND2,
NRXN1, and
ASTN2, genes that play an important role in neuronal functioning but—except for
NRXN1—have not been associated with schizophrenia before. We studied the occurrence of CNVs at these four loci in an additional cohort of 752 patients and 706 normal controls from The Netherlands. We identified eight additional CNVs, of which the four that affect coding sequences were found only in the patient cohort. Our study supports a role for rare CNVs in schizophrenia susceptibility and identifies at least three candidate genes for this complex disorder.
The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability ...attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A genome-wide scan was performed, using nonparametric linkage analyses, to find susceptibility loci for type 2 diabetes mellitus in the Dutch population. We studied 178 families from The Netherlands, ...who constituted 312 affected sibling pairs. The first stage of the genome scan consisted of 270 DNA markers, with an average intermarker spacing of 13 cM. Because obesity and type 2 diabetes mellitus are interrelated, the data set was stratified for the subphenotype body mass index, corrected for age and gender. This resulted in a suggestive maximum multipoint LOD score of 2.3 (single-point P value, 9.7 × 10−4; genome-wide P value, 0.028) for the most obese 20% pedigrees of the data set, between marker loci D18S471 and D18S843. In the lowest 80% obese pedigrees, two interesting loci on chromosome 2 and 19 were found, with LOD scores of 1.5 and 1.3. We provide independent evidence that the chromosome 18p11 locus, reported earlier from a Finnish/Swedish population, is of definite interest for type 2 diabetes mellitus in connection with obesity. Subsequently, our results indicate that two novel loci may reside on chromosomes 2 and 19, with minor effects involved in the development of type 2 diabetes mellitus in the Dutch population.
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