Infrequent and rare genetic variants in the human population vastly outnumber common ones. Although they may contribute significantly to the genetic basis of a disease, these seldom-encountered variants may also be miss-identified as pathogenic if no correct references are available. Somatic and germline TP53 variants are associated with multiple neoplastic diseases, and thus have come to serve as a paradigm for genetic analyses in this setting. We searched 14 independent, globally distributed datasets and recovered TP53 SNPs from 202,767 cancer-free individuals. In our analyses, 19 new missense TP53 SNPs, including five novel variants specific to the Asian population, were recurrently identified in multiple datasets. Using a combination of in silico, functional, structural, and genetic approaches, we showed that none of these variants displayed loss of function compared to the normal TP53 gene. In addition, classification using ACMG criteria suggested that they are all benign. Considered together, our data reveal that the TP53 coding region shows far more polymorphism than previously thought and present high ethnic diversity. They furthermore underline the importance of correctly assessing novel variants in all variant-calling pipelines associated with genetic diagnoses for cancer.
Colorectal cancer (CRC) is a complex disease that develops as a consequence of both genetic and environmental risk factors in interplay with epigenetic mechanisms, such as microRNAs (miRNAs). CRC cases are predominantly sporadic in which the disease develops with no apparent hereditary syndrome. The last decade has seen the progress of genome-wide association studies (GWAS) that allowed the discovery of several genetic regions and variants associated with weak effects on sporadic CRC. Collectively these variants may enable a more accurate prediction of an individual's risk to the disease and its prognosis. However, the number of variants contributing to CRC is still not fully explored.SNPs in genes encoding the miRNA sequence or in 3'UTR regions of the corresponding binding sites may affect miRNA transcription, miRNA processing, and/or the fidelity of the miRNA-mRNA interaction. These variants could plausibly impact miRNA expression and target mRNA translation into proteins critical for cellular integrity, differentiation, and proliferation.In the present chapter, we describe the different aspects of variations related to miRNAs and other non-coding RNAs (ncRNAs) and evidence from studies investigating these candidate genetic alterations in support to their role in CRC development and progression.
- MeSH
- 3' Untranslated Regions genetics MeSH
- Genome-Wide Association Study MeSH
- Epigenesis, Genetic MeSH
- Genetic Predisposition to Disease MeSH
- Gene-Environment Interaction MeSH
- Polymorphism, Single Nucleotide * MeSH
- Cocarcinogenesis MeSH
- Colorectal Neoplasms diagnosis epidemiology genetics MeSH
- Humans MeSH
- MicroRNAs genetics MeSH
- RNA, Untranslated genetics MeSH
- Polyadenylation MeSH
- Prognosis MeSH
- Disease Progression MeSH
- Gene Expression Regulation, Neoplastic genetics MeSH
- Risk Factors MeSH
- RNA, Neoplasm genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
HtrA serine peptidase 3 (HTRA3) is an important reproduction-related gene. In this study, we cloned the full-length coding sequence of the porcine HTRA3 gene using RT-PCR. Sequence analysis of this gene revealed that the pig HTRA3 gene encodes a protein of 453 amino acids, which has high homology with the HTRA3 protein of five species: water buffalo (96 %), killer whale (96 %), sperm whale (96 %), Yangtze River dolphin (96 %) and smalleared galago (93 %). Phylogenetic analysis revealed that the pig HTRA3 gene has a closer genetic relationship with the HTRA3 gene of cattle. PCR-HpaIIRFLP was established to detect the GU373693:c.1140 G>A substitution of the porcine HTRA3 gene coding sequence, and eight pig breeds displayed obvious genotype and allele frequency differences at this mutation locus. Association of this SNP with litter size traits was assessed in Large White (N = 200) and Landrace (N = 200) pig populations, and the results demonstrated that this polymorphic locus was significantly associated with the litter size of all parities in Large White and Landrace sows (P < 0.05). Therefore, the HTRA3 gene could be a useful candidate for increasing the litter size in pigs. These data serve as a foundation for further insight into this novel porcine gene.
- MeSH
- Gene Frequency MeSH
- Phylogeny MeSH
- Genotype MeSH
- Polymorphism, Single Nucleotide genetics MeSH
- Cloning, Molecular MeSH
- Polymerase Chain Reaction MeSH
- Swine MeSH
- Sequence Analysis, DNA MeSH
- Serine Endopeptidases genetics metabolism MeSH
- Cattle MeSH
- Litter Size MeSH
- Animals MeSH
- Check Tag
- Cattle MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Nod-like receptors (NLRs) are important innate pattern recognition receptors and regulators of inflammation or play a role during development. We systematically analysed 41 non-synonymous single nucleotide polymorphisms (SNPs) in 21 NLR genes in a Czech discovery cohort of sporadic colorectal cancer (CRC) (1237 cases, 787 controls) for their association with CRC risk and survival. Five SNPs were found to be associated with CRC risk and eight with survival at 5% significance level. In a replication analysis using data of two large genome-wide association studies (GWASs) from Germany (DACHS: 1798 cases and 1810 controls) and Scotland (2210 cases and 9350 controls) the associations found in the Czech discovery set were not confirmed. However, expression analysis in human gut-related tissues and immune cells revealed that the NLRs associated with CRC risk or survival in the discovery set were expressed in primary human colon or rectum cells, CRC tissue and/or cell lines, providing preliminary evidence for a potential involvement of NLRs in general in CRC development and/or progression. Most interesting was the finding that the enigmatic development-related NLRP5 (also known as MATER) was not expressed in normal colon tissue but in colon cancer tissue and cell lines. Future studies may show whether regulatory variants instead of coding variants might affect the expression of NLRs and contribute to CRC risk and survival.
- MeSH
- Survival Analysis MeSH
- Genetic Predisposition to Disease MeSH
- Genetic Variation * MeSH
- Genetic Association Studies * MeSH
- Hematopoiesis genetics MeSH
- Polymorphism, Single Nucleotide genetics MeSH
- Colorectal Neoplasms genetics MeSH
- Humans MeSH
- NLR Proteins genetics MeSH
- Open Reading Frames genetics MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Risk Factors MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Geographicals
- Czech Republic MeSH
OBJECTIVE AND DESIGN: Prosthetic joint infection (PJI) is a severe complication of total joint arthroplasty (TJA). We conducted a genetic association study that investigated whether selected coding variants of the genes for Toll-like receptors (TLR)2 and TLR4 may contribute to genetic susceptibility for PJI. SUBJECTS AND METHODS: In total, 350 patients with TJA (98 with PJI/252 without PJI), and 189 unrelated healthy Czech individuals without TJA were enrolled in our study. Three missense polymorphisms of the genes encoding for TLR2 (TLR2 R753Q, rs5743708) and TLR4 (TLR4 D299G, rs4986790 and T399I, rs4986791) were genotyped by "TaqMan" assay. RESULTS: The frequencies of less common variants for the investigated TLR2/TLR4 polymorphisms in healthy individuals were similar to those observed in other Caucasian populations. Importantly, the distribution of TLR2/TLR4 genotype alleles did not differ between the patients with PJI and the control groups of patients with nonseptic prostheses/healthy individuals. CONCLUSION: Our data suggest that structural genetic variants of the receptors TLR2 and TLR4 do not substantially affect the risk of prosthetic joint infection.
- MeSH
- Arthroplasty MeSH
- Prosthesis-Related Infections genetics MeSH
- Infections MeSH
- Polymorphism, Single Nucleotide MeSH
- Joints surgery MeSH
- Middle Aged MeSH
- Humans MeSH
- Prostheses and Implants adverse effects MeSH
- Aged MeSH
- Staphylococcal Infections genetics MeSH
- Staphylococcus MeSH
- Toll-Like Receptor 2 genetics MeSH
- Toll-Like Receptor 4 genetics MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Located in the Sudan belt, the Chad Basin forms a remarkable ecosystem, where several unique agricultural and pastoral techniques have been developed. Both from an archaeological and a genetic point of view, this region has been interpreted to be the center of a bidirectional corridor connecting West and East Africa, as well as a meeting point for populations coming from North Africa through the Saharan desert. METHODOLOGY/PRINCIPAL FINDINGS: Samples from twelve ethnic groups from the Chad Basin (n = 542) have been high-throughput genotyped for 230 coding region mitochondrial DNA (mtDNA) Single Nucleotide Polymorphisms (mtSNPs) using Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight (MALDI-TOF) mass spectrometry. This set of mtSNPs allowed for much better phylogenetic resolution than previous studies of this geographic region, enabling new insights into its population history. Notable haplogroup (hg) heterogeneity has been observed in the Chad Basin mirroring the different demographic histories of these ethnic groups. As estimated using a Bayesian framework, nomadic populations showed negative growth which was not always correlated to their estimated effective population sizes. Nomads also showed lower diversity values than sedentary groups. CONCLUSIONS/SIGNIFICANCE: Compared to sedentary population, nomads showed signals of stronger genetic drift occurring in their ancestral populations. These populations, however, retained more haplotype diversity in their hypervariable segments I (HVS-I), but not their mtSNPs, suggesting a more ancestral ethnogenesis. Whereas the nomadic population showed a higher Mediterranean influence signaled mainly by sub-lineages of M1, R0, U6, and U5, the other populations showed a more consistent sub-Saharan pattern. Although lifestyle may have an influence on diversity patterns and hg composition, analysis of molecular variance has not identified these differences. The present study indicates that analysis of mtSNPs at high resolution could be a fast and extensive approach for screening variation in population studies where labor-intensive techniques such as entire genome sequencing remain unfeasible.
- MeSH
- Biodiversity MeSH
- Phylogeny MeSH
- Genotype * MeSH
- Polymorphism, Single Nucleotide * MeSH
- DNA, Mitochondrial genetics MeSH
- Population Dynamics MeSH
- Fresh Water MeSH
- Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Czech Republic MeSH
Haploinsufficiency of FOXF1 causes alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a lethal neonatal lung developmental disorder. We describe two similar heterozygous CNV deletions involving the FOXF1 enhancer and re-analyze FOXF1 missense mutation, all associated with an unexpectedly mitigated disease phenotype. In one case, the deletion of the maternal allele of the FOXF1 enhancer caused pulmonary hypertension and histopathologically diagnosed MPV without the typical ACD features. In the second case, the deletion of the paternal enhancer resulted in ACDMPV rather than the expected neonatal lethality. In both cases, FOXF1 expression in lung tissue was higher than usually seen or expected in patients with similar deletions, suggesting an increased activity of the remaining allele of the enhancer. Sequencing of these alleles revealed two rare SNVs, rs150502618-A and rs79301423-T, mapping to the partially overlapping binding sites for TFAP2s and CTCF in the core region of the enhancer. Moreover, in a family with three histopathologically-diagnosed ACDMPV siblings whose missense FOXF1 mutation was inherited from the healthy non-mosaic carrier mother, we have identified a rare SNV rs28571077-A within 2-kb of the above-mentioned non-coding SNVs in the FOXF1 enhancer in the mother, that was absent in the affected newborns and 13 unrelated ACDMPV patients with CNV deletions of this genomic region. Based on the low population frequencies of these three variants, their absence in ACDMPV patients, the results of reporter assay, RNAi and EMSA experiments, and in silico predictions, we propose that the described SNVs might have acted on FOXF1 enhancer as hypermorphs.
- MeSH
- Child MeSH
- Adult MeSH
- Phenotype MeSH
- Forkhead Transcription Factors genetics MeSH
- Genomic Imprinting MeSH
- Polymorphism, Single Nucleotide * MeSH
- Humans MeSH
- Mutation, Missense * MeSH
- Infant, Newborn MeSH
- Prognosis MeSH
- Sequence Deletion * MeSH
- Persistent Fetal Circulation Syndrome genetics pathology prevention & control MeSH
- Enhancer Elements, Genetic * MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Humans MeSH
- Infant, Newborn MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.
- MeSH
- Genome-Wide Association Study MeSH
- DNA MeSH
- Carcinoma, Pancreatic Ductal * genetics MeSH
- Genetic Predisposition to Disease MeSH
- Genome, Human MeSH
- Polymorphism, Single Nucleotide genetics MeSH
- Humans MeSH
- Pancreatic Neoplasms * genetics pathology MeSH
- Case-Control Studies MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
OBJECTIVES: ATP-Binding Cassette (ABC) transporters may cause treatment failure by transporting of anticancer drugs outside of the tumor cells. Multidrug resistance-associated protein 1 coded by the ABCC1 gene has recently been suggested as a potential prognostic marker in breast cancer patients. This study aimed to explore tagged haplotype covering nucleotide binding domain 1 of ABCC1 in relation with corresponding transcript levels in tissues and clinical phenotype of breast cancer patients. METHODS: The distribution of twelve ABCC1 polymorphisms was assessed by direct sequencing in peripheral blood DNA (n = 540). RESULTS: Tumors from carriers of the wild type genotype in rs35623 or rs35628 exhibited significantly lower levels of ABCC1 transcript than those from carriers of the minor allele (p = 0.003 and p = 0.004, respectively). The ABCC1 transcript levels significantly increased in the order CT-GT>CC-GT>CC-GG for the predicted rs35626-rs4148351 diplotype. Chemotherapy-treated patients carrying the T allele in rs4148353 had longer disease-free survival than those with the GG genotype (p = 0.043). On the other hand, hormonal therapy-treated patients with the AA genotype in rs35628 had significantly longer disease-free survival than carriers of the G allele (p = 0.012). CONCLUSIONS: Taken together, our study shows that genetic variability in the nucleotide binding domain 1 has a significant impact on the ABCC1 transcript level in the target tissue and may modify survival of breast cancer patients.
- MeSH
- Survival Analysis * MeSH
- Polymorphism, Single Nucleotide * MeSH
- Middle Aged MeSH
- Humans MeSH
- RNA, Messenger genetics MeSH
- Breast Neoplasms genetics physiopathology MeSH
- Multidrug Resistance-Associated Proteins genetics metabolism MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also indicates a role of ghrelin in cancer development. METHODS: We conducted a case-control study to examine the association of common genetic variants in the genes coding for ghrelin (GHRL) and its receptor (GHSR) with colorectal cancer risk. Pairwise tagging was used to select the 11 polymorphisms included in the study. The selected polymorphisms were genotyped in 680 cases and 593 controls from the Czech Republic. RESULTS: We found two SNPs associated with lower risk of colorectal cancer, namely SNPs rs27647 and rs35683. We replicated the two hits, in additional 569 cases and 726 controls from Germany. CONCLUSION: A joint analysis of the two populations indicated that the T allele of rs27647 SNP exerted a protective borderline effect (Ptrend = 0.004).
- MeSH
- Alleles MeSH
- Child MeSH
- DNA, Neoplasm genetics MeSH
- Adult MeSH
- Genetic Predisposition to Disease MeSH
- Ghrelin genetics metabolism MeSH
- Incidence MeSH
- Colorectal Neoplasms epidemiology genetics metabolism MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Polymorphism, Genetic * MeSH
- Receptors, Ghrelin genetics metabolism MeSH
- Retrospective Studies MeSH
- Risk Factors MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Geographicals
- Czech Republic MeSH
- Germany MeSH
