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Results for “fine-mapping”

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PubMed2002

Interval and composite interval mapping of somatic cell score, yield, and components of milk in dairy cattle.

Single-marker, interval-mapping (IM) and composite interval mapping (CIM) were used to detect quantitative trait loci (QTL) controlling milk, fat and protein yields, and somatic cell score (SCS). A granddaughter design was used to combine molecular genetic information with predicted transmitting abilities (PTA) and estimated daughter yield deviations (DYD) from eight Dairy Bull DNA Repository Holstein families. Models that included and excluded weights accounting for the uncertainty of the response variable were evaluated in each trait, family and phenotype (DYD and PTA) combination. The genotypic information consisted of 174 microsatellite markers along 29 Bos taurus autosomes. The average number of informative markers per autosome was three and the number of informative sons per family and marker varied between 21 and 173. Within-family results from the least squares single-marker analyses were used in expectation-maximization likelihood IM and CIM implemented with QTL Cartographer. Different CIM model specifications, offering complementary control on the background QTL outside the interval under study, were evaluated. Permutation techniques were used to calculate the genome-wide threshold test statistic values based on 1,000 samples. Results from the DYD and PTA analyses were highly consistent across traits and families. The minor differences in the estimates from the models that accounted for or ignored the uncertainty of the DYD (variance) and PTA (inverse of reliability) may be associated to the elevated and consistent precision of the DYD and PTA among sons. The CIM model best supported by the data had 10 markers controlling for background effects. On autosome (BTA) three, a QTL at 32 cM influencing protein yield was located in family five and a QTL at 74 cM for fat yield was located in family eight. Two map positions associated with SCS were detected on BTA 21, one at 33 cM in family one and the other at 84 cM in family three. A QTL for protein yield was detected between 26 and 36 cM on BTA six, family six, and a QTL for milk yield was detected at 116 cM on BTA seven in family three. The IM and CIM approaches detected a QTL at 3 cM on BTA 14 influencing fat yield in family four. Two map positions on BTA 29 were associated with significant variation of milk (0 cM) and fat yield (14 cM) in family seven. These results suggest the presence of one QTL with pleiotropic effects on multiple traits or multiple QTL within the marker interval. Findings from this study could be used in subsequent fine-mapping work and applied to marker-assisted selection of dairy production and health traits.

Animals↗

PubMed2026

Integrative cross-tissue transcriptome-wide association and metabolomic analysis reveals novel genetic risk loci for aortic aneurysm.

BACKGROUND: Aortic aneurysm (AA) is a life-threatening cardiovascular condition with a strong genetic component, however, its molecular mechanisms remain poorly understood. Although genome-wide association studies (GWAS) have identified numerous risk loci, most prior studies have investigated genetic and metabolic factors separately, leaving the causal pathways from genetic variants to disease largely unexplored. METHODS: We established an integrative framework combining cross-tissue transcriptome-wide association studies (TWAS) with metabolomic mediation analysis. First, we integrated GWAS data from FinnGen R12 with multi-tissue expression quantitative trait loci (eQTL) data from Genotype-Tissue Expression Project (GTEx) V8, then performed cross-tissue TWAS using the Unified Test for MOlecular SignaTures (UTMOST) and single-tissue validation with the Functional Summary-based Imputation (FUSION) to prioritize susceptibility genes. Second, we applied Mendelian randomization (MR), colocalization, and Fine-mapping Of CaUsal gene Sets (FOCUS) to assess causality and identify high-confidence genes. Third, we performed metabolite mediation analysis to uncover metabolic pathways linking genetic variants to disease risk. Finally, we validated key findings in mouse models of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) using Quantitative Real-Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) and Western blotting. RESULTS: We identified multiple novel susceptibility genes for AA and its subtypes. Key genes included ADH family members (ADH1A, ADH1B, ADH4, ADH6) and ZNF827, which showed cross-subtype associations with strong colocalization evidence in vascular tissues. Metabolite mediation analysis revealed significant pathways involving N-acetylphenylalanine and methionine sulfoxide. Functional enrichment revealed distinct biological mechanisms: AA and AAA were primarily associated with metabolic pathways, whereas TAA-related genes were enriched in developmental and contractile processes. PheWAS indicated no significant off-target associations. Critically, experimental validation in mouse models confirmed significant upregulation of ZNF827 in TAA and ADH6 in AAA at both mRNA and protein levels, corroborating the genetic predictions. CONCLUSION: This integrated cross-omics analysis identifies novel genetic loci and, crucially, uncovers specific nutrient-related metabolic pathways that mediate genetic risk. These findings provide a mechanistic basis for future nutritional and metabolic intervention studies in AA and its subtypes.

MAGMA↗

PubMed2005

Functional role of C-terminal sequence elements in the transporter associated with antigen processing.

TAP delivers antigenic peptides into the endoplasmic reticulum (ER) that are subsequently bound by MHC class I molecules. TAP consists of two subunits (TAP1 and TAP2), each with a transmembrane (TMD) and a nucleotide-binding (NBD) domain. The two TAP-NBDs have distinct biochemical properties and control different steps during the peptide translocation process. We noted previously that the nonhomologous C-terminal tails of rat TAP1 and TAP2 determine the distinct functions of TAP-NBD1 and -NBD2. To identify the sequence elements responsible for the asymmetrical NBD function, we constructed chimeric rat TAP variants in which we systematically exchanged sequence regions of different length between the two TAP-NBDs. Our fine-mapping studies demonstrate that a nonhomologous region containing the alpha6/beta10-loop in conjunction with the downstream switch region is directly responsible for the functional separation of the TAP-NBDs. The alpha6/beta10-loop determines the nonsynonymous nucleotide binding of NBD1 and NBD2, whereas the switch region seems to play a critical role in regulating the functional cross-talk between the structural domains of TAP. Based on our findings, we postulate that these two sequence elements build a minimal functional unit that controls the asymmetry of the two TAP-NBDs.

ATP-Binding Cassette Transporters↗

PubMed2026

FM-GPT: Bayesian fine mapping for phenome-wide transcriptome-wide association studies.

Transcriptome-wide association studies (TWAS) integrate genome wide association studies with expression quantitative trait locus reference panels to identify genes associated with traits of interest. However, linkage disequilibrium and correlated gene expression can induce spurious TWAS signals, motivating fine mapping methods to prioritize putatively causal genes within associated loci. The rapid growth of large-scale phenomic resources (e.g. electronic health records (EHRs)) has shifted genetic studies from single-trait analyses to phenome-wide investigations that jointly evaluate many closely related phenotypes. We introduce FM-GPT (Fine-mapping of causal Genes for Phenome-wide Transcriptome-wide association studies), a novel Bayesian fine mapping method for prioritizing causal genes across multiple correlated phenotypes with potentially mixed outcome types (e.g., binary, count or continuous) in phenome-wide TWAS. FM-GPT performs gene-guided dimension reduction of the phenotypes and reveals pleiotropic or phenotype-specific effects of the identified genes. In simulations, FM-GPT identified true causal genes more accurately than other fine mapping methods while controlling false positives. We applied FM-GPT to two applications using data from UK Biobank: a brain-wide genetic analysis of MRI data derived regional cortical thickness measures and a phenome-wide genetic analysis of clinical phenotypes derived from EHR data. FM-GPT greatly narrowed down the set size of putatively causal genes and identified: 1. genes with pleiotropic effects on regional cortical thickness across the cerebral cortex, including five genes BCAS3, LRRC37A, NOS2P3, ARL17B and UBB on chromosome 17 regulating neuronal morphology and cortical organization; and 2. genes that influence multiple medical conditions across the circulatory, metabolic, digestive, respiratory and genitourinary systems, revealing two major axes of variation among these conditions that point to a potential trade-off in gene regulation between immune and metabolic functions. These results highlight FM-GPT's power to disentangle complex gene-phenotype relationships in large-scale phenome-wide studies, uncovering shared biological mechanisms across diverse human traits and advancing translational and comorbidity research.

Bayesian fine mapping↗

PubMed2026

Developmental patterning of adipose tissue by abd-A and Abd-B homeotic genes in Drosophila melanogaster.

The Bithorax Complex (BX-C) homeobox proteins specify segmental identities along the anterior-posterior axis during Drosophila embryogenesis. Differential expression of the BX-C genes abd-A and Abd-B distinguishes abdominal from thoracic adipocytes, yet the mechanism regulating this heterogeneity remains poorly understood. Here, we identify cis-regulatory elements (CREs) and transcription factors that direct abdominal-specific expression of abd-A and Abd-B in the larval fat body. Fine-mapping analyses identified a 627-bp CRE within the Abd-B locus and a ~6-kb CRE within the abd-A locus sufficient to drive heterogeneous expression. Yeast one-hybrid screening combined with functional analyses identified Lola, Lolal, and Combgap as key repressors of Abd-B, whereas Piragua (Prg) and Seven up (Svp) function as transcriptional activators, indicating that adipocyte heterogeneity in postembryonic adipose tissue is actively regulated. In turn, lola and prg are repressed by Abd-B, whereas lolal and svp are activated, forming a feedback circuit further modulated by Wnt signaling, which promotes lola and lolal expression while repressing svp. CUT&RUN analyses suggest that these interactions are direct, with dTCF/Pan and Abd-B occupancy detected at target loci. Together, our findings define a transcriptional circuit that regulates Abd-B gene transcription to pattern adipose tissue and may establish the developmental basis of fat depot specialization.

Abd-B↗

PubMed2026

Multimodal atlas of human atherosclerosis links granular vascular cell states to coronary artery disease risk.

Advances in single-cell and spatial assays have revolutionized the scale and resolution of molecular tissue profiling. Here we present MetaPlaq, a multimodal atlas of human atherosclerotic arterial beds comprising over a million cells across single-cell transcriptomics, epigenomics and high-resolution spatial expression assays. We map granular cell states and disease-relevant transcriptional programs within the native tissue context of coronary arteries. Furthermore, we map cardiovascular GWAS signals to smooth muscle cells (SMCs) and endothelial cells (ECs) and uncover the cis-regulatory architecture governing their phenotypic transitions. Our comprehensive epigenomic reference allowed us to build cell-specific enhancer-gene link maps and multimodal gene regulatory networks (GRNs) underlying disease-relevant states such as osteogenic SMCs and ECs undergoing mesenchymal transition. We also integrate SMC and EC disease-associated gene sets with GRNs to nominate key transcription factors such as PRRX1, BNC2 and ELK3 regulating atherosclerosis-relevant transcriptional programs. Finally, we layer single-cell and spatial modalities to fine-map GWAS variants with improved cell and anatomical context. We highlight candidate cell-specific regulatory mechanisms at less characterized CAD loci, including FGD5 and MCF2L in ECs. Together, this atlas represents an important step towards fully interpreting genetic risk loci and informing new therapeutic strategies for cardiovascular disease.

Journal Article↗

PubMed2026

Integrating multi-ancestry common and rare variant mapping accelerates therapeutic target discovery.

Integrating human genetics into therapeutic discovery accelerates drug development. However, ancestral biases in historical cohorts have left critical functional variation largely uncharted. Here, we leverage the diverse NIH All of Us Research Program to conduct comprehensive common- and rare-variant association analyses for 624 quantitative traits across 369,655 ancestrally diverse individuals. We identified 6,181 genome-wide significant locus-trait associations (526 novel) and 416 gene-trait associations (105 novel) via rare-variant burden testing. By integrating fine-mapping with computational variant-effect predictors, we systematically prioritized rare, likely causal variants driving these signals. Jointly modeling common and rare variation with protein-class annotations significantly improved the identification of known drug targets compared to common-variant analysis alone. Notably, we identified NRG4 as a high-confidence candidate therapeutic target for preserving kidney function. Our findings demonstrate that characterization of rare and common variation across diverse populations enhances causal gene discovery and identifies novel, actionable therapeutic targets.

Journal Article↗

PubMed2003

Fine mapping and identification of candidate pulmonary adenoma susceptibility 1 genes using advanced intercross lines.

In the present study, we used newly developed F(11) generation mouse advanced intercross lines (AIL) to fine map Pas1-3 quantitative trait loci (QTL). The (A/J x C57BL/6) F(11) AIL mouse population was created by crossing lung tumor-resistant C57BL/6 mice with lung tumor-susceptible A/J mice. By selectively genotyping 30% of the population, we have confirmed the Pas1 QTL and narrowed it to an interval of approximately 1.0 cM or 1.3 Mb in the vicinity of the Kras2 gene. The Pas2 QTL was detected by both ANOVA and regression analysis but not by MapMaker EXP/QTL software. In addition, an interaction between the Pas1 and Pas2 QTLs was revealed. However, the Pas3 QTL was not confirmed in this study. It was either lost during the development of the AIL or too weak to be detected using AIL. The Pas1 locus is now sufficiently fine-mapped that candidate gene(s) for the Pas1 locus can be characterized by positional cloning. In this study, all 27 of the known or predicted genes located in the Pas1 candidate region were characterized as possible candidate Pas genes. Six genes were selected for additional analyses because of their relevant function in tumorigenesis or allelic changes between A/J and C57BL/6 mice. The Lrmp gene bears amino acid polymorphisms among various mouse strains that are highly correlated with the Pas1 allele status. The Pas1c1 gene (RIKEN Ak016641), encoding an intermediate filament tail domain-containing protein, produces alternatively spliced transcripts across inbred strains of mice, and its splicing pattern cosegregates with the Pas1 allele. The genetic and expression data support these two genes as strong candidates for the Pas1 locus. Of the other four genes (Eca39, RIKEN Ak015530, mHoj-1, and Krag), no functional polymorphisms or differential gene expression were found in Eca39, mHoj-1, and Krag between lung tumor-susceptible and -resistant strains. The Ak015530 carries an amino acid polymorphism, but this polymorphism does not cosegregate with mouse lung tumor susceptibility. Thus, these 4 genes are less likely candidates for the Pas1 locus.

Adenoma↗

PubMed2001

Large-scale analysis of sequence tags in Xp11.4-11.3 and evaluation of candidate genes for X-linked ocular diseases.

The gene-rich region of Xp11.4-Xp11.3 was characterized by increasing the physical marker density. Sequence tags (STSs) were generated by IRS- and DOP-PCR techniques, subsequent cloning, sequencing, and creation of primer pairs for single-copy sites. A total of 224 novel STSs were collected, providing an average marker density of 18 kb in the Xp11.4-Xp11.3 region which is assumed to be approximately 4 Mb in size. Sequence analysis of generated and established STSs via data base searches identified a novel gene highly homologous with the protein phosphatase 1 inhibitor 2 (IPP-2) and two pseudogenes; all of which map to the approximately 1.5 Mb proximal region of the critical region for X-linked congenital stationary night blindness type I (CSNB1) between markers DXS993 and DXS228. Using well-defined DNA panels, 69 STSs were fine-mapped to this approximately 1.5 Mb region, providing a marker coverage of one marker per 22 kb. No allelic loss was observed when the total STS content was applied to patient DNAs by PCR-mediated amplification. However, given the association of this region with a number of inherited ocular diseases, the data presented here provide valuable tools for genetic linkage and large-scale association studies.

Journal Article↗

PubMed2004

The ldis1 lens mutation in RIIIS/J mice maps to chromosome 8 near cadherin 1.

PURPOSE: We have discovered a spontaneous and severe mutation that leads to partial or complete disruption of the lens and cataract in the RIIIS/J inbred strain of mice. The purpose of this study was to determine the mode of inheritance, specificity, and range of phenotypes using histological, ophthalmic, quantitative electron microscopic, and microarray-based methods. We also have fine-mapped the mutation, ldis1 (lens disrupter 1), and have evaluated positional candidate genes. METHODS: Eyes from mutant RIIIS/J animals and from an F2 intercross between RIIIS/J and DBA/2J were examined and scored to map the ldis1 mutation. Axons in the optic nerve were counted. Messenger RNA from mutant eyes was hybridized to Affymetrix short oligomer microarrays and compared to five control strains. Expression differences were used to evaluate molecular sequellae of the mutation. RESULTS: Mice that are homozygous for ldis1 have small eyes. Lenses are without exception opaque, deformed, dislocated, fragmented, and small. In contrast, retinal architecture and ganglion cell numbers are within normal range. We have not detected any other ldis1-associated ocular or systemic abnormalities. ldis1 is recessive and maps to chromosome 8 at about 106.5 Mb between D8Mit242 and D8Mit199 with a peak LOD score near cadherin 1. The homologous human chromosomal interval is 16q22.1. The expression of several downstream crystallin transcripts are severely affected in the mutant, as are the expression levels of multiple members of the transforming growth factor superfamily and the glutathione S-transferases. CONCLUSIONS: We have discovered and mapped a recessive mutation to mouse chromosome 8 between 105 and 109 Mb. Homozygous mutant mice have a selective and severe effect on lens integrity. On the basis of the phenotype and the locus position, several candidate genes have been identified.

Animals↗

PubMed2002

Genetic regulation of bone mineral density in mice.

Peak bone mass is a major determinant of risk of osteoporotic fracture. Family and twin studies have found a strong genetic component to the determination of bone mineral density (BMD). However, BMD is a complex trait whose expression is confounded by environmental influences and polygenic inheritance. The number, locations and effects of the individual genes contributing to natural variation in this trait are all unknown. The extreme difficulty of dissecting out environmental factors from genetic ones in humans has motivated the investigation of animal models. Genetically distinct animal strains raised under strict environmental control are critical tools for defining genetic regulation. The availability of inbred strains, combined with its relative fecundity, has established the mouse as the best model system for the study of mammalian genetics and physiology. Importantly, genes identified in murine analyses can usually be readily mapped to particular human chromosomal regions because of the high degree of synteny that exists between the mouse and human genomes. We employed quantitative trait locus (QTL) analysis to examine peak BMD in 24 recombinant inbred (RI) mouse strains, derived from a cross between C57BL/6 (B6) and DBA/2 (D2) progenitors (BXD RI). The distribution of BMD values among these strains clearly indicated the presence of strong genetic influences, with an estimated narrow sense heritability of 35%. The differences in peak whole body BMD in the BXD strains were integrated with a large database of genetic markers previously defined in the RI BXD strains to generate chromosome map sites for QTL locations. This QTL analysis provisionally identified a number of chromosomal sites linked to BMD. In the second phase of our BMD QTL mapping efforts, we used three independent mouse populations (all derived from B6 and D2 progenitor strains) to confirm and narrow the genetic locations of 4 QTLs (on chromosomes 1, 2, 4, and 11) that strongly influence the acquisition of peak BMD in mice. Using a novel, fine-mapping approach (recombinant inbred segregation testing), we have succeeded in narrowing two of the BMD-related chromosomal regions and in the process eliminated a number of candidate genes. The homologous regions in the human genome for each of these murine QTLs have been identified in recent human genetic studies. In light of this, we believe that findings in mice should aid in the identification of specific candidate genes for study in humans.

Journal Article↗

PubMed2005

Multiple sclerosis: a haplotype association study.

Results are presented from a genomewide haplotype association study on multiple sclerosis (MS) cases from Tasmania, an island state of Australia. Cases were ascertained on strict clinical and radiological grounds and on the fact that they had at least one grandparent born in the state. This enriched for early settler chromosomes among present day Tasmanians with MS and increased the chances of finding common haplotype sharing at disease predisposition loci in distant relatives sharing common ancestral haplotypes. Four-to-five close relatives were also collected for each of 170 cases and 105 population-based controls. All were genotyped at a 5cM resolution, haplotypes reconstructed and sharing estimated using an empirical approach based on sorting haplotypes to find the most common at each locus and then generating a test statistic for excess sharing in the cases based on permutation testing. Five initial loci were found where there was an excess sharing in the cases. These were fine-mapped with 10-12 additional markers. Only loci on chromosomes 6 and 10 remained after fine mapping. These loci demonstrate an increase in sharing of multi-marker haplotypes in MS cases compared to both population control transmitted haplotypes and case non-transmitted haplotypes.

Haplotypes↗

PubMed1991

Development of a system for efficient chromosome walking in Arabidopsis.

The small genome size of Arabidopsis and the low level of repetitive DNA sequences make this crucifer an attractive system for chromosome walking to isolate genes. Mapping of a mutant locus relative to restriction fragment length polymorphism (RFLP) markers provides the first step towards isolating the corresponding gene. The RFLP marker closest to the target gene serves as a starting point. The distance between gene and marker is generally in the range of 50-200 kb. In order to facilitate chromosome walking of this magnitude, we constructed a yeast artificial chromosome (YAC) library of Arabidopsis. Large fragments of Arabidopsis DNA were cloned into a YAC vector and transformed into yeast. The library contains more than 10 equivalents of the Arabidopsis genome. YACs containing sequences of RFLP markers of Arabidopsis revealed an average insert size of 150 kb. Thus, 1-3 (contiguous) YACs should be sufficient to clone genes from Arabidopsis by chromosome walking. In order to use the system to isolate genes involved in the signal transduction of abscisic acid, we fine-mapped the mutant loci abi-1 and abi-2, which confer abscisic acid insensitivity, relative to RFLPs and isolated the corresponding YACs.

Abscisic Acid↗

PubMed1995

Humoral responses to linear epitopes on the HIV-1 envelope in seropositive volunteers after vaccine therapy with rgp160.

Humoral responses to the HIV-1 envelope were investigated in 30 human volunteers enrolled in a phase I vaccine therapy trial of rgp160 (LAI/LAV) using two techniques that emphasize detection of antibody response against linear (continuous) epitopes: immunoblotting and PEPSCAN. Seven fusion proteins containing large portions from constant regions 1, 2, 3, and 5, and variable region 3 of gp120 and two regions in the transmembrane protein, gp41, were employed in immunoblots to quantitatively measure immune response as a function of immunization. In addition, the entire gp160 (LAI/LAV) envelope protein was constructed in duplicate sets of 211 overlapping 12-mer peptides to fine-map the changes. Immunoblotting defined significant changes in reactivity to epitopes in constant regions; of 28 volunteers completing the trial, the percentage with reactivity against C1 changed from 62 to 100%; for C2, from 0 to 46%; for C3, from 0 to 82%; and for a constant region in gp41, from 25 to 68%. PEPSCAN on a subset (n = 8) of these volunteers identified new reactivity to epitopes throughout the envelope, concentrated in V1, C3, and C5 in gp120 and several peptides in gp41. Completely immunized patients responded to double the number of linear epitopes compared with two patients receiving alum alone. The results verify that the response to rgp160 is significantly broadened after immunization, providing additional evidence that HIV-1-infected volunteers can expand their antibody repertoire against a protein from a pathogen during chronic infection with that same pathogen. These results expand those previously obtained in this patient cohort, by defining explicitly the immunogenic regions recognized postvaccination and by providing methodology for quantitating those changes.

AIDS Vaccines↗

PubMed1993

Confirmation of chromosome 9p linkage in familial melanoma.

Malignant melanoma occurs as a familial cancer in 5%-10% of cases where it segregates in a manner consistent with autosomal dominant inheritance. Evidence from cytogenetics, fine-mapping studies of deletions in melanomas, and recent linkage studies supports the location of a human melanoma predisposition gene on the short arm of chromosome 9. We have carried out linkage analysis using the 9p markers IFNA and D9S126 in 26 Australian melanoma kindreds. Multipoint analysis gave a peak lod score of 4.43, 15 cM centromeric to D9S126, although a lod score of 4.13 was also found 15 cM telomeric of IFNA. These data confirm the existence of a melanoma susceptibility gene on 9p and indicate that this locus most probably lies outside of the IFNA-D9S126 interval. No significant heterogeneity was found between families, when either pairwise or multipoint data were analyzed using HOMOG.

Adult↗

PubMed1997

Loss of heterozygosity studies and deletion mapping identify two putative chromosome 14q tumor suppressor loci in renal oncocytomas.

Renal oncocytoma is considered to be a benign tumor that shares some phenotypic features with chromophobe renal cell carcinoma (RCC). Recently, we described high frequencies of allelic loss at 1p, 2p, 6p, 10p, 13q, 14q, 17p, and 21q, which correlate significantly with the chromophobe subtype of RCC. To investigate the genetic relationship between these two entities, we examined 12 oncocytomas for loss of heterozygosity (LOH) at these regions. In addition, we included markers for 3p, 5q, 7q, 11p, and 22q. The only chromosomal region showing similarly high frequencies of allelic loss for both subtypes was 14q. Therefore, a genetic relationship between renal oncocytoma and chromophobe RCC seems questionable. Eight of 12 oncocytomas (67%) showed LOH at 14q, a frequency that was significantly higher (P < 0.001, chi(2) test) than the frequencies of LOH in all other regions. To define regions potentially harboring novel tumor suppressor genes, we performed multifluorescence microsatellite analysis with 13 markers spanning 14q. Interstitial deletions at different regions of 14q were detected, with the highest frequencies at D14S258 (14q23-24.3) and D14S292 (14q32.1-32.2). 14q LOH might be associated with advanced-stage RCCs or other tumors, but it does not seem to indicate progression in oncocytomas. Its role in pathogenesis of renal oncocytomas remains to be clarified. Here, we provide evidence for two distinct tumor suppressor gene loci at 14q in renal oncocytoma, which will be useful for further fine-mapping studies of these critical regions.

Adenoma, Oxyphilic↗

PubMed1998

Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system.

About one-third of sporadic basal cell carcinomas (BCCs) of the skin and 10-15% of primitive neuroectodermal tumors (PNETs) of the central nervous system show mutations in the PTCH tumor suppressor gene. The PTCH gene product (Ptch) functions as a transmembrane receptor for the Sonic hedgehog protein (Shh) and interacts with another transmembrane protein called Smoh. To further elucidate the significance of alterations in the Shh signaling pathway, we investigated 31 sporadic BCCs and 15 PNETs for the mutation and/or expression of SMOH, PTCH, SHH, and GL11. In addition, we fine-mapped the SMOH gene locus by fluorescence in situ hybridization to chromosomal band 7q32. Mutational analysis identified four BCCs with somatic missense mutations in SMOH affecting codon 535 (TGG==>TTG: Trp==>Leu) in three tumors and codon 199 (CGG==>TGG: Arg==>Trp) in one tumor. A missense mutation at codon 533 (AGC==>AAC: Ser==>Asn) was found in one PNET. PTCH mutations were detected in eight BCCs and one PNET. Two BCCs demonstrated mutations in both SMOH and PTCH. The majority of tumors showed an increased expression of SMOH, PTCH, and GL11 transcripts as compared with that of normal skin and nonneoplastic brain tissue, respectively. In contrast, only one BCC and one PNET expressed SHH mRNA at levels detectable by reverse transcription-PCR, and no SHH gene mutations were found. In summary, our results indicate that both PTCH and SMOH represent important targets for genetic alterations in sporadic BCCs and PNETs.

Adolescent↗

PubMed1998

A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers.

The cellular protooncogene MYC encodes a nuclear transcription factor that is involved in regulating important cellular functions, including cell cycle progression, differentiation, and apoptosis. Dysregulated MYC expression appears critical to the development of various types of malignancies, and thus factors involved in regulating MYC expression may also play a key role in the pathogenesis of certain cancers. We have cloned one such MYC regulatory factor, termed CTCF, which is a highly evolutionarily conserved-11-zinc finger transcriptional factor possessing multiple DNA sequence specificity. CTCF binds to a number of important regulatory regions within the 5' noncoding sequence of the human MYC oncogene, and it can regulate its transcription in several experimental systems. CTCF mRNA is expressed in cells of multiple different lineages. Enforced ectopic expression of CTCF inhibits cell growth in culture. Southern blot analyses and fluorescence in situ hybridization (FISH) with normal human metaphase chromosomes showed that the human CTCF is a single-copy gene situated at chromosome locus 16q22. Cytogenetic studies have pointed out that chromosome abnormalities (deletions) at this locus frequently occur in many different human malignancies, suggesting the presence of one or more tumor suppressor genes in the region. To narrow down their localization, several loss of heterozygosity (LOH) studies of chromosome arm 16q in sporadic breast and prostate cancers have been carried out to define the most recurrent and smallest region(s) of overlap (SRO) for commonly deleted chromosome arm 16q material. For CTCF to be considered as a candidate tumor suppressor gene associated with tumorigenesis, it should localize within one of the SROs at 16q. Fine-mapping of CTCF has enabled us to assign the CTCF gene to about a 2 centiMorgan (cM) interval of 16q22.1 between the somatic cell hybrid breakpoints CY130(D) and CY4, which is between markers D16S186 (16AC16-101) and D16S496 (AFM214zg5). This relatively small region, containing the CTCF gene, overlaps the most frequently observed SROs for common chromosomal deletions found in sporadic breast and prostate tumors. In one of four analyzed paired DNA samples from primary breast cancer patients, we have detected a tumor-specific rearrangement of CTCF exons encoding the 11-zinc-finger domain. Therefore, taken together with other CTCF properties, localization of CTCF to a narrow cancer-associated chromosome region suggests that CTCF is a novel candidate tumor suppressor gene at 16q22.1.

Breast Neoplasms↗