Mutation screening of CHD5 in melanoma-prone families linked to 1p36 revealed no deleterious coding or splice site changes

<p>Abstract</p> <p>Background</p> <p>A subset of cutaneous malignant melanoma and dysplastic nevi (CMM/DN) families is linked to 1p36. To date, no CMM/DN susceptibility gene has been identified at this locus. Data from mouse studies identified chromodomain helicase DNA binding protein 5 (<it>CHD5</it>) as a tumor suppressor affecting cellular proliferation and apoptosis via the <it>CDKN2A</it>/p53 pathway. Based on these findings, we felt it was important to screen <it>CHD5 </it>as a familial CMM/DN susceptibility gene.</p> <p>Methods</p> <p>Eight unrelated CMM/DN families showing prior evidence of linkage to the 1p36 locus were identified for <it>CHD5 </it>mutation screening. One CMM/DN affected and one unaffected individual from each family were selected for sequencing of the <it>CHD5 </it>coding exons and their respective intron-exon boundaries. <it>CHD5 </it>variants that were identified solely among affecteds in the screening panel were further assessed by sequencing additional affected and unaffected members of these families to determine if the variant co-segregated with the CMM/DN phenotype.</p> <p>Results</p> <p>Single nucleotide polymorphisms in the <it>CHD5 </it>intronic and coding regions were identified among affecteds in the screening panel. None of these variants completely co-segregated with CMM/DN affection status among these eight families.</p> <p>Conclusion</p> <p>There is no evidence to support <it>CHD5 </it>as a major melanoma susceptibility gene among the eight CMM/DN families screened.</p

A genome-wide linkage scan for body mass index on Framingham Heart Study families

BACKGROUND: Genome-wide scan data from a community-based sample was used to identify the genetic factors that affect body mass index (BMI). BMI was defined as weight (kg) over the square of height (m), where weight and height were obtained from the first measurement available between the ages of 40 and 50 years. RESULTS: Significant familial correlations were observed in mother:father (spouse) relative pairs and in all relative pairs examined except parent:daughter pairs. Single-point sib-pair regression analysis provided nominal evidence for linkage (p < 0.05) of loci to BMI at 23 markers. Multi-point sib-pair regression analysis provided nominal evidence for linkage to BMI at 42 loci on 12 chromosomes. Empirical p-values showed results consistent with the multi-point results; all but three of the loci identified by multi-point analysis were also significant. CONCLUSION: The largest regions of nominally significant linkage were found on chromosomes 2, 3, and 11. The most significant evidence for linkage was obtained with markers D2S1788, D2S1356, D2S1352, D3S1744, and D11S912 from multi-point sib-pair single-trait regression analysis. Our results are in agreement with some of the recently published reports on BMI using various data sets including the Framingham Heart Study data

Genomic regions linked to alcohol consumption in the Framingham Heart Study

BACKGROUND: Pedigree, demographic, square-root transformed maximum alcohol (SRMAXAPD) and maximum cigarette (MAXCPD) consumption, and genome-wide scan data from the Framingham Heart Study (FHS) were used to investigate genetic factors that may affect alcohol and cigarette consumption in this population-based sample. RESULTS: A significant sister:sister correlation greater than spouse correlation was observed for MAXCPD only. Single-point sib-pair regression analysis provided nominal evidence for linkage of loci to both SRMAXAPD and MAXCPD consumption traits, with more significant evidence of linkage to SRMAXAPD than to MAXCPD. One genomic region, chr9q21.11, exhibits significant multi-point sib-pair regression to SRMAXAPD. CONCLUSION: SRMAXAPD exhibits greater evidence for genetic linkage than does MAXCPD in the FHS sample. Four regions of the genome exhibiting nominal evidence for linkage to SRMAXAPD in the FHS sample correspond to regions of the genome previously identified as linked to alcoholism or related traits in the family data set ascertained on individuals affected with alcohol dependence known as COGA

Identification of susceptibility loci for complex diseases in a case-control association study using the Genetic Analysis Workshop 14 dataset

Although current methods in genetic epidemiology have been extremely successful in identifying genetic loci responsible for Mendelian traits, most common diseases do not follow simple Mendelian modes of inheritance. It is important to consider how our current methodologies function in the realm of complex diseases. The aim of this study was to determine the ability of conventional association methods to fine map a locus of interest. Six study populations were selected from 10 replicates (New York) from the Genetic Analysis Workshop 14 simulated dataset and analyzed for association between the disease trait and locus D2. Genotypes from 45 single-nucleotide polymorphisms in the telomeric region of chromosome 3 were analyzed by Pearson's chi-square tests for independence to test for association with the disease trait of interest. A significant association was detected within the region; however, it was found 3 cM from the documented location of the D2 disease locus. This result was most likely due to the method used for data simulation. In general, this study showed that conventional case-control association methods could detect disease loci responsible for the development of complex traits

Linkage analysis of the GAW14 simulated dataset with microsatellite and single-nucleotide polymorphism markers in large pedigrees

Recent studies have suggested that a high-density single nucleotide polymorphism (SNP) marker set could provide equivalent or even superior information compared with currently used microsatellite (STR) marker sets for gene mapping by linkage. The focus of this study was to compare results obtained from linkage analyses involving extended pedigrees with STR and single-nucleotide polymorphism (SNP) marker sets. We also wanted to compare the performance of current linkage programs in the presence of high marker density and extended pedigree structures. One replicate of the Genetic Analysis Workshop 14 (GAW14) simulated extended pedigrees (n = 50) from New York City was analyzed to identify the major gene D2. Four marker sets with varying information content and density on chromosome 3 (STR [7.5 cM]; SNP [3 cM, 1 cM, 0.3 cM]) were analyzed to detect two traits, the original affection status, and a redefined trait more closely correlated with D2. Multipoint parametric and nonparametric linkage analyses (NPL) were performed using programs GENEHUNTER, MERLIN, SIMWALK2, and S.A.G.E. SIBPAL. Our results suggested that the densest SNP map (0.3 cM) had the greatest power to detect linkage for the original trait (genetic heterogeneity), with the highest LOD score/NPL score and mapping precision. However, no significant improvement in linkage signals was observed with the densest SNP map compared with STR or SNP-1 cM maps for the redefined affection status (genetic homogeneity), possibly due to the extremely high information contents for all maps. Finally, our results suggested that each linkage program had limitations in handling the large, complex pedigrees as well as a high-density SNP marker set

Identifying rheumatoid arthritis susceptibility genes using high-dimensional methods

Although several genes (including a strong effect in the human leukocyte antigen (HLA) region) and some environmental factors have been implicated to cause susceptibility to rheumatoid arthritis (RA), the etiology of the disease is not completely understood. The ability to screen the entire genome for association to complex diseases has great potential for identifying gene effects. However, the efficiency of gene detection in this situation may be improved by methods specifically designed for high-dimensional data. The aim of this study was to compare how three different statistical approaches, multifactor dimensionality reduction (MDR), random forests (RF), and an omnibus approach, worked in identifying gene effects (including gene-gene interaction) associated with RA. We developed a test set of genes based on previous linkage and association findings and tested all three methods. In the presence of the HLA shared-epitope factor, other genes showed weaker effects. All three methods detected SNPs in PTPN22 and TRAF1-C5 as being important. But we did not detect any new genes in this study. We conclude that the three high-dimensional methods are useful as an initial screening for gene associations to identify promising genes for further modeling and additional replication studies

Telomere Length and the Risk of Cutaneous Malignant Melanoma in Melanoma-Prone Families with and without CDKN2A Mutations

Introduction: Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations. Materials and Methods We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT. Results: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02–7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction. Discussion Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk

Increased matrix metalloproteinase activation in esophageal squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Esophageal squamous cell carcinomas (ESCC) are usually asymptomatic and go undetected until they are incurable. Cytological screening is one strategy to detect ESCC at an early stage and has shown promise in previous studies, although improvement in sensitivity and specificity are needed. Proteases modulate cancer progression by facilitating tumor invasion and metastasis. In the current study, matrix metalloproteinases (MMPs) were studied in a search for new early detection markers for ESCC.</p> <p>Methods</p> <p>Protein expression levels of MMPs were measured using zymography in 24 cases of paired normal esophagus and ESCC, and in the tumor-associated stroma and tumor epithelium in one sample after laser capture microdissection (LCM). MMP-3 and MMP-10 transcripts in both the epithelium and stroma in five cases were further analyzed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR).</p> <p>Results</p> <p>Gelatin zymography showed bands corresponding in size to MMP-2, MMP-3, MMP-9, and MMP-10 enzymes in each of the 24 cancer cases. MMP levels tended to be higher in tumors than paired normal tissue; however, only the 45 kDa band that corresponds to the activated form of MMP-3 and MMP-10 was strongly expressed in all 24 tumors with little or no expression in the paired normal foci. LCM-based analysis showed the 45 kDA band to be present in both the stromal and epithelial components of the tumor microenvironment, and that MMP-3 and MMP-10 mRNA levels were higher in tumors than paired normal tissues for each compartment.</p> <p>Conclusions</p> <p>Increased levels of MMPs occur in ESCC suggesting their up-regulation is important in esophageal tumorigenesis. The up-regulated gene products have the potential to serve as early detection markers in the clinic.</p

Identification of unique expression signatures and therapeutic targets in esophageal squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Esophageal squamous cell carcinoma (ESCC), the predominant histological subtype of esophageal cancer, is characterized by high mortality. Previous work identified important mRNA expression differences between normal and tumor cells; however, to date there are limited <it>ex vivo </it>studies examining expression changes occurring during normal esophageal squamous cell differentiation versus those associated with tumorigenesis. In this study, we used a unique tissue microdissection strategy and microarrays to measure gene expression profiles associated with cell differentiation versus tumorigenesis in twelve cases of patient-matched normal basal squamous epithelial cells (NB), normal differentiated squamous epithelium (ND), and squamous cell cancer. Class comparison and pathway analysis were used to compare NB versus tumor in a search for unique therapeutic targets.</p> <p>Results</p> <p>As a first step towards this goal, gene expression profiles and pathways were evaluated. Overall, ND expression patterns were markedly different from NB and tumor; whereas, tumor and NB were more closely related. Tumor showed a general decrease in differentially expressed genes relative to NB as opposed to ND that exhibited the opposite trend. FSH and IgG networks were most highly dysregulated in normal differentiation and tumorigenesis, respectively. DNA repair pathways were generally elevated in NB and tumor relative to ND indicating involvement in both normal and pathological growth. PDGF signaling pathway and 12 individual genes unique to the tumor/NB comparison were identified as therapeutic targets, and 10 associated ESCC gene-drug pairs were identified. We further examined the protein expression level and the distribution patterns of four genes: ODC1, POSTN, ASPA and IGF2BP3. Ultimately, three genes (ODC1, POSTN, ASPA) were verified to be dysregulated in the same pattern at both the mRNA and protein levels.</p> <p>Conclusions</p> <p>These data reveal insight into genes and molecular pathways mediating ESCC development and provide information potentially useful in designing novel therapeutic interventions for this tumor type.</p