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In Print: Last Month's Microarray Papers of Note: May 1, 2012


Journal: Animal Genetics. 2012 Apr 10. [Epub ahead of print]

Title: Whole-genome association study for energy balance and fat/protein ratio in German Holstein bull dams.

Authors: Tetens J, et al.

The aim of this study was to detect SNPs associated with energy balance and fat/protein ratio in German Holstein bull dams belonging to the research herd Karkendamm. Bull dams were genotyped using the Illumina Bovine SNP 50K BeadChip. Across all observed lactation days, 19 SNPs located in four different intervals on chromosomes 1, 14, 16, and 27 were detected. For EB, seven markers across four chromosomes were identified. There was no overlap between markers associated with FPR and EB. SNPs associated with FPR were mostly located in QTL regions for milk production traits, especially in the region of DGAT1, whereas SNPs associated with EB mainly showed positional relationships to previously described QTL regions affecting functional traits, especially fertility.

Journal: Anticancer Research. 2012 Apr;32(4):1259-65.

Title: Comparison of genomic signatures of non-small cell lung cancer recurrence between two microarray platforms.

Authors: Chang J, et al.

The authors analyzed gene expression in frozen lung cancer tissue from 59 selected patients who had undergone surgical resection of non-small cell lung cancer. These patients were divided into two groups: group R, patients who had a tumor recurrence within four years; and group NR, patients who remained disease-free four years following initial surgery. Each RNA sample was assayed twice using Affymetrix and Illumina arrays. Thirteen genes that were differentially expressed between R and NR were identified by Affymetrix, while 21 genes were identified by Illumina. In common, a total of six genes were detected by both systems. Using univariate analysis, four of these six genes were associated with survival. A risk score of survival was calculated according to the four-gene expression. There was a significant difference in overall survival between low- and high-risk groups.

Journal: Breast Cancer Research and Treatment. 2012 Apr;132(2):379-89.

Title: Prediction of BRCA2-association in hereditary breast carcinomas using array-CGH.

Authors: Joosse S, et al.

The authors set out to develop a test to identify BRCA2 association in breast tumors based on the sample's genomic signature. A BRCA2 classifier was built using array-CGH profiles of 28 BRCA2-mutated and 28 sporadic breast tumors, and the classifier was validated on an independent group of 19 BRCA2-mutated and 19 sporadic breast tumors. Subsequently, the authors tested 89 breast tumors from suspected hereditary breast and ovarian cancer, or HBOC, families, in which either no BRCA1/2 mutation or an unknown variant had been found by routine diagnostics. Using the classifier, the authors could separate BRCA1-like, BRCA2-like, and sporadic-like tumors, leading them to conclude that their method could be applied as an additional test to help clinicians in decision-making and classifying sequence variants of unknown significance.

Journal: Clinical and Vaccine Immunology. 2012 Apr 11. [Epub ahead of print]

Title: Peptide-microarray analysis of in silico predicted epitopes for the serological diagnosis of Toxoplasma gondii in infected humans.

Authors: Maksimov P, et al.

The authors selected 20 peptides mimicking linear epitopes on GRA1, GRA2, GRA4, and MIC3 antigenic T. gondii proteins in silico using the software ABCpred. Another 18 peptides representing previously published epitopes derived from GRA1, SAG1, NTPase1, and NTPase2 antigens were added to the panel, and a peptide microarray assay was designed to test the diagnostic performance of the selected peptides with human sera collected from 184 patients. They concluded that the bioinformatic approach could be used for epitope prediction and that peptide microarray testing could be used to select T. gondii epitopes as candidate antigens for serological diagnosis.

Journal: Clinical Cancer Research. 2012 Apr 15;18(8):2360-73.

Title: DNA methylation profiling defines clinically relevant biological subsets of non-small cell lung cancer.

Authors: Walter K, et al.

The authors set out to determine if epithelial-like non-small cell lung cancer tumors could be distinguished from mesenchymal-like NSCLCs on the basis of DNA methylation patterns. Using microfluidics-based gene expression analysis and array-based genome-wide methylation profiling, they derived classifiers for both gene expression and methylation in cell lines and tested these classifiers in surgically resected NSCLC tumors. They validated the approach using quantitative reverse transcriptase PCR and methylation-specific PCR in formalin-fixed biopsies from patients with NSCLC who went on to fail front-line chemotherapy. According to the authors, patterns of methylation divide NSCLCs into epithelial-like and mesenchymal-like subsets as defined by gene expression and these signatures are similarly correlated in NSCLC cell lines and tumors. They also identified several differentially methylated regions, including one in ERBB2 and one in ZEB2. The methylation status in these regions is associated with an epithelial phenotype in NSCLC cell lines, surgically resected tumors, and formalin-fixed biopsies from patients with NSCLC who went on to fail front-line chemotherapy.

Journal: Cytogenetic and Genome Research. 2012 Apr 20. [Epub ahead of print]

Title: Copy number changes on the X chromosome in women with and without highly skewed X-chromosome inactivation.

Authors: Jobanputra V, et al.

Looking to determine if microdeletions or microduplications below the resolution of a standard karyotype may be a significant cause of highly skewed X-inactivation in women without a cytogenetically detected X-chromosome anomaly, the authors performed SNP microarray analysis using the Affymetrix 6.0 platform for 45 cases and 45 controls. These cases and controls did not differ in the frequency of X-chromosome copy number changes or in the frequency of copy number changes that contained genes. However, one woman with HSXI had a 5.5-megabase deletion in Xp22.2p22.1. This deletion could affect the viability of male conceptions and may have led to the dysmorphology found in female carriers. The authors concluded that HSXI in a blood sample is rarely due to X-chromosome copy number changes detectable by microarray.

Journal: Developmental Medicine and Child Neurology. 2012 Apr 19. [Epub ahead of print]

Title: Microdeletions detected using chromosome microarray in children with suspected genetic movement disorders: a single-centre study.

Authors: Dale R, et al.

The authors examined whether chromosomal microarrays are valuable tools in the investigation of children with suspected genetic movement disorders. For the study's purposes, a genetic movement disorder was suspected if there was a positive first-degree family history, or two or more of the following factors: normal or near-normal magnetic resonance imaging, negative history of brain injury, and negative investigations for metabolic disorders. Tic disorders were excluded. Twenty-five patients were prospectively recruited with the following primary movement disorders: dystonia, paroxysmal kinesigenic dyskinesia, tremor, chorea, myoclonus, and paroxysmal non-kinesigenic dyskinesia. Comorbid associated features were common, particularly developmental delay or intellectual disability and attention-deficit-hyperactivity disorder. CMA was performed using an Agilent Technologies array CGH 60K array. Seven out of twenty-five patients had a microdeletion determined by CMA. None of the microdeletions were considered benign variants. Four patients had a deletion of a known movement disorder gene including paroxysmal kinesigenic dyskinesia and TITF1. Three patients had microdeletions of unknown but potential significance. All seven patients had associated neurodevelopmental or behavioral problems.

Journal: Environmental Microbiology. 2012 Apr 20. [Epub ahead of print]

Title: Analysis of the microbial gene landscape and transcriptome for aromatic pollutants and alkane degradation using a novel internally calibrated microarray system.

Authors: Vilchez-Vargas R, et al.

The authors developed a custom array system, as well as a normalization strategy that they claim can be applied to any microarray designed to monitor pollutant degradation and support cross-platform comparisons. Array probes were designed from curated databases for selected aromatic catabolic gene families and alkane degradation genes. The array system was applied to assess the catabolic gene landscape and transcriptome of aromatic contaminated environmental samples, confirming the abundance of catabolic gene subfamilies previously detected by functional metagenomics, but also revealing the presence of previously undetected catabolic groups and specifically their expression under pollutant stress.

Journal: European Journal of Human Genetics. 2012 Apr 18. [Epub ahead of print]

Title: Comprehensive oligonucleotide array-comparative genomic hybridization analysis: new insights into the molecular pathology of the DMD gene.

Authors: Ishmukhametova A, et al.

The authors report on the effectiveness of a custom-designed oligonucleotide-based comparative genomic hybridization microarray to interrogate copy number across the entire 2.2-megabase genomic region of the Duchenne muscular dystrophy gene and its applicability in diagnosis. The high-resolution array successfully detected a series of 42 previously characterized large rearrangements of various size, localization, and type. Additionally, the technique succeeded in identifying a small duplication of 191 basepairs in one patient previously negative for DMD mutation, according to the authors.

Journal: European Journal of Human Genetics. 2012 Apr 25. [Epub ahead of print]

Title: Genome-wide scan with nearly 700,000 SNPs in two Sardinian sub-populations suggests some regions as candidate targets for positive selection.

Authors: Piras I, et al.

This paper explores the genetic structure and signatures of natural selection in different sub-populations from the Italian island of Sardinia, relying on information from nearly 700,000 autosomal SNPs genotyped with the Affymetrix Genome-Wide Human SNP 6.0 Array. The genetic structure of the Sardinian population and its position within the context of other Mediterranean and European human groups were investigated in depth by comparing the authors' data with publicly available data sets. Principal components and admixture analyses suggest a clustering of the examined samples in two significantly differentiated sub-populations, Ogliastra and Southern Sardinia. Differentiation of these sub-populations was still evident when they were pooled together with supplementary Sardinian samples from HGDP and compared with several other European, North-African, and Near Eastern populations.

Journal: Genetics in Medicine. 2012 Apr 26. [Epub ahead of print]

Title: Uniparental disomy: can SNP array data be used for diagnosis?

Authors: Tucker T, et al.

The purpose of this study was to validate chromosomal microarray analysis for the identification of uniparental disomy in a clinical laboratory. In the first phase, nine cases with uniparental disomy for chromosomes 7, 14, and 15 identified by conventional polymorphic microsatellite marker analysis were analyzed on the Affymetrix SNP 6.0 array. In the second phase, four cases of uniparental disomy 15 showing heterozygosity for all microsatellite markers were analyzed using the same array. CMA detected blocks of homozygosity in eight of the nine cases in the first phase, while second phase analysis of molecularly defined heterodisomy failed to detect blocks of homozygosity in three of the four cases. The four cases in which microarray did not detect blocks of homozygosity all involved chromosome 15. The authors concluded that a normal chromosomal microarray result for chromosome 15 does not exclude the possibility of uniparental disomy.

Journal: Human Molecular Genetics. 2012 Apr 15;21(8):1907-17.

Title: Admixture mapping identifies a locus on 6q25 associated with breast cancer risk in US Latinas.

Authors: Fejerman L, et al.

Among US Latinas and Mexican women, those with higher European ancestry have increased risk of breast cancer, according to the authors. They combined an admixture mapping and genome-wide association mapping approach to search for genomic regions that may explain this observation. Latina women with breast cancer and Latina controls were genotyped using Affymetrix and Illumina arrays. The authors inferred locus-specific genetic ancestry and compared the ancestry between cases and controls. They also performed SNP association analyses in regions of interest. The authors identified one region where genetic ancestry was significantly associated with breast cancer risk: 6q25. A second region on 11p15 showed a trend toward association. In both regions, breast cancer risk decreased with higher indigenous American ancestry.

Journal: Human Molecular Genetics. 2012 Apr 1;21(7):1665-72.

Title: A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese.

Authors: Kiyotani A, et al.

To identify genetic polymorphisms associated with clinical outcomes of patients with tamoxifen treatment, the authors conducted a genome-wide association study of 462 Japanese patients with hormone receptor-positive invasive breast cancer receiving adjuvant tamoxifen therapy. Of them, 240 patients were analyzed by genome-wide genotyping using the Illumina Human610-Quad BeadChips, and two independent sets of 105 and 117 cases were used for replication studies. In the GWAS, they detected significant associations with recurrence-free survival at 15 SNPs on nine chromosomal loci that satisfied a genome-wide significance threshold. Among them, rs10509373 in the C10orf11 gene on 10q22 was significantly associated with recurrence-free survival in the replication study and a combined analysis indicated a strong association of this SNP with recurrence-free survival in breast cancer patients treated with tamoxifen.

Journal: Human Reproduction. 2012 Apr 3. [Epub ahead of print]

Title: No evidence of somatic DNA copy number alterations in eutopic and ectopic endometrial tissue in endometriosis.

Authors: Saare M, et al.

The authors used SNP arrays to detect somatic copy number aberrations, inherited DNA copy number variations, and copy-neutral loss of heterozygosity patterns in patients with endometriosis. The Illumina HumanOmniExpress array was used to detect de novo somatic genomic alterations in eutopic and ectopic endometria from 11 women by comparatively analyzing DNA from peripheral blood, eutopic endometrium, and a pure population of endometriotic cells harvested from endometriotic lesions by laser capture microdissection. Based on subsequent data analysis, the authors determined that LCM DNA can be used successfully for detection of genetic changes as all inherited CNVs were identified in all tissues studied. At the same time, no unique SCNAs or cases of cn-LOH were found in either eutopic or ectopic endometrium when compared with blood DNA. The authors suggested that molecular mechanisms other than chromosomal rearrangements most likely underlie the onset and progression of endometriosis.

Journal: Investigative Ophthalmology and Visual Science. 2012 Apr 24;53(4):2089-105.

Title: DNA methylation is associated with altered gene expression in AMD.

Authors: Hunter A, et al.

The authors aimed to assess the potential contribution of epigenetic regulation of antioxidant genes relevant to age-related macular degeneration pathogenesis. Using the Illumina Infinium HumanMethylation27 array platform, they performed DNA bisulfite sequencing to compare the methylation status in postmortem retina pigment epithelium/choroid between patients with AMD and age-matched controls. Gene expression was assessed with the Affymetrix Exon Array and TaqMan gene expression assays were used for confirmation of the expression array results. The data suggested that the glutathione S-transferase isoform mu1 and mu5 promoter undergo epigenetic repression in AMD RPE/choroid, which may increase susceptibility to oxidative stress in AMD retinas.

Journal: Molecular Autism. 2012 Apr 2;3(1):2. [Epub ahead of print]

Title: Evidence of novel fine-scale structural variation at autism spectrum disorder candidate loci.

Authors: Hedges D, et al.

The authors examined gamma-aminobutyric acid receptors and genes in related pathways for structural variation that may be associated with autism. Using custom-designed 244,000-marker comparative genomic hybridization arrays, they screened 168 autism cases and 149 controls. Prioritized CNV events were confirmed using quantitative PCR, and confirmed loci were evaluated on an additional set of 170 cases and 170 control individuals that were not included in the original discovery set. Loci that remained interesting were subsequently screened via quantitative PCR on an additional set of 755 cases and 1,809 unaffected family members. The authors found rare deletions in autistic individuals at JAKMIP1, NRXN1, neuroligin4Y, OXTR, and ABAT. They also detected common insertion/deletion polymorphisms at several loci, including GABBR2 and NRXN3.

Journal: PLoS One. 2012;7(4):e35307.

Title: Pooled sample-based GWAS: A cost-effective alternative for identifying colorectal and prostate cancer risk variants in the Polish population.

Authors: Gaj P, et al.

To identify new SNPs associated with prostate cancer and colorectal cancer in the Polish population, a genome-wide association study was performed using DNA sample pools on Affymetrix Genome-Wide Human SNP 6.0 arrays. The GWAS selected six and 24 new candidate SNPs associated with prostate and colorectal cancer susceptibility, respectively. In a replication study, 17 of these associations were confirmed as significant in additive model of inheritance. Seven of them remained significant after correction for multiple hypothesis testing. Additionally, 17 previously reported risk variants have been identified, five of which remained significant after correction.

Journal: Prenatal Diagnosis. 2012 Apr;32(4):351-61.

Title: Prenatal chromosomal microarray analysis in a diagnostic laboratory; experience with >1000 cases and review of the literature.

Authors: Bremen A, et al.

The authors evaluated the results of prenatal chromosomal microarray analysis of more than 1,000 fetal samples referred for testing and compared these data to published reports. Clinically significant copy number variations were observed in 85 out of 1,115 cases, or 7.6 percent overall; and in 45 out of 1,075 cases, or 4.2 percent, if 40 abnormal cases with known chromosome abnormalities or familial genomic imbalances were excluded. Eighteen, or 1.6 percent, of the 1,115 cases had variants of unclear clinical significance. Of 1,075 cases having no previously known cytogenetic abnormality or family history, 18, or 1.7 percent, had clinically significant genomic changes undetectable by conventional prenatal chromosome analysis.

Journal: Prenatal Diagnosis. 2012 Apr;32(4):383-8.

Title: Array CGH analysis in high-risk pregnancies: comparing DNA from cultured cells and cell-free fetal DNA.

Authors: Gruchy N, et al.

The authors performed bacterial artificial chromosome array comparative genomic hybridization on 38 fetal samples from high-risk pregnancies with previously normal karyotypes. From the 38 specimens, they obtained DNA with a better quality profile using cell-free fetal DNA compared to cellular DNA. Aberrations of clinical relevance were detected in three fetuses, and copy number variations considered as benign polymorphism were detected in one case using both sources of DNA. The authors concluded that cell-free fetal DNA from amniotic fluid supernatant can be used for array CGH, even in late pregnancy when culture is no longer available.

Journal: Prenatal Diagnosis. 2012 Apr;32(4):344-50.

Title: Referral patterns for microarray testing in prenatal diagnosis.

Authors: Shaffer L, et al.

The authors set out to understand the prenatal referral patterns from the United States, Canada, and Israel for two whole-genome microarray platforms, each with a different resolution. Physicians selected one of the two array designs to be performed on 1,483 prenatal specimens for a one-year period. The authors retrospectively examined detection rates, indications for study, and physician array selection. Their lower resolution array showed a 32 percent decrease in the detection of results of unclear clinical significance while retaining the ability to detect all but one significant abnormality identified by the higher resolution array. A majority of samples were referred for abnormal ultrasound findings. While labs in the US and Canada utilized the higher resolution array more often for this indication, Israel preferred the lower resolution array. Referral patterns for parental anxiety were similar for the US and Israel, and few cases were referred for advanced maternal age or family history of a genetic condition from either Canada or Israel.

BioArray News spoke with lead author Lisa Shaffer about the study last month (BAN 4/10/2012).

The Scan

Single-Cell Sequencing Points to Embryo Mosaicism

Mosaicism may affect preimplantation genetic tests for aneuploidy, a single-cell sequencing-based analysis of almost three dozen embryos in PLOS Genetics finds.

Rett Syndrome Mouse Model Study Points to RNA Editing Possibilities

Investigators targeted MECP2 in mutant mouse models of Rett syndrome, showing in PNAS that they could restore its expression and dial down symptoms.

Investigators Find Shared, Distinct Genetic Contributors to Childhood Hodgkin Lymphoma

An association study in JAMA Network Open uncovers risk variants within and beyond the human leukocyte antigen locus.

Transcriptomic, Epigenetic Study Appears to Explain Anti-Viral Effects of TB Vaccine

Researchers report in Science Advances on an interferon signature and long-term shifts in monocyte cell DNA methylation in Bacille Calmette-Guérin-vaccinated infant samples.