Landscape of somatic allelic imbalances and copy number alterations in HER2-amplified breast cancer
ABSTRACT: A survey of the somatic allelic imbalances and copy number alterations in HER2-amplified breast cancer. Genomic profiling of 26 breast tumors with amplification of HER2 using 1M and 2.5M Illumina SNP beadchips. Sample identifiers correspond to GSE21259 where sample annotations may be extracted.
Project description:Genomic profiling to identify common features of breast tumors with BRCA2 mutations. Gene expression data and genomic profiling data were used to identify common features of breast tumors with BRCA2 mutations. The associated expression data and genomic data are either present in Array-express under accession number E-TABM-854 or undergoing submission.
Project description:Hibernomas are benign tumors with morphological features resembling brown fat. They consistently display cytogenetic rearrangements, typically translocations, involving chromosome band 11q13. Here we demonstrate that these aberrations are associated with concomitant deletions of AIP and MEN1, tumor suppressor genes that are located 3 Mb apart and that underlie the hereditary syndromes pituitary adenoma predisposition and multiple endocrine neoplasia type I. MEN1 and AIP displayed a low expression in hibernomas whereas the expression of genes up-regulated in brown fat-PPARA, PPARG, PPARGC1A, and UCP1-was high. Thus, loss of MEN1 and AIP is likely to be pathogenetically essential for hibernoma development. Simultaneous loss of two tumor suppressor genes has not previously been shown to result from a neoplasia-associated translocation. Furthermore, in contrast to the prevailing assumption that benign tumors harbor relatively few genetic aberrations, the present analyses demonstrate that a considerable number of chromosome breaks are involved in the pathogenesis of hibernoma. Global copy number analysis was performed using single nucleotide polymorphism (SNP) array. Cases 1-14 were hybridized onto Illumina Human1M-Duo v3.0 (and Human CNV370-Quad v3.0) BeadChip (Illumina, San Diego, CA, USA), following standard protocols supplied by the manufacturer. Case 15 was analyzed using Illumina Human Omni-Quad BeadChip. Normal blood DNA was analyzed in cases 1, 2, 4 and 6 using the Human CNV370-Quad v3.0 BeadChip. Data analysis was done using the BeadStudio software (Illumina).
Project description:Chromosomal instability is central to the process of carcinogenesis. The detection of somatic chromosomal alterations in small premalignant lesions genome-wide remains challenging since sample heterogeneity dilutes the aberrant cell information. We introduced an analytic metric termed "delta-θ", and applied this metric to a titrated cancer cell model using a pair of cancer cell line and matched lymphoblastoid cell line. We examined heterogeneous clinical specimens including bronchial biopsies and brushings with this metric. Distinctive genomic variation were successfully detected across the whole genome in invasive cancer cases (6/6), carcinoma in situ (3/3), and high grade dysplasia (severe or moderate) (3/11). We modeled titration series (100%, 25%, 12.5%, 6.3%, 3.1%, 1.6% and 0% tumor content) mixing the genomic DNA of the cell line pair. We also investigated 30 malignant/premalignant samples from 18 patients with heavy smoking histories (6 invasive lung cancer, 3 carcinoma in situ,15 dysplasia, 3 hyperplasia and 3 normal histology) using Illumina HumanOmni2.5 and Human 660w SNP microarrays. All of them were paired with matched reference blood DNA and analyzed.
Project description:We performed Illumina Infinium whole-genome SNP-CN profiling of KMS11, MM.1S, and RPMI8226 multiple myeloma cell lines to detect gene copy number variants distinct to each cell line Three multiple myeloma cell lines (KMS11, MM.1S, and RPMI8226)
Project description:Suicide and suicide attempts are complex behaviors that result from the interaction of different factors, including genetic variants that increase the predisposition to suicidal behaviors. Copy number variations (CNVs) are deletions or duplications of a segment of DNA usually larger than one kilobase. These structural genetic changes, although quite rare, have been associated with genetic liability to mental disorders, such as autism, schizophrenia, and bipolar disorder. No genome-wide level studies have been published investigating the potential role of CNVs in suicidal behaviors. Based on single-nucleotide polymorphism array data, we followed the Penn-CNV standards to detect CNVs in 1,608 subjects, comprising 475 suicide and suicide attempt cases and 1,133 controls. Although the initial algorithms determined the presence of CNVs on chromosomes 6 and 12 in seven and eight cases, respectively, compared with none of the controls, visual inspection of the raw data did not support this finding. Furthermore we were unable to validate these findings by CNV-specific real-time polymerase chain reaction. Additionally, rare CNV burden analysis did not find an association between the frequency or length of rare CNVs and suicidal behavior in our sample population. Although our findings suggest CNVs do not play an important role in the etiology of suicidal behaviors, they are not inconsistent with the strong evidence from the literature suggesting that other genetic variants account for a portion of the total phenotypic variability in suicidal behavior.
Project description:Suicidal behavior (SB) has a complex etiology of genes, environment or both. One of the genetic components in SB could be copy number variations (CNVs), since CNVs are implicated in a range of neurodevelopmental disorders. However, a recently published genome-wide and case-control study failed to observe a significant role of CNVs in SB (see E-MTAB-3519). Here we complement those initial observations by conducting a brief CNV-association study, for the first time in a family-based trio-sample with severe suicide attempt (SA) outcome in offspring (n=660 trios; the GISS sample, see http://www.ncbi.nlm.nih.gov/pubmed/23422793 and refs therein). For association testing, we here used the FBAT-CNV methodology (http://www.ncbi.nlm.nih.gov/pubmed/18228561), which allows for CNV association testing directly on the raw intensity values (Illumina log R ratio), evaluating any type of CNVs (e.g. de novo or inherited) without reliance on CNV calling algorithms and robust to control selection biases. Here we have deposited these raw logR-values for 88,450 on-chip CNV-loci of the HumanOmni1-Quad_v1 chip, arranged in a standard pedigree format used as input for FBAT-CNV analysis in SVS software (goldenhelix.com): column 1 is the family ID, column 2 is the Subject type (1 = offspring, 2 = mother, 3 = father), column 3 is the father ID (? for missing), column 4 is the mother ID (? for missing), column 5 is the sex (1 = female, 0 = male), column 6 is the affection status (1 = suicide attempt, 0 = not affected) and columns 7 and onward are the logR-values for each CNV-loci as is listed in the header row. We observed experiment-wide significant association (P ≤ 5.6 x 10-7) of two proximal CNVs at chromosome 14 (Illumina markers cnvi0108946 and cnvi0118308, with NCBI 36.3 start positions 22794779 and 22582820). However, these CNV-associations mapped to T-cell receptor regions, and therefore most likely reflect inter-individual variation in somatic rearrangements occurring in white blood cells (as our source of DNA was blood), rather than association with SA. In conclusion, our results did not suggest any major role of CNVs in SA etiology, in line with the results of the recent case-control study (see E-MTAB-3519).
Project description:In colorectal cancer (CRC), chromosomal instability (CIN) is typically studied using comparative-genomic hybridization (CGH) arrays. We studied paired (tumor and surrounding healthy) fresh-frozen tissue from 86 CRC patients using Illumina’s Infinium-based SNP array. This method allowed us to study CIN in CRC, with simultaneous analysis of copy number (CN) and B-allele frequency (BAF), which is a representation of allelic composition. This data helped us to detect mono-allelic and bi-allelic amplifications/deletion, copy neutral loss of heterozygosity, and levels of mosaicism for mixed cell populations, some of which can not be assessed with other methods that do not measure BAF. We identified associations between CN abnormalities and different CRC phenotypes (MSI, histological diagnosis, location, tumor grade, stage, MSI and presence of lymph node metastasis). We showed commonalities between regions of CN change observed in CRC and the regions reported in previous studies of other solid cancers (e.g., amplifications of 20q, 13q, 8q, 5p and deletions of 18q, 17p and 8p). From the Therapeutic Target Database we found relevant drugs, targeted to the genes located in these regions with CN changes, approved or in trials for other cancers and common diseases. These drugs may be considered for future therapeutic trials in CRC, based on personalized cytogenetic diagnosis. We also found many regions harboring genes which are not currently targeted by any relevant drugs that may be considered for future drug discovery studies. Our study shows the application of high-density SNP arrays for cytogenetic study in CRC and its importance for personalized treatment. DNA was extracted from colon tissue samples provided by 86 CRC patients. Each patient provided paired CRC tumor tissue and adjacent normal colon mucosa samples, which were fresh-frozen after resection. Samples were genotyped using Illumina's Infinium-based 610 Quad and CytoSNP 12 microarray chips. The genotype data from paired tumor and normal samples was used to detect tumor-specific chromosomal instabilities in copy number, including copy-neutral LOH, which cannot be assessed by many other cytogenetic methods. Supplementary file "GSE34678_raw_GPL8887.txt" includes the raw data for Samples using GPL8887 (GSM853162-GSM853239); supplementary file "GSE34678_raw_GPL13829.txt" includes the raw data for Samples using GPL13829 (GSM853240-GSM853363).
Project description:Genome-wide association studies (GWAS) have been pivotal to increasing our understanding of intestinal disease. However, the mode by which genetic variation results in phenotypic change remains largely unknown, with many associated polymorphisms likely to modulate gene expression. Analyses of expression quantitative trait loci (eQTL) to date indicate that as many as 50% of these are tissue specific. Here we report a comprehensive eQTL scan of intestinal tissue. Subjects who had undergone ileal pouch anal anastomosis and closure of ileostomy at least one year prior to recruitment were prospectively enrolled at Mount Sinai Hospital in Toronto. Endoscopically and histologically normal tissue biopsies from the afferent limb of these individuals were obtained and preserved in RNAlater. Total RNA was extracted with the QIAGEN miRNeasy Kit and mRNA analysis was performed on Affymetrix Human Gene 1.0 ST arrays. DNA was obtained from whole-blood samples from the same individuals and genotyped using the Illumina beadchips. Cis- and trans-eQTL analyses were carried out on 173 subjects encompassing the expression levels of 19,047 unique autosomal genes listed in the NCBI database and over 580K dbSNPs (Call Rate ≥ 95%; MAF ≥ 5%; Hardy–Weinberg equilibrium (HWE) χ2 p-values ≥ 10-6). This work was done in a custom software pipeline and the Kruskal-Wallis test was used to compare expression values across different genotypes. False discovery rate correction for multiple testing was applied at an alpha level of 5%.