Rare Germline Copy Number Variations and Disease Susceptibility in Familial Melanoma
TL;DR: The results suggest that rare cosegregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in this study warrant further evaluation in future genetic analyses of melanoma.
About: This article is published in Journal of Investigative Dermatology.The article was published on 2016-12-01 and is currently open access. It has received 13 citations till now. The article focuses on the topics: CDKN2A & Germline mutation.
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TL;DR: 200 germline CNVs associated with breast cancer susceptibility and their relevance to prognosis were identified and 21 CNV regions (overlapping with 22 genes) also showed association with prognosis.
Abstract: Breast cancer is one of the most common cancers among women, and susceptibility is explained by genetic, lifestyle and environmental components. Copy Number Variants (CNVs) are structural DNA variations that contribute to diverse phenotypes via gene-dosage effects or cis-regulation. In this study, we aimed to identify germline CNVs associated with breast cancer susceptibility and their relevance to prognosis. We performed whole genome CNV genotyping in 422 cases and 348 controls using Human Affymetrix SNP 6 array. Principal component analysis for population stratification revealed 84 outliers leaving 366 cases and 320 controls of Caucasian ancestry for association analysis; CNVs with frequency > 10% and overlapping with protein coding genes were considered for breast cancer risk and prognostic relevance. Coding genes within the CNVs identified were interrogated for gene- dosage effects by correlating copy number status with gene expression profiles in breast tumor tissue. We identified 200 CNVs associated with breast cancer (q-value < 0.05). Of these, 21 CNV regions (overlapping with 22 genes) also showed association with prognosis. We validated representative CNVs overlapping with APOBEC3B and GSTM1 genes using the TaqMan assay. Germline CNVs conferred dosage effects on gene expression in breast tissue. The candidate CNVs identified in this study warrant independent replication.
46 citations
07 Jul 2020
TL;DR: The results of the epigenetic and genomic transcriptome modulation analysis improve the understanding of SKCM pathobiology and may aid in the development of more effective therapies.
Abstract: Skin cutaneous melanoma (SKCM) is characterized by both epigenetic DNA methylation (MET) abnormalities and genomic copy number variations (CNVs). The resulting transcriptome dysregulation promotes progression of many cancers. In this study, DNA copy numbers and MET, as well as mRNA expression, were examined in 466 SKCM samples from The Cancer Genome Atlas. Our results indicate that CNVs-correlated (CNVcor) genes and MET-correlated (METcor) genes are coregulated to a remarkable degree. In addition, integrative multi-omics analysis of both METcor and CNVcor genes revealed four SKCM subtypes with differing prognoses; these subtypes were validated with independent data. Immune cell scores were markedly elevated in the iC1 subtype, which had the best prognosis. Immune cell infiltration correlated with DNA MET or CNV level in SKCM. In the iC3 subtype, which was associated with the most aggressive SKCM cases, FAM135B gene mutation frequencies were increased, while CD8A, GBP5, KIAA0040, and SAMHD1 expression were downregulated, suggesting that these genes play important roles in cancer development and immune responses. Taken together, the results of our epigenetic and genomic transcriptome modulation analysis improve our understanding of SKCM pathobiology and may aid in the development of more effective therapies.
10 citations
Cites background from "Rare Germline Copy Number Variation..."
...Genome alternations, like DNA mutations or copy number variations (CNVs), frequently take place during tumorigenesis and can promote cancer development [6]....
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TL;DR: It is strongly suggested that coblockade of TIGIT and PD-1 may enhance antitumor CD8þ T-cell responses in patients with melanoma, because TIGit-positive cells often coexpress PD-2 (Inozume et al., 2016).
10 citations
Cites background from "Rare Germline Copy Number Variation..."
...Investigators from the National Cancer Institute studied the role of CNVs in melanoma prone families (Shi et al., 2016) by comparing structural alterations in affected and unaffected family members and spouse controls....
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...role of CNVs in melanoma prone families (Shi et al., 2016) by comparing structural alterations in affected and unaffected family members and spouse controls....
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TL;DR: A five-step pipeline to identify dosage-sensitive genes (DSGs) and analyzed their characterization in colorectal cancer showed that the pipeline performed better than existing methods, and the result was significantly overlapped between solid tumor and cell line.
Abstract: Dosage effect is one of the common mechanisms of somatic copy number alteration in the development of colorectal cancer, yet the roles of dosage-sensitive genes (DSGs) in colorectal cancer (CRC) remain to be characterized more deeply In this study, we developed a five-step pipeline to identify DSGs and analyzed their characterization in CRC Results showed that our pipeline performed better than existing methods, and the result was significantly overlapped between solid tumor and cell line We also found that the top five DSGs (PSMF1, RAF1, PTPRA, MKRN2, and ELP3) were associated with the progression of CRC By analyzing the characterization, DSGs were enriched in driver genes and they drove sub-pathways of CRC In addition, immune-related DSGs are associated with CRC progression Our results also showed that the CRC samples affected by high microsatellites have fewer DSGs, but a higher overlap with DSGs in microsatellite low instability and microsatellite stable samples In addition, we applied DSGs to identify potential drug targets, with the results showing that 22 amplified DSGs were more sensitive to four drugs In conclusion, DSGs play an important role in CRC, and our pipeline is effective to identify them
7 citations
Cites background from "Rare Germline Copy Number Variation..."
...Existing studies have shown that SCNA affects development and other functions,(5) and different levels of SCNAmay have adverse effects on cancers.(6,7) Thus, SCNA could also be used as an important prognostic marker for cancer....
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TL;DR: The findings suggest a limited role of CNPs in explaining eGFR variability, and hidden Markov models are used to identify copy number polymorphic regions (CNPs) from high-throughput SNP arrays for African and European ancestry participants in the ARIC study.
Abstract: Genome-wide association studies (GWAS) using single nucleotide polymorphisms (SNPs) have identified more than 50 loci associated with estimated glomerular filtration rate (eGFR), a measure of kidney function. However, significant SNPs account for a small proportion of eGFR variability. Other forms of genetic variation have not been comprehensively evaluated for association with eGFR. In this study, we assess whether changes in germline DNA copy number are associated with GFR estimated from serum creatinine, eGFRcrea. We used hidden Markov models (HMMs) to identify copy number polymorphic regions (CNPs) from high-throughput SNP arrays for 2,514 African (AA) and 8,645 European ancestry (EA) participants in the Atherosclerosis Risk in Communities (ARIC) study. Separately for the EA and AA cohorts, we used Bayesian Gaussian mixture models to estimate copy number at regions identified by the HMM or previously reported in the HapMap Project. We identified 312 and 464 autosomal CNPs among individuals of EA and AA, respectively. Multivariate models adjusted for SNP-derived covariates of population structure identified one CNP in the EA cohort near genome-wide statistical significance (Bonferroni-adjusted p = 0.067) located on chromosome 5 (876-880kb). Overall, our findings suggest a limited role of CNPs in explaining eGFR variability.
5 citations
References
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Cold Spring Harbor Laboratory1, Emory University2, University of Washington3, National Institutes of Health4, North Shore-LIJ Health System5, University of Tampere6, Vanderbilt University7, Columbia University8, University College London9, University of California, Los Angeles10, University of Chicago11, Albert Einstein College of Medicine12
TL;DR: Findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
Abstract: We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
2,770 citations
TL;DR: The results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia, and disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways.
Abstract: Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.
1,762 citations
TL;DR: Functional studies have shown many of these conserved sites to be transcriptional regulatory elements that sometimes reside inside unrelated neighboring genes, such sequence-conserved elements generally harbor sites for tissue-specific DNA-binding proteins.
Abstract: Transcriptional control is a major mechanism for regulating gene expression. The complex machinery required to effect this control is still emerging from functional and evolutionary analysis of genomic architecture. In addition to the promoter, many other regulatory elements are required for spatiotemporally and quantitatively correct gene expression. Enhancer and repressor elements may reside in introns or up- and downstream of the transcription unit. For some genes with highly complex expression patterns—often those that function as key developmental control genes—the cis-regulatory domain can extend long distances outside the transcription unit. Some of the earliest hints of this came from disease-associated chromosomal breaks positioned well outside the relevant gene. With the availability of wide-ranging genome sequence comparisons, strong conservation of many noncoding regions became obvious. Functional studies have shown many of these conserved sites to be transcriptional regulatory elements that sometimes reside inside unrelated neighboring genes. Such sequence-conserved elements generally harbor sites for tissue-specific DNA-binding proteins. Developmentally variable chromatin conformation can control protein access to these sites and can regulate transcription. Disruption of these finely tuned mechanisms can cause disease. Some regulatory element mutations will be associated with phenotypes distinct from any identified for coding-region mutations.
903 citations
TL;DR: Although PARP is specifically cleaved during apoptosis, cells lacking this molecule apoptosed normally in response to treatment with anti-Fas, tumor neurosis factor alpha, gamma-irradiation, and dexamethasone, indicating thatPARP is dispensable in apoptosis and that PARP-/- thymocytes are not hypersensitive to ionizing radiation.
Abstract: Mice lacking the gene encoding poly(ADP-ribosyl) transferase (PARP or ADPRT) display no phenotypic abnormalities, although aged mice are susceptible to epidermal hyperplasia and obesity in a mixed genetic background. Whereas embryonic fibroblasts lacking PARP exhibit normal DNA excision repair, they grow more slowly in vitro. Here we investigated the putative roles of PARP in cell proliferation, cell death, radiosensitivity, and DNA recombination, as well as chromosomal stability. We show that the proliferation deficiency in vitro and in vivo is most likely caused by a hypersensitive response to environmental stress. Although PARP is specifically cleaved during apoptosis, cells lacking this molecule apoptosed normally in response to treatment with anti-Fas, tumor neurosis factor alpha, gamma-irradiation, and dexamethasone, indicating that PARP is dispensable in apoptosis and that PARP-/- thymocytes are not hypersensitive to ionizing radiation. Furthermore, the capacity of mutant cells to carry out immunoglobulin class switching and V(D)J recombination is normal. Finally, primary PARP mutant fibroblasts and splenocytes exhibited an elevated frequency of spontaneous sister chromatid exchanges and elevated micronuclei formation after treatment with genotoxic agents, establishing an important role for PARP in the maintenance of genomic integrity.
579 citations
TL;DR: The utility of SNP-CGH is demonstrated with two Infinium whole-genome genotyping BeadChips, assaying 109,000 and 317,000 SNP loci, and the statistical ability to detect common aberrations was modeled by analysis of an X chromosome titration model system, and sensitivity was modeling by titration of gDNA from a tumor cell with that of its paired normal cell line.
Abstract: Array-CGH is a powerful tool for the detection of chromosomal aberrations. The introduction of high-density SNP genotyping technology to genomic profiling, termed SNP-CGH, represents a further advance, since simultaneous measurement of both signal intensity variations and changes in allelic composition makes it possible to detect both copy number changes and copy-neutral loss-of-heterozygosity (LOH) events. We demonstrate the utility of SNP-CGH with two Infinium whole-genome genotyping BeadChips, assaying 109,000 and 317,000 SNP loci, to detect chromosomal aberrations in samples bearing constitutional aberrations as well tumor samples at sub-100 kb effective resolution. Detected aberrations include homozygous deletions, hemizygous deletions, copy-neutral LOH, duplications, and amplifications. The statistical ability to detect common aberrations was modeled by analysis of an X chromosome titration model system, and sensitivity was modeled by titration of gDNA from a tumor cell with that of its paired normal cell line. Analysis was facilitated by using a genome browser that plots log ratios of normalized intensities and allelic ratios along the chromosomes. We developed two modes of SNP-CGH analysis, a single sample and a paired sample mode. The single sample mode computes log intensity ratios and allelic ratios by referencing to canonical genotype clusters generated from ∼120 reference samples, whereas the paired sample mode uses a paired normal reference sample from the same individual. Finally, the two analysis modes are compared and contrasted for their utility in analyzing different types of input gDNA: low input amounts, fragmented gDNA, and Phi29 whole-genome pre-amplified DNA.
547 citations