Patterns of somatic uniparental disomy identify novel tumor suppressor genes in colorectal cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE64114 | GEO | 2015/09/02
SECONDARY ACCESSION(S): PRJNA270333
REPOSITORIES: GEO
Similar Datasets
Project description:Colorectal cancer (CRC) is characterized by specific patterns of copy number alterations (CNAs), which helped with the identification of driver oncogenes and tumor suppressor genes (TSGs). More recently, the usage of single nucleotide polymorphism arrays provided information of copy number neutral loss of heterozygosity, thus suggesting the occurrence of somatic uniparental disomy (UPD) and uniparental polysomy (UPP) events. The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs and CNAs in sporadic CRC. Our results indicate that regions showing high frequencies of UPD/UPP mostly coincide with regions typically involved in genomic losses. Among them, chromosome arms 3p, 5q, 9q, 10q, 14q, 17p, 17q, 20p, 21q and 22q preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. Several regions affected by recurrent UPDs/UPPs contain well-known TSGs, as well as novel candidates such as ARID1A, DLC1, TCF7L2 and DMBT1. In addition, VCAN, FLT4, SFRP1 and GAS7 were also frequently involved in regions of UPD/UPP and displayed high levels of methylation. Finally, sequencing and fluorescence in situ hybridization analysis of the gene APC underlined that a somatic UPD event might represent the second hit to achieve biallelic inactivation of this TSG in colorectal tumors. In summary, our data define a profile of somatic UPDs/UPPs in sporadic CRC and highlights the importance of these events as a mechanism to achieve the inactivation of TSGs.
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Project description:The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs, CNAs and genome-wide methylation status in sporadic CRC. Our results indicate that regions showing high frequencies of UPDs/UPPs mostly coincide with regions typically involved in genomic losses such as chromosome arms 1p, 5q, 8p, 14q, 17p, 18q, 20p, and 22q. Of these, chromosome arms 5q, 14q, 17p, and 20p preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. In addition, the genes CSPG2, FLT4, SFRP1, DLK1, and GAS7 were frequently involved in regions of UPDs/UPPs and showed high levels of methylation revealing that UPDs/UPPs can result in the duplication of hypermethylated inactive genes. This dataset includes the array CGH of 30 colorectal cancers.
2015-09-02 | GSE64109 | GEO
Project description:The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs, CNAs and genome-wide methylation status in sporadic CRC. Our results indicate that regions showing high frequencies of UPDs/UPPs mostly coincide with regions typically involved in genomic losses such as chromosome arms 1p, 5q, 8p, 14q, 17p, 18q, 20p, and 22q. Of these, chromosome arms 5q, 14q, 17p, and 20p preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. In addition, the genes CSPG2, FLT4, SFRP1, DLK1, and GAS7 were frequently involved in regions of UPDs/UPPs and showed high levels of methylation revealing that UPDs/UPPs can result in the duplication of hypermethylated inactive genes.
2015-09-02 | GSE64112 | GEO
Project description:The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs, CNAs and genome-wide methylation status in sporadic CRC. Our results indicate that regions showing high frequencies of UPDs/UPPs mostly coincide with regions typically involved in genomic losses such as chromosome arms 1p, 5q, 8p, 14q, 17p, 18q, 20p, and 22q. Of these, chromosome arms 5q, 14q, 17p, and 20p preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. In addition, the genes CSPG2, FLT4, SFRP1, DLK1, and GAS7 were frequently involved in regions of UPDs/UPPs and showed high levels of methylation revealing that UPDs/UPPs can result in the duplication of hypermethylated inactive genes. This dataset includes the array CGH of 30 colorectal cancers.
2015-09-02 | GSE64110 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-09-02 | E-GEOD-64114 | biostudies-arrayexpress
Project description:The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs, CNAs and genome-wide methylation status in sporadic CRC. Our results indicate that regions showing high frequencies of UPDs/UPPs mostly coincide with regions typically involved in genomic losses such as chromosome arms 1p, 5q, 8p, 14q, 17p, 18q, 20p, and 22q. Of these, chromosome arms 5q, 14q, 17p, and 20p preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. In addition, the genes CSPG2, FLT4, SFRP1, DLK1, and GAS7 were frequently involved in regions of UPDs/UPPs and showed high levels of methylation revealing that UPDs/UPPs can result in the duplication of hypermethylated inactive genes. A total of 32 primary tumors from the colon and rectum were collected from the Hospital Clinic of Barcelona under the supervision of an experienced pathologist. DNA was extracted and bisulfited according to manufacturer's protocols. Matched patient DNA from normal mucosa was used as a reference for these experiments. This dataset includes methylation data for 29 colorectal cancers (only including those with good QC).
2015-09-02 | E-GEOD-64112 | biostudies-arrayexpress
Project description:The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs, CNAs and genome-wide methylation status in sporadic CRC. Our results indicate that regions showing high frequencies of UPDs/UPPs mostly coincide with regions typically involved in genomic losses such as chromosome arms 1p, 5q, 8p, 14q, 17p, 18q, 20p, and 22q. Of these, chromosome arms 5q, 14q, 17p, and 20p preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. In addition, the genes CSPG2, FLT4, SFRP1, DLK1, and GAS7 were frequently involved in regions of UPDs/UPPs and showed high levels of methylation revealing that UPDs/UPPs can result in the duplication of hypermethylated inactive genes. This dataset includes the array CGH of 30 colorectal cancers. A total of 30 primary tumors from the colon and rectum were collected from the Hospital Clinic of Barcelona under the supervision of an experienced pathologist. DNA was extracted and labeled according to manufacturer's protocols. Matched patient DNA from normal mucosa was used as a reference for these experiments.
2015-09-02 | E-GEOD-64110 | biostudies-arrayexpress
Project description:The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs, CNAs and genome-wide methylation status in sporadic CRC. Our results indicate that regions showing high frequencies of UPDs/UPPs mostly coincide with regions typically involved in genomic losses such as chromosome arms 1p, 5q, 8p, 14q, 17p, 18q, 20p, and 22q. Of these, chromosome arms 5q, 14q, 17p, and 20p preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. In addition, the genes CSPG2, FLT4, SFRP1, DLK1, and GAS7 were frequently involved in regions of UPDs/UPPs and showed high levels of methylation revealing that UPDs/UPPs can result in the duplication of hypermethylated inactive genes. This dataset includes the array CGH of 30 colorectal cancers. A total of 30 primary tumors from the colon and rectum were collected from the Hospital Clinic of Barcelona under the supervision of an experienced pathologist. DNA was extracted and labeled according to manufacturer's protocols. Matched patient DNA from normal mucosa was used as a reference for these experiments.
2015-09-02 | E-GEOD-64109 | biostudies-arrayexpress
Project description:Hemimegalencephaly (HME) is a heterogeneous cortical malformation characterized by enlargement of one cerebral hemisphere. Somatic variants in mammalian target of rapamycin (mTOR) regulatory genes have been implicated in some HME cases; however, ∼70% have no identified genetic etiology. Here, we screened two HME patients to identify disease-causing somatic variants. DNA from leukocytes, buccal swabs, and surgically resected brain tissue from two HME patients were screened for somatic variants using genome-wide genotyping arrays or sequencing of the protein-coding regions of the genome. Functional studies were performed to evaluate the molecular consequences of candidate disease-causing variants. Both HME patients evaluated were found to have likely disease-causing variants in DNA extracted from brain tissue but not in buccal swab or leukocyte DNA, consistent with a somatic mutational mechanism. In the first case, a previously identified disease-causing somatic single nucleotide in MTOR was identified. In the second case, we detected an overrepresentation of the alleles inherited from the mother on Chromosome 16 in brain tissue DNA only, indicative of somatic uniparental disomy (UPD) of the p-arm of Chromosome 16. Using methylation analyses, an imprinted locus on 16p spanning ZNF597 was identified, which results in increased expression of ZNF597 mRNA and protein in the brain tissue of the second case. Enhanced mTOR signaling was observed in tissue specimens from both patients. We speculate that overexpression of maternally expressed ZNF597 led to aberrant hemispheric development in the patient with somatic UPD of Chromosome 16p possibly through modulation of mTOR signaling.
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Project description:Robertsonian translocations (ROBs) are whole arm rearrangements involving the acrocentric chromosomes 13-15 and 21-22 and carriers are at increased risk for aneuploidy and thus uniparental disomy (UPD). Chromosomes 14 and 15 are imprinted with expression of genes dependent on the parental origin of the chromosome. Correction of a trisomic or monosomic conceptus for chromosomes 14 or 15 would lead to one of the established UPD 14mat/pat or UPD 15 (Prader-Willi/Angelman) syndromes (PWS/AS). In view of this, prenatal UPD testing should be considered for balanced carriers of a ROB, fetuses with a familial or de novo balanced ROB that contains chromosome 14 or 15 or with a normal karyotype when a parent is a carrier of a balanced ROB with a 14 or 15. Individuals with congenital anomalies and an abnormal phenotype and carry a ROB involving the two imprinted chromosomes should also be UPD tested.
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