Analysis of copy number profiles of several tumor samples of same patient reveals the successive steps in tumorigenesis
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Eric Letouzé
PROVIDER: E-GEOD-19195 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:We present the first computational approach to reconstruct the sequence of copy number alterations driving carcinogenesis from the analysis of several tumor samples of a same patient. Applied to BAC array-CGH and SNP array data from bladder and breast cancers, this method proved highly valuable to establish the clonal relationships between primary tumors and recurrences and to identify the chromosome aberrations at the initiation of tumorigenesis. Keywords: Comparative Genomic Hybridization An algorithm was developed to reconstruct tumors lineage and the sequence of copy number alterations along tumorigenesis from the analysis of several samples from a same patient. The data here consist in CGH data from 58 bladder tumors. 50 of these tumors come from independent samples and were used to compute the frequencies of breakpoints at each location. The 8 other samples (S1_A, S1_B, S2_A, S2_B, S3_A, S3_B, S3_C and S3_D) are multiple tumors from 3 patients. They were used to reconstruct the sequence of chromosome aberrations along cancer development in these 3 patients.
2010-05-19 | E-GEOD-19193 | biostudies-arrayexpress
Project description:We used genome-wide microarray comparative genomic hybridization to investigate the response of control HT1080 cells and HT1080 cells infected with a lentivirus expressing eGFP, GLI2-eGFP or CCND1-RFP to challenge with methotrexate to address the question if GLI2 overexpression induces genomic instability. Keywords: aCGH Array CGH experiments of cell line genomic DNA as test samples and normal human genomic DNA as reference sample.
2009-01-05 | E-GEOD-10132 | biostudies-arrayexpress
Project description:Background: Germline polymorphisms can influence gene expression networks in normal mammalian tissues and can affect disease susceptibility. We and others have shown that analysis of this genetic architecture can identify single genes and whole pathways that influence complex traits including inflammation and cancer susceptibility. Whether germline variants affect gene expression in tumors which have undergone somatic alterations, and the extent to which these variants influence tumor progression, is unknown. Results: Using an integrated linkage and genomic analysis of a mouse model of skin cancer that produces both benign tumors and malignant carcinomas, we document major changes in germline control of gene expression during skin tumor development resulting from cell selection, somatic genetic events, and changes in the tumor microenvironment. The number of significant expression Quantitative Trait Loci (eQTLs) is progressively reduced in benign and malignant skin tumors when compared to normal skin. However, novel tumor-specific eQTLs are detected for several genes associated with tumor susceptibility, including Interleukin 18, Granzyme E, Sprouty homolog 2, and MAP kinase kinase 4. Conclusions: We conclude that the genetic architecture is substantially altered in tumors, and that eQTL analysis of tumors can identify host factors that influence the tumor microenvironment, MAP kinase signaling, and cancer susceptibility. A backcross was generated using male Mus spretus and female FVB/N mice; female F1 hybrids were mated with male FVB/N mice. Backcross mice (8-12 weeks old) received a single dose of DMBA (25 µg per mouse in 200 µl acetone). Starting one week after the initiation tumors were promoted with TPA (200 µl of 10-4 M solution in acetone) twice weekly for 20 weeks. Initiation and promotion were performed on doral back skin. DNA from 62 Carcinomas and matched untreated tails (used for normal DNA comparison) was obtained from tissue that was snap frozen when animals were sacrificed.
2010-12-23 | E-GEOD-26273 | biostudies-arrayexpress
Project description:Co-amplification at chromosomes 8p11-8p12 and 11q12-11q14 occurs often in breast tumors, suggesting possible cooperation between genes in these regions in oncogenesis. We used high resolution array comparative genomic hybridization (array CGH) to map the minimal amplified regions. The 8p and 11q amplicons are complex and consist of at least four amplicon cores at each site. Candidate genes mapping to these regions were identified by combining copy number and RNA and protein expression analyses. Funcational analysis for transformation was further carried out with candidate genes to determine candidate oncogenes. Near tiling path coverage of 8p11q array CGH experiments with breast cell lines and ductal invasive and lymph node-negative breast tumors.
2009-09-02 | E-GEOD-12761 | biostudies-arrayexpress
Project description:Primary serous ovarian carcinoma (OVCA) and serous Fallopian tube carcinoma (FTC), both belonging to the BRCA-linked tumour spectrum, share many properties and are treated similarly. However, a detailed molecular comparison has been lacking. We hypothesized that comparative genomic studies of serous OVCAs and FTCs should point to gene regions critically involved in their tumorigenesis. Array comparative genomic hybridization (array CGH) analysis indicated that serous OVCAs and serous FTCs displayed common but also more distinctive patterns of recurrent changes. Targeted gene identification using a dedicated multiplex ligation-dependent probe amplification (MLPA) probe set directly identified EIF2C2 on 8q as a potentially important driver gene. Other previously unappreciated gained/amplified genes included PSMB4 on 1q, MTSS1 on 8q, TEAD4 and TSPAN9 on 12p, and BCAS4 on 20q. SPINT2 and ACTN4 on 19q were predominantly found in FTCs. Gains/amplifications of CCNE1 and MYC, often in conjunction with changes in genes of the AKT pathway, EVI1 and PTK2, seemed to be involved at earlier stages, whereas changes of ERBB2 were associated with advanced stages. The only BRCA1-mutated FTC shared common denominators with the sporadic tumours. In conclusion, the data suggest that serous OVCAs and FTCs, although related, exhibit differences in genomic profiles. In addition to known pathways, new genes/pathways are likely to be involved, with changes in an miRNA-associated gene, EIF2C2, as one important new feature. Dedicated MLPA sets constitute potentially important tools for differential diagnosis and may provide footholds for tailored therapy. This study also includes 13 of the 14 Fallopian tube carcinoma samples T10112, T10119, T10116, T10118, T10121, T10129, T10109, T10125, T10117, T10126, T10102c, T10107, T10131a (i.e., GSM172360..GSM172530) in Series GSE7180. Genome-wide array CGH experiments of serous ovarian and Fallopian tube carcinomas to determine DNA-change profiles for both tumour types.
2008-07-08 | E-GEOD-12040 | biostudies-arrayexpress
Project description:Basal cell carcinomas (BCCs) have relative genomic stability and relatively benign clinical behavior but whether these two are related causally is unknown. To investigate the effects of introducing genomic instability into murine BCCs, we have compared ionizing radiation-induced tumorigenesis in Ptch1+/- mice vs. that in Ptch1+/- mice carrying mutant Blm alleles. We found that BCCs in Ptch1+/- Blmtm3Brd/tm3Brd mice had a trend towards greater genomic instability as measured by array CGH and that these mice developed significantly more microscopic BCCs than did Ptch1+/- Blm+/tm3Brd or Ptch1+/- Blm+/+ mice. The mutant Blm alleles also markedly enhanced the formation of rhabdomyosarcomas (RMS), another cancer to which Ptch1+/- mice and PTCH1+/- (basal cell nevus syndrome) patients are susceptible. Highly recurrent but different copy number changes were associated with the two tumor types and included losses of chromosomes 4 and 10 in all BCCs and gain of chromosome 10 in 80% of RMSs. Loss of chromosome 11 and 13, including the Trp53 and Ptch1 loci respectively, occurred frequently in BCCs, suggesting tissue-specific selection for genes or pathways that collaborate with Ptch deficiency in tumorigenesis. Despite the quantitative differences, there was no dramatic qualitative difference in the BCC or RMS tumors associated with the mutant Blm genotype. We investigated the effect of Blm deficiency on ionizing radiation-induced basal cell carcinoma and rhabdomyosarcoma tumorigenesis in Ptch1+/- mice. Six BCC and five RMS samples were obtained from separate mice. Liver tissue from each mouse was used as the normal reference.
2010-05-15 | E-GEOD-19880 | biostudies-arrayexpress
Project description:Breast cancers that are “triple-negative” for the clinical markers ESR1, PGR, and HER2 typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that the combined inactivation of Rb and p53 pathways is sufficient to suppress the physiological cell death of mammary involution. Furthermore, concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency and predisposes highly penetrant, metastatic adenocarcinomas. The tumors are poorly differentiated and have histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Gene expression analyses demonstrate that the tumors share attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader, triple-negative class defined by clinical markers. These studies establish a unique animal model of aggressive forms of breast cancer for which there are no effective, targeted treatments. Rb, p53, and Brca1 are associated with inherited forms of cancer, but defects in these pathways are also found together in a subset of breast cancer patients without a family history of the disease. Simultaneous inactivation of all three pathways causes more aggressive disease than do pair-wise combinations, indicating that the pathways play non-overlapping roles in tumor prevention. We investigated the effect of perturbation of Rb family pathways, p53, and/or Brca1 in mouse mammary epithelium. Eighteen tumors were compared to normal spleen DNA.
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