Recurrent breakpoint genes in colorectal cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Daoud Sie
PROVIDER: E-GEOD-63216 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Response to drug therapy in individual colorectal cancer (CRC) patients is associated with tumor biology. Here we describe the genomic landscape of tumor samples of a homogeneous well-annotated series of patients with metastatic CRC of two phase III clinical trials, CAIRO and CAIRO2. DNA copy number aberrations of 349 patients are determined. Within three treatment arms, 194 chromosomal sub-regions are associated with progression free survival PFS (uncorrected single-test p-values < 0.005). These sub-regions are filtered for effect on mRNA expression, using an independent data set from The Cancer Genome Atlas (TCGA) which returned 171 genes. Three chromosomal regions are associated with a significant difference in PFS between treatment arms with or without irinotecan. One of these regions, 6q16.1-q21, correlates in vitro with sensitivity to SN-38, the active metabolite of irinotecan. This genomic landscape of metastatic CRC reveals a number of DNA copy number aberrations associated with response to drug therapy. aCGH data of colorectal cancers of patients from 2 clinical trials (CAIRO, CAIRO2). 105 patients were treated with capecitabine first line (CAIRO arm A), 111 patients were treated with capecitabine and irinotecan first line (CAIRO arm B), and 133 patients were treated with capecitabine, oxaliplatin and bevacizumab (CAIRO2 arm A).
2014-11-14 | E-GEOD-36864 | biostudies-arrayexpress
Project description:Background & Aims: The metastatic process is complex and remains a major obstacle in the management of colorectal cancer (CRC). To gain a better insight into the biologic events driving the metastatic process we investigated genomic aberrations in a large cohort of matched CRC primaries and distant metastases from various sites. Methods: In total, 62 primary colorectal cancers, 62 matched normal specimens, and 68 matched metastases (from liver, lung, ovary, omentum, and distant lymph nodes) were analyzed by high resolution array comparative genomic hybridization (array CGH) for DNA copy number changes. Findings were validated using a publicly available dataset consisting of 21 primary tumors and matched liver metastases. Fluorescence in situ hybridization (FISH) was used to confirm some of the DNA copy number changes observed. Results: Overall patterns of DNA copy number aberrations were highly similar between primary tumors and their metastases, confirming clonality. Additional copy number aberrations in metastasis are rare and rather than recurrent they were sporadic for individual patients. The only recurrent differences between primary tumors and their metastases were two chromosomal regions, 6q21 and 8q24.21 encompassing the MYC oncogene, that coamplified in three metastases of two patients (3.2%). FISH analysis confirmed the high level co-amplification in the metastasis, which were not detected in their primary tumors. Conclusions: Primary CRC and their metastases show highly similar patterns of DNA copy number changes, additional copy number aberrations in metastasis are rare and recurrences exceptional. These observations are consistent with the hypothesis that the metastatic potential is predestined early in the development of the primary tumor. In total, 62 primary colorectal cancers, 62 matched normal specimens, and 68 matched metastases (liver, lung, ovarian, omentum and distant lymph nodes) were analyzed by high resolution array comparative genomic hybridization (array CGH).
2014-02-10 | E-GEOD-38479 | biostudies-arrayexpress
Project description:BACKGROUND: Infection with high-risk types of human papillomavirus (hrHPV) is associated with cervical, anogenital and oropharyngeal cancers. A role for hrHPV in lung cancer has been proposed, although previous reports on the contribution of hrHPV infection to lung cancer have provided contradictory results. The current study evaluated hrHPV prevalence in lung tumor specimens of different histological subtypes in a Western study population using a validated test algorithm for hrHPV detection in formalin-fixed paraffin-embedded (FFPE) tumor specimen (i.e., GP5+6+-PCR and p16INK4A immunohistochemistry). MATERIALS AND METHODS: Tumor tissue specimens from 228 lung cancer patients were subjected to GP5+6+-PCR and p16INK4A immunohistochemistry. hrHPV-positive tumors were further characterized using genotyping of GP5+/6+-PCR products, HPV E7 transcript analysis, loss of heterozygosity (LOH) analysis and array comparative genomic hybridization (arrayCGH), and the clinical history of patients was retrieved. RESULTS: Three patients (3/228, 1.3%) with hrHPV-positive lung tumors were identified, revealing hrHPV types 16, 18 and 33, respectively. All three patients (1 male, 2 females) had a history of hrHPV-associated disease; two cervical carcinoma, and one oropharyngeal carcinoma. Further characterization revealed identical hrHPV genotype, pattern of p16INK4A expression, HPV E7 mRNA expression, and genomic aberrations in the individual pairings of lung tumor and foregoing hrHPV-associated cancer. CONCLUSION: The present study found molecular evidence that supports association of hrHPV in lung cancer with the presence of pulmonary metastasis of a hrHPV-positive cancer that originated elsewhere, and not with primary lung cancer in a Western population. 2 lung cancer samples (FFPE), 1 cervical cancer sample (FFPE), 1 head and neck cancer sample (FFPE)
2013-07-01 | E-GEOD-40777 | biostudies-arrayexpress
Project description:The genetic cause for PPB in association with renal tumor and small bowel polyps remains to be identified. Activation of components of the mTOR signalling pathway in the disease lesions suggests that this signal transduction route may be involved in disease pathogenesis and that rapamycin, an inhibitor of mTOR, might be effective in the treatment of PPB and associated lesions. A combination of molecular cytogenetics and gene-specific mutation screens were performed to search for an underlying genetic cause for PPB in association with small bowel polyps. Immunohistochemical analysis to measure mTOR activation was performed on tissue from renal and lung tumor and small bowel polyps from the index case
2010-04-02 | E-GEOD-15521 | biostudies-arrayexpress
Project description:Human papillomavirus (HPV) induced immortalization of human foreskin keratinocytes (HFK) is a two-step process, including 1) the bypass of replicative senescence and acquisition of an extended lifespan, and 2) the outgrowth of immortal cells. Our previous study showed that the immortalization capacity of HPV is type dependent, as reflected by the presence or absence of a crisis period before reaching immortality. In the present study we determined how the HPV-type specific immortalization capacity relates to DNA damage induction and overall genomic instability. Early passage HFKs transduced with HPV types 16, 18, 31, 33, 35, 45, 51, 59, 66 and 70 showed an increased number of double strand DNA breaks compared to controls, without significant differences between the various HPV-types. However, immortal descendants of HPV-transduced HFKs that underwent a crisis period (HPV45-, 51-, 59-, 66- and 70-transduced HFKs) showed significantly more chromosomal aberrations compared to those without a crisis period (HPV16-, 18-, 31-, and 35-transduced HFKs) (p<0.01). In particular, regions on chromosome 5p, 8, and 9q were significantly more frequently altered in cells with crisis. Interestingly, the hTERT locus at 5p was exclusively gained in cell lines with crisis. Chromothripsis was detected in one of the HPV16-immortalized cell lines in which multiple rearrangements within chromosome 8 resulted in a gain of c-MYC. In conclusion, the present study shows that upon HPV-induced immortalization, the number of chromosomal aberrations is inversely related to the immortalization capacity of the virus type. This suggests that hrHPV types with reduced immortalization capacity in vitro, as reflected by a crisis period, require more genetic host cell aberrations to trigger immortalization. DNA copy number analysis of human keratinocytes transformed by high-risk HPV
2016-08-01 | E-GEOD-72063 | biostudies-arrayexpress
Project description:BACKGROUND: Because of the distinct clinical presentation of early and advanced stage ovarian cancer, we aim to clarify whether these disease entities are solely separated by time of diagnosis or whether they arise from distinct molecular events. METHODS: Sixteen early and sixteen advanced stage ovarian carcinomas, matched for histological subtype and differentiation grade, were included. Genomic aberrations were compared for each early and advanced stage ovarian cancer by array comparative genomic hybridization. To study how the aberrations correlate to the clinical characteristics of the tumors we clustered tumors based on the genomic aberrations. RESULTS: The genomic aberration patterns in advanced stage cancer equalled those in early stage, but were more frequent in advanced stage (p?=?0.012). Unsupervised clustering based on genomic aberrations yielded two clusters that significantly discriminated early from advanced stage (p?=?0.001), and that did differ significantly in survival (p?=?0.002). These clusters however did give a more accurate prognosis than histological subtype or differentiation grade. CONCLUSION: This study indicates that advanced stage ovarian cancer either progresses from early stage or from a common precursor lesion but that they do not arise from distinct carcinogenic molecular events. Furthermore, we show that array comparative genomic hybridization has the potential to identify clinically distinct patients. Sixteen early and sixteen advanced stage ovarian carcinomas
2012-08-22 | E-GEOD-24418 | biostudies-arrayexpress
Project description:Nodal marginal zone lymphoma is a poorly defined entity in the WHO classification, largely based on criteria by exclusion and the diagnosis often remains subjective. Follicular Lymphoma lacking t(14;18), have similar characteristics which results in a major potential diagnostic overlap which this study aims to dissect. Four subgroups of lymphoma samples (n=56) were analyzed with high-resolution arrayCGH; Nodal marginal zone lymphoma, t(14;18)-negative Follicular Lymphoma, localized t(14:18)-positive Follicular Lymphoma and disseminated t(14;18)-positive Follicular Lymphoma. Gains on chromosomes 7, 8 and 12 were observed in all subgroups. The mean number of aberrations was higher in disseminated t(14;18)-positive Follicular Lymphoma compared to localized t(14:18)-positive Follicular Lymphoma (p<0.01) and the majority of alterations in localized t(14:18)-positive Follicular Lymphoma were also found in disseminated t(14;18)-positive Follicular Lymphoma. Nodal marginal zone lymphoma was marked by 3q gains with amplifications of four genes. A different overall pattern of aberrations was seen in t(14;18)-negative Follicular Lymphoma compared to t(14;18)-positive Follicular Lymphoma. t(14;18)-negative Follicular Lymphoma is marked by specific (focal) gains on chromosome 3 as observed in Nodal marginal zone lymphoma. Our results support the notion that localized t(14:18)-positive Follicular Lymphoma represents an early phase of disseminated t(14;18)-positive Follicular Lymphoma. t(14;18)-negative Follicular Lymphoma bears aberrations that are more alike Nodal marginal zone lymphoma, suggesting a relation between these groups. Four subgroups of follicular lymphoma were analyzed: NMZL (n=14), t-FL (n=12), LOC t+FL (n=16), DIS t+FL (n=14).
2013-07-16 | E-GEOD-40641 | biostudies-arrayexpress
Project description:Background & aim: Flat adenomas form a specific phenotype of colorectal adenomas that has been associated with more severe molecular changes and consequently a more aggressive clinical behavior compared to their polypoid counterparts. In the present study we set out to compare one of the molecular changes most explicitly associated with adenoma to carcinoma progression, i.e. chromosomal instability, between flat and polypoid colorectal adenomas. Methods: Consecutive series of 83 flat and 35 polypoid adenomas were analyzed for DNA copy number changes using a high resolution arrayCGH platform as well as for mutations in the adenomatous polyposis coli (APC) gene. Gene ontology on the genes located on the significantly different regions was performed. Results: Overall, flat adenomas show similar DNA copy number changes as polypoid adenomas. Patterns of DNA copy number changes differed between the two phenotypes with significantly more frequently loss of 5q14.3 and 5q15-q23.3 in flat adenomas, while loss of 1p36.32-p35.3, 10q25.2-q25.3, 17p12 and chromosome 18 were more frequent in polypoid adenomas. The 5q15-q23.3 region harbors the APC locus, therefore mutation status of APC was investigated, showing significantly less mutations in flat adenomas. Pathway analysis and datamining linked the 5q region to inflammation. Conclusion: These results provide evidence that flat and polypoid adenomas have partly overlapping DNA copy number changes, while alterations more specific to flat adenomas have associations with inflammation. Loss of 5q has been associated with aggressive behavior and this could serve as an explanation for a more aggressive clinical behavior of flat lesions. FFPE colorectal tissue samples of 35 polypoid adenomas and 83 flat adenomas. Test samples were compared to an external pool of normal male/female reference DNA.
2012-10-04 | E-GEOD-30479 | biostudies-arrayexpress
Project description:Genomic profiling of human squamous cell carcinoma cell lines cells and corresponding primary tumors Descriptive experiment, studying DNA copy number alterations in 6 newly established human squamous cell carcinoma cell lines cells and corresponding 6 primary tumors.
2014-04-30 | E-GEOD-57201 | biostudies-arrayexpress
Project description:High-resoution array comparative genomic hybridization of pulmonary carcinoids with a favorable and a poor disease outcome. Data set from a complementary experiment looking for differentially expressed genes is also deposited at ArrayExpress under accession ID E-MEXP-3790 (http://www.ebi.ac.uk/arrayexpress/experiments/E-MEXP-3790).
2013-06-21 | E-MEXP-3806 | biostudies-arrayexpress