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Unsupervised two-view learning, or detection of dependencies between two paired data sets, is typically done by some variant of canonical correlation analysis (CCA). CCA searches for a linear projection for each view, such that the correlations between the projections are maximized. The solution is invariant to any linear transformation of either or both of the views; for tasks with small sample size such flexibility implies overfitting, which is even worse for more flexible nonparametric orarXiv:1101.5919v1 fatcat:4mnjxltdofffzome7fyg6iwk7u
more »... nel-based dependency discovery methods. We develop variants which reduce the degrees of freedom by assuming constraints on similarity of the projections in the two views. A particular example is provided by a cancer gene discovery application where chromosomal distance affects the dependencies between gene copy number and activity levels. Similarity constraints are shown to improve detection performance of known cancer genes.
The association of microRNA alterations with progression and treatment outcome has been revealed in different types of cancers. To find miRNAs involved in imatinib response we performed miRNA microarray followed by RT-qPCR verification of 9 available diagnostic bone marrow core biopsies from 9 CML patients including 4 imatinib-resistant and 5 imatinib-responder patients. Only one differentially expressed miRNA, miR-181c, was found when the imatinib-resistant group was compared withdoi:10.1186/1755-8166-6-27 pmid:23866735 pmcid:PMC3751646 fatcat:ljtxocdjtrgrndtbvbbnh5yhfu
more »... onders. Significant down-regulation of miR-181c in imatinib-resistant versus imatinib-responders was confirmed by qRT-PCR. Some miR-181c target genes such as PBX3, HSP90B1, NMT2 and RAD21 have been associated with drug response.
The genetic changes leading to thyroid cancer are poorly characterized. We studied DNA copy number changes by comparative genomic hybridization (CGH) in 69 primary thyroid carcinomas. In papillary carcinoma , DNA copy number changes were rare (3 of 26 , 12%). The changes were all gains , and they were associated with old age (P ؍ 0.01) and the presence of cervical lymph node metastases at presentation (P ؍ 0.08). DNA copy number changes were much more frequent in follicular carcinoma (16 ofdoi:10.1016/s0002-9440(10)65407-7 pmid:10329606 pmcid:PMC1866579 fatcat:nw7je2b6xfbunfn7oxwyy52m7u
more »... 20, 80%) than in papillary carcinoma (P < 0.0001), and follicular carcinomas had more often deletions (13/20 versus 0/26 , P < 0.0001). Loss of chromosome 22 was common in follicular carcinoma (n ؍ 7 , 35%) , it was more often seen in widely invasive than in minimally invasive follicular carcinoma (54% versus 0% , P ؍ 0.04) , and it was associated with old age at presentation (P ؍ 0.01). In three of the four patients with follicular carcinoma who died of cancer , the tumor had loss of chromosome 22. DNA copy number changes were found in 5 (50%) of the 10 medullary carcinomas studied. Four of these five carcinomas had deletions , and in two of them there was deletion of chromosome 22. Eleven (85%) of the thirteen anaplastic carcinomas investigated had DNA copy number changes , of which five had deletions , and one had deletion of chromosome 22. The most common gains in anaplastic carcinoma were in chromosomes 7p (p22-pter , 31%) , 8q (q22-qter , 23%) , and 9q (q34qter , 23%). We conclude that DNA copy number changes are frequent in follicular , medullary, and anaplastic thyroid carcinoma but rare in papillary carcinoma when studied by CGH. Loss of chromosome 22 is particularly common in follicular carcinoma , and it is associated with the widely invasive type. (Am J Pathol 1999, 154:1539 -1547) The great majority of all thyroid cancers are either papillary, follicular, or anaplastic carcinomas, which are thought to be derived from follicular cells. Only 5% to 10% are medullary carcinomas, which originate from the C-cells. 1 This histopathological classification of thyroid carcinomas into four major subtypes has been considered as established, and each of the four entities have typical clinical features. Papillary carcinoma frequently gives rise to cervical lymph node metastases, but distant metastases are rare. This pattern is reversed in follicular carcinoma, which often has distant bone metastases, but cervical lymph node metastases are rare. Papillary and follicular carcinoma are frequently found in the same thyroid as anaplastic carcinoma, suggesting that some anaplastic carcinomas originate from pre-existing differentiated carcinoma. 2, 3 The molecular genetic events in the evolution of different types of thyroid carcinomas are poorly characterized. However, the central role of mutations in the RET protooncogene, located at 10q11.2, in the genesis of hereditary medullary thyroid carcinoma is now well recognized, and used in screening of this disorder. More than 95% of patients with MEN 2A have missense germ line mutations that involve either exon 10 or 11 of this receptor tyrosine kinase, 4 and all patients with MEN 2B have the same missense mutation in RET exon 16 at amino acid position 918 within what is predicted to be the tyrosine kinase catalytic domain. 5 Moreover, sporadic medullary carcinomas have somatic mutations in RET codon 918 in 33% to 67% of cases, 6 and familial non-MEN medullary carcinomas display also frequently RET mutations. 7 A hypodiploid chromosomal number in the range of 34 to 44 has been found in primary medullary carcinoma tissue. 8, 9 Medullary carcinoma has been found to be associated with a constitutional minute deletion in the short arm of chromosome 20 (del(20)(p12.2)). 10 In cytogenetic studies, only ϳ30 cases with clonal chromosomal abnormalities have been described in papillary carcinoma.          The karyotypic abnormalities are usually simple. An intrachromosomal rearrangement inv(10)(q11q21) resulting in the juxtaposition of sequences encoding the intracellular tyrosine kinase domain of RET with 5Ј sequences from one of three unrelated genes has been considered as characteristic and has been identified in up to 30% of papillary carcinomas. 12, 14, 15, 17, 20 In many cases, it has been the only anomaly. Activation of other receptor tyrosine kinase genes, such as the proto-oncogenes TRK (encodes a cell Supported by grants from the
Olfactory neuroblastoma is an unusual neuroectodermal malignancy, which is thought to arise at the olfactory membrane of the sinonasal tract. Due to its rarity, little is understood regarding its molecular and cytogenetic abnormalities. The aim of the current study is to identify specific DNA copy number changes in olfactory neuroblastoma. Thirteen dissected tissue samples were analyzed using array comparative genomic hybridization. Our results show that gene copy number profiles of olfactorydoi:10.1038/modpathol.2008.57 pmid:18408657 fatcat:sdsapkhdencp5mkacjf4lt7pdu
more »... uroblastoma samples are complex. The most frequent changes included gains at 7q11.22-q21.11, 9p13.3, 13q, 20p/q, and Xp/q, and losses at 2q31.1, 2q33.3, 2q37.1, 6q16.3, 6q21.33, 6q22.1, 22q11.23, 22q12.1, and Xp/q. Gains were more frequent than losses, and high-stage tumors showed more alterations than low-stage olfactory neuroblastoma. Frequent changes in high-stage tumors were gains at 13q14.2-q14.3, 13q31.1, and 20q11.21-q11.23, and loss of Xp21.1 (in 66% of cases). Gains at 5q35, 13q, and 20q, and losses at 2q31.1, 2q33.3, and 6q16-q22, were present in 50% of cases. The identified regions of gene copy number change have been implicated in a variety of tumors, especially carcinomas. In addition, our results indicate that gains in 20q and 13q may be important in the progression of this cancer, and that these regions possibly harbor genes with functional relevance in olfactory neuroblastoma.
Sakari Knuutila Kirsi Autio Yan Aalto Haartman Institute and Helsinki University Hospital Helsinki, Finland Correction In the article entitled Bone Marrow in Polycythemia Vera, Chronic Myelocytic Leukemia ...doi:10.1016/s0002-9440(10)64579-8 pmid:10934171 pmcid:PMC1850112 fatcat:qy5gfnjnwnhvjh2f2ib4rblmba
BMC Medical Genomics
DNA amplifications alter gene dosage in cancer genomes by multiplying the gene copy number. Amplifications are quintessential in a considerable number of advanced cancers of various anatomical locations. The aims of this study were to classify human cancers based on their amplification patterns, explore the biological and clinical fundamentals behind their amplificationpattern based classification, and understand the characteristics in human genomic architecture that associate withdoi:10.1186/1755-8794-1-15 pmid:18477412 pmcid:PMC2397431 fatcat:bbg2tjciyzentouovzxq6yfnii
more »... mechanisms. Methods: We applied a machine learning approach to model DNA copy number amplifications using a data set of binary amplification records at chromosome sub-band resolution from 4400 cases that represent 82 cancer types. Amplification data was fused with background data: clinical, histological and biological classifications, and cytogenetic annotations. Statistical hypothesis testing was used to mine associations between the data sets. Results: Probabilistic clustering of each chromosome identified 111 amplification models and divided the cancer cases into clusters. The distribution of classification terms in the amplificationmodel based clustering of cancer cases revealed cancer classes that were associated with specific DNA copy number amplification models. Amplification patterns -finite or bounded descriptions of the ranges of the amplifications in the chromosome -were extracted from the clustered data and expressed according to the original cytogenetic nomenclature. This was achieved by maximal frequent itemset mining using the cluster-specific data sets. The boundaries of amplification patterns were shown to be enriched with fragile sites, telomeres, centromeres, and light chromosome bands. Conclusions: Our results demonstrate that amplifications are non-random chromosomal changes and specifically selected in tumor tissue microenvironment. Furthermore, statistical evidence showed that specific chromosomal features co-localize with amplification breakpoints and link them in the amplification process.
Only 29 cases of constitutional 9q22 deletions have been published and all have been sporadic. Most associate with Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS, MIM #109400) due to haploinsufficiency of the PTCH1 gene (MIM *601309). Methods and Results: We report two mentally retarded female siblings and their cognitively normal father, all carrying a similar 5.3 Mb microdeletion at 9q22.2q22.32, detected by array CGH (244 K). The deletion does not involve the PTCH1 gene, butdoi:10.1186/1750-1172-6-45 pmid:21693067 pmcid:PMC3135502 fatcat:vmo24lycjbdj7d6t7cg5h5sjue
more »... nstead 30 other gene,s including the ROR2 gene (MIM *602337) which causing both brachydactyly type 1 (MIM #113000) and Robinow syndrome (MIM #268310), and the immunologically active SYK gene (MIM *600085). The deletion in the father was de novo and FISH analysis of blood lymphocytes did not suggest mosaicism. All three patients share similar mild dysmorphic features with downslanting palpebral fissures, narrow, high bridged nose with small nares, long, deeply grooved philtrum, ears with broad helix and uplifted lobuli, and small toenails. All have significant dysarthria and suffer from continuous middle ear and upper respiratory infections. The father also has a funnel chest and unilateral hypoplastic kidney but the daughters have no malformations. Conclusions: This is the first report of a familial constitutional 9q22 deletion and the first deletion studied by array-CGH which does not involve the PTCH1 gene. The phenotype and penetrance are variable and the deletion found in the cognitively normal normal father poses a challenge in genetic counseling. Methods Cytogenetic analysis Chromosome metaphase spreads of patients 1, 3, and the healthy mother were analyzed by standard G-banding karyotype analysis (400 band resolution). Additional subtelomere-fluoresence in situ hybridization (FISH)
Distinct characteristic features categorize Merkel cell carcinoma (MCC) into two subgroups according to the Merkel cell polyomavirus infection. Many mutational studies on MCC have been carried out in recent years without identifying a prominent driver mutation. However, there is paucity reporting the expression of cancer genes at the RNA level in MCC tumors. In this study, we studied the RNA expression profiles of 26 MCC tumors, with a goal to identify prospective molecular targets that coulddoi:10.1186/s12885-017-3233-5 pmid:28359267 pmcid:PMC5374569 fatcat:ccszva3clrhzzdklfypfefok74
more »... prove the treatment strategies of MCC. Methods: RNA expression of 50 cancer-related genes in 26 MCC tumors was analyzed by targeted amplicon based next-generation sequencing using the Ion Torrent technology and the expression compared with that of normal, non-cancerous skin samples. Sequencing data were processed using Torrent Suite™ Software. Expression profiles of MCV-negative and MCV-positive tumors were compared. Fluorescence in situ hybridization was performed to study ALK rearrangements and immunohistochemistry to study ALK expression in tumor tissue. Results: ALK, CDKN2A, EZH2 and ERBB4 were overexpressed, and EGFR, ERBB2, PDGFRA and FGFR1 were underexpressed in MCC tumors compared to normal skin. In the MCV-negative tumors, MET, NOTCH1, FGFR3, and SMO were overexpressed and JAK3 and NPM1 were under-expressed compared to the MCV-positive tumors. Conclusions: High expression of ALK, CDKN2A and EZH2 was recorded in MCC tumors. No ALK fusion was seen by FISH analysis. Overexpression of EZH2 suggests its potential as a drug target in MCC.
Syventävien opintojen kirjallinen työ Tampereen yliopisto Lääketieteen yksikkö Toukokuu 2014 ______________________________________________________ Tampereen yliopisto Lääketieteen yksikkö Lastentautien tutkimuskeskus Nelli Vanhapiha: Burkitt lymphoma and Ewing sarcoma in a child with Williams syndrome Kirjallinen työ, 5 s. Ohjaaja: dosentti Olli Lohi Toukokuu 2014 Avainsanat: kromosomitranslokaatio, kehityshäiriö, syöpäriski ______________________________________________________ Tiivistelmädoi:10.1002/pbc.25055 pmid:24753445 fatcat:7nxjhkf4qnc3rixchypm3pwx3i
more »... ausseloste Williamsin syndroomaa sairastavasta lapsesta, jolla diagnosoitiin ensin Burkittin lymfooma ja myöhemmin Ewingin sarkooma Williamsin syndrooma on verrattain harvinainen kehityshäiriö (prevalenssi 1/10 000), jonka saa aikaan kromosomaalinen mikrodeleetio toisessa kromosomin 7 kopiossa alueella 11q23. Noin 28 geenin kattava deleetio saa aikaan tyypillisen fenotyypin, johon kuuluu sydämen epämuodostuma (tavallisesti supravalvulaarinen aorttastenoosi), tyypilliset kasvonpiirteet sekä älyllinen kehitysvammaisuus, joka on vaihtelevan tasoista. Oireyhtymälle tyypillisiin neurokognitiivisiin erityispiirteisiin kuuluvat kielen kehityksen viivästyminen, puutteet näönvaraisessa tulkinnassa sekä ylenpalttinen empaattisuus. Williamsin syndrooman ei ole osoitettu lisäävän riskiä sairastua syöpään. Kuitenkin useat julkaisut ovat osoittaneet, että kromosomin 7 mutaatiot ovat tavallisia useissa erityyppisissä kasvaimissa. Erityisesti hematologisissa maligniteeteissa ja pediatrisissa sarkoomissa kromosomitranslokaatiot ovat yleisiä, mutta mekanismi, joka saa aikaan translokaation syntymisen, ymmärretään vain osittain. Kuvaamme ainutlaatuisen potilaan, jolla on varhaislapsuudessa diagnosoitu kehityshäiriö, Williamsin syndrooma. Potilas sairasti myöhemmin sekä Burkittin lymfooman että Ewingin sarkooman. Molempien syöpien osalta potilas on nyt remissiossa. Edeltävästi kirjallisuudessa on raportoitu ainoastaan 14 tapausta, joissa Williamsin syndroomaa sairastavalla on diagnosoitu jokin maligniteetti, eikä ainuttakaan, jossa sairastettuja syöpiä olisi useampi. Abstract Williams syndrome (WS) is a relatively rare multisystem neurodevelopmental disorder caused by a hemizygous deletion of contiguous genes on chromosome 7q11.23. Although WS does not predispose carriers to cancers, alterations of chromosome 7 are common in several human neoplasms. We report here a patient with WS and two different cancers, Burkitt lymphoma and Ewing sarcoma. Array-CGH analysis of the patient blood revealed a constitutive 1.4 million base pair deletion at 7q11.23, compatible with WS diagnosis.
We show the molecular mechanisms involved in Darpp-32 overexpression and its biological role in upper gastrointestinal adenocarcinomas (UGC). A tumor tissue array of 377 samples was developed and used to detect DARPP-32 DNA amplification and protein overexpression, which occurred in 32% and 60% of UGCs, respectively. Concomitant overexpression of mRNA for Darpp-32 and its truncated isoform t-Darpp was observed in 68% of tumors (P < 0.001). When Darpp-32 and t-Darpp were overexpressed in AGS anddoi:10.1158/0008-5472.can-05-1433 pmid:16061638 fatcat:7daw4vvitvc2lpx3mugjdjqvsu
more »... RKO gastrointestinal cells, up to a 4-fold reduction in the apoptosis rate was observed (terminal deoxynucleotidyl transferase-mediated nick-end labeling and Annexin V assays) in response to camptothecin, sodium butyrate, and ceramide. However, the introduction of mutations in phosphorylation sites abrogated this effect. Expression of Darpp-32 and t-Darpp preserved the mitochondrial transmembrane potential and was associated with increased levels of Bcl2 protein. A reversal of Bcl2 protein level was obtained using small interfering RNAs for Darpp-32 and t-Darpp. Luciferase assays using the p53 and p21 reporter plasmids and probing of immunoblots with antibodies specific for p53 transcriptional targets, such as Hdm2 and p21, indicated that neither Darpp-32 nor t-Darpp interfere with p53 function. Altogether, we show more frequent mRNA and protein overexpression of Darpp-32 than DNA amplification, suggesting that, in addition to amplification, transcriptional or posttranscriptional mechanisms may play an important role. The expression of Darpp-32 and t-Darpp is associated with a potent antiapoptotic advantage for cancer cells through a p53-independent mechanism that involves preservation of mitochondrial potential and increased Bcl2 levels. (Cancer Res 2005; 65(15): 6583-92)
We performed a comparative genomic hybridization study on 25 lung adenocarcinoma samples from younger patients (<41 y of age) and compared the results with a previous comparative genomic hybridization analysis of lung adenocarcinoma samples from older patients (50 -81 y of age). Twenty of the 25 tumor samples from younger patients had DNA copy number changes. Gains, losses, and high-level amplifications were seen more frequently in the specimens from the younger group. The most strikingdoi:10.1038/modpathol.3880533 pmid:11950910 fatcat:lrymjgeponhj5ggup2uj3r4sja
more »... ce between the two groups was the high frequency of gains and/or highlevel amplifications in the long arm of chromosome 20 in the samples from the younger patients (14/25, 56%) compared with that in the samples from the older patients (2/24, 8%, P < .001). Gains in the long arm of chromosome 22 and of the chromosomal band 11q13 were also detected significantly more often in the younger group. No correlation was found between DNA copy number changes and clinical parameters. Our results suggest that amplification of genes in the long arm of chromosome 20 may be important in the tumorigenesis of lung adenocarcinoma in young adults. Several candidate genes have already been described in the long arm of chromosome 20, particularly in breast cancer.
DNA copy number changes were studied by comparative genomic hybridization on 10 tumor specimens of squamous cell carcinoma of cervix obtained from Korean patients. DNA was extracted from paraffin‐embedded sections after removal of non‐malignant cells by microdissection technique. Copy number changes were found in 8/10 tumors. The most frequent changes were chromosome 19 gains (n=6) and losses on chromosomes 4 (n=4), 5 (n=3), and 3p (n=3). A novel finding was amplification in chromosome armdoi:10.1155/2001/174645 pmid:11455035 pmcid:PMC4617954 fatcat:2z2zq3getfaybc3rs76vh5jaai
more »... pter in 2 cases. Gains in 1, 3q, 5p, 6p, 8q, 16p, 17, and 20q and losses at 2q, 6q, 8p, 9q, 10p, 11, 13, 16q, and 18q were observed in at least one of the cases.
Pancreatic cancer (PC) is an aggressive malignancy with a dismal prognosis. To improve patient survival, the development of screening methods for early diagnosis is pivotal. Oncogenomic alterations present in tumor tissue are a suitable target for non-invasive screening efforts, as they can be detected in tumor-derived cells, cell-free nucleic acids, and extracellular vesicles, which are present in several body fluids. Since stool is an easily accessible source, which enables convenient anddoi:10.3390/biom12050652 pmid:35625579 pmcid:PMC9171580 fatcat:5vhnxzfdyjbo3k6hdx27atmtp4
more »... -effective sampling, it could be utilized for the screening of these traces. Herein, we explore the various oncogenomic changes that have been detected in PC tissue, such as chromosomal aberrations, mutations in driver genes, epigenetic alterations, and differentially expressed non-coding RNA. In addition, we briefly look into the role of altered gut microbiota in PC and their possible associations with oncogenomic changes. We also review the findings of genomic alterations in stool of PC patients, and the potentials and challenges of their future use for the development of stool screening tools, including the possible combination of genomic and microbiota markers.
Epithelioid sarcoma is a distinctive, rare soft tissue sarcoma that typically involves the distal extremities in young adults, and shows epithelioid morphology and immunohistochemical markers of epithelial differentiation. The genetic background of epithelioid sarcoma is poorly understood, and knowledge of it could give insights into the pathogenesis of this tumor and its possible relationship with other malignant tumors. In this study, we analyzed DNA copy number changes in 30 epithelioiddoi:10.1038/modpathol.3880203 pmid:11048803 fatcat:xr77ipa7gvek5dfzyual4ef5oq
more »... mas by comparative genomic hybridization. DNA was extracted from microdissected samples of formaldehyde-fixed and paraffin-embedded tumors with a minimum of 60% of tumor cells in each sample. Sixteen tumors (53%) showed DNA copy number changes at one to six different genomic sites. The majority of the changes were gains, seen in 14 tumors, whereas 10 tumors showed losses. The most common recurrent gains were at 11q13 (five cases), 1q21-q23 (four cases), 6p21.3 (three cases), and 9q31-qter (three cases). High-level amplifications were detected once in 6p21.3-p21.1 and once in 9q32-qter. Recurrent losses were seen at 9pter-p23 (three cases), 13q22-q32 (three cases), 1p13-p22 (two cases), 3p12-p14 (two cases), 4q13-q33 (two cases), 9p21 (two cases), and 13q32-qter (two cases). The most common recurrent gain at 11q13 was seen in both classic cases and angiomatoid and rhabdoid variants supporting the relationship of these variants with the classic epithelioid sarcoma. Expression of cyclin D1 gene, located in 11q13, was immunohistochemically detected in nine of 15 cases including three of five cases with gain of 11q13, suggesting its involvement in epithelioid sarcoma. The observed comparative genomic hybridization changes give targets for future genetic studies on epithelioid sarcoma.
No clear patterns in molecular changes underlying the malignant processes in lung cancer of different histological types have been found so far. To identify critical genes in lung cancer progression we compared the expression profile of cancer related genes in 14 pulmonary adenocarcinoma patients with normal lung tissue by using the cDNA array technique. Principal component analyses (PCA) and permutation test were used to detect the differentially expressed genes. The expression profiles of 10doi:10.1038/sj.onc.1205726 pmid:12173052 fatcat:ldynna2zzfbqfnlaj6t7r7auk4
more »... enes were confirmed by semiquantitative real-time RT -PCR. In tumour samples, as compared to normal lung tissue, the up-regulated genes included such known tumour markers as CCNB1, PLK, tenascin, KRT8, KRT19 and TOP2A. The downregulated genes included caveolin 1 and 2, and TIMP3. We also describe, for the first time, down-regulation of the interesting SOCS2 and 3, DOC2 and gravin. We show that silencing of SOCS2 is not caused by methylation of exon 1 of the gene. In conclusion, by using the cDNA array technique we were able to reveal marked differences in the gene expression level between normal lung and tumour tissue and find possible new tumour markers for pulmonary adenocarcinoma.
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