Gene Summary

Gene:COL1A2; collagen type I alpha 2 chain
Aliases: OI4
Summary:This gene encodes the pro-alpha2 chain of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIB, recessive Ehlers-Danlos syndrome Classical type, idiopathic osteoporosis, and atypical Marfan syndrome. Symptoms associated with mutations in this gene, however, tend to be less severe than mutations in the gene for the alpha1 chain of type I collagen (COL1A1) reflecting the different role of alpha2 chains in matrix integrity. Three transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:collagen alpha-2(I) chain
Source:NCBIAccessed: 15 March, 2017


What does this gene/protein do?
Show (26)
Pathways:What pathways are this gene/protein implicaed in?
Show (3)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Supratentorial Neoplasms
  • Genome-Wide Association Study
  • Stomach Cancer
  • Cell Movement
  • CpG Islands
  • Thymidine Kinase
  • Cluster Analysis
  • Immunohistochemistry
  • Neoplasm Invasiveness
  • Base Sequence
  • Systems Biology
  • Polymorphism
  • rab GTP-Binding Proteins
  • Teratoma
  • Messenger RNA
  • DNA Methylation
  • Tissue Plasminogen Activator
  • Liver Cancer
  • Statistics as Topic
  • Loss of Heterozygosity
  • Down-Regulation
  • Signal Transduction
  • Newborns
  • Biomarkers, Tumor
  • Cancer Gene Expression Regulation
  • Hepatocellular Carcinoma
  • Taiwan
  • Childhood Cancer
  • Chromosome 7
  • Oligonucleotide Array Sequence Analysis
  • TIMP2
  • Collagen
  • Epigenetics
  • Case-Control Studies
  • Genetic Predisposition
  • Collagen Type I
  • Gene Expression Profiling
  • DNA-Binding Proteins
  • Squamous Cell Carcinoma
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: COL1A2 (cancer-related)

Zhuo C, Li X, Zhuang H, et al.
Elevated THBS2, COL1A2, and SPP1 Expression Levels as Predictors of Gastric Cancer Prognosis.
Cell Physiol Biochem. 2016; 40(6):1316-1324 [PubMed] Related Publications
BACKGROUND/AIMS: Gastric cancer (GC) is an important health problem. Classification based on molecular subtypes may help to determine the prognosis of patients with GC. Tumor invasion and metastasis are important factors affecting the prognosis of cancer. We aimed to identify genes related to tumor invasion and metastasis, which may serve as indicators of good GC prognosis.
METHODS: Tumor tissues and adjacent normal tissues were collected from 105 patients with primary GC who were treated by undergoing radical surgery. Samples were used for tissue microarray analysis. Identified genes with altered expression were further analyzed using the Gene Ontology (Go) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The expression levels of THBS2, COL1A2 and SPP1 were analyzed by RT-PCR, western blot and immunohistochemistry. The overall survival curves of patients with high and low expression of each gene of interest were plotted and compared.
RESULTS: Forty-three genes were identified. THBS2, COL1A2 and SPP1 were selected for further analysis. Altered expression levels of THBS2, COL1A2 and SPP1 in tumor tissues were confirmed. Patients with low THBS2 expression had a better prognosis; the expression of COL1A2 and SPP1 might not affect the prognosis of patients with GC.
CONCLUSION: THBS2, but not COL1A2 and SPP1, may serve as an indicator of GC prognosis.

Hass HG, Vogel U, Scheurlen M, Jobst J
Gene-expression Analysis Identifies Specific Patterns of Dysregulated Molecular Pathways and Genetic Subgroups of Human Hepatocellular Carcinoma.
Anticancer Res. 2016; 36(10):5087-5095 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma comprises of a group of heterogeneous tumors of different etiologies. The multistep process of liver carcinogenesis involves various genetic and phenotypic alterations. The molecular pathways and driver mutations involved are still under investigation.
MATERIALS AND METHODS: DNA micorarray technology was used to identify differentially expressed genes between human hepatocarcinoma and non-tumorous liver tissues to establish a unique specific gene-expression profile independent of the underlying liver disease. The validity of this global gene-expression profile was tested for its robustness against biopsies from other liver entities (cirrhotic and non-cirrhotic liver) by diagnosing HCC in blinded samples.
RESULTS: Most of the consistently and strongly overexpressed genes were related to cell-cycle regulation and DNA replication [27 genes, e.g. cyclin B1, karyopherin alpha 2 (KPNA2), cyclin-dependent kinase 2 (CDC2)], G-protein depending signaling [e.g. Rac GTPase activating protein 1 (RACGAP1), Rab GTPase YPT1 homolog (RAB1), and ADP-ribosylation factor-like 2 (ARL2)] and extracellular matrix re-modelling or cytoskeleton structure [22 genes, e.g. serine proteinase inhibitor 1 kazal-type (SPINK1), osteopontin (OPN), secreted protein acidic and rich in cysteine (SPARC), collagen type 1 alpha2 (COL1A2), integrin alpha6 (ITGA6), and metalloproteinase 12 (MMP12)]. Furthermore, significantly differentially expressed genes (e.g. calcium-binding proteins, G-proteins, oncofetal proteins) in relation to tumor differentiation were detected using gene-expression analysis.
CONCLUSION: It is suggested that these significantly dysregulated genes are highly specific and potentially utilizable as prognostic markers and may lead to a better understanding of human hepatocarcinogenesis.

Huang QX, Cui JY, Ma H, et al.
Screening of potential biomarkers for cholangiocarcinoma by integrated analysis of microarray data sets.
Cancer Gene Ther. 2016 Feb-Mar; 23(2-3):48-53 [PubMed] Related Publications
Cholangiocarcinoma (CCA) continues to harbor a difficult prognosis and it is difficult to diagnose in its early stages. The molecular mechanisms of CCA oncogenesis and progression are poorly understood. This study aimed to identify candidate biomarkers for CCA. Integrated analysis of microarray data sets was performed to identify differentially expressed genes (DEGs) between CCA and normal tissues. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed to identify the functions of DEGs. Furthermore, the protein-protein interaction (PPI) network of DEGs was constructed. The expressions of DEGs were validated in human CCA tissues by qRT-PCR. A set of 712 DEGs were identified in CCA compared with normal tissues, including 306 upregulated and 406 downregulated DEGs. It can be shown from the KEGG pathway analysis that some pathways may have important roles in pathology of CCA, including peroxisome proliferator-activated receptor signaling pathway, bile secretion, cell cycle, fat digestion and absorption. PPI network indicated that the significant hub proteins were PKM, SPP1 and TPM1. The abnormally overexpression PKM, SPP1 and TPM1 were closely related to oncogenesis and progression of CCA. PKM, SPP1, TPM1, COL1A1 and COL1A2 may serve as candidate biomarkers for diagnosis and prognosis of CCA.

Koroknai V, Ecsedi S, Vízkeleti L, et al.
Genomic profiling of invasive melanoma cell lines by array comparative genomic hybridization.
Melanoma Res. 2016; 26(2):100-7 [PubMed] Related Publications
Malignant melanoma is one of the most aggressive human cancers. Invasion of cells is the first step in metastasis, resulting in cell migration through tissue compartments. We aimed to evaluate genomic alterations specifically associated with the invasive characteristics of melanoma cells. Matrigel invasion assays were used to determine the invasive properties of cell lines that originated from primary melanomas. Array comparative genomic hybridization analyses were carried out to define the chromosome copy number alterations (CNAs). Several recurrent CNAs were identified by array comparative genomic hybridization that affected melanoma-related genes. Invasive primary cell lines showed high frequencies of CNAs, including the loss of 7q and gain of 12q chromosomal regions targeting PTPN12, ADAM22, FZD1, TFPI2, GNG11, COL1A2, SMURF1, VGF, RELN and GLIPR1 genes. Gain of the GDNF (5p13.1), GPAA1, PLEC and SHARPIN (8q24.3) genes was significantly more frequent in invasive cell lines compared with the noninvasive ones. Importantly, copy number gains of these genes were also found in cell lines that originated from metastases, suggesting their role in melanoma metastasis formation. The present study describes genomic differences between invasive and noninvasive melanoma cell lines that may contribute toward the aggressive phenotype of human melanoma cells.

Kalmár A, Péterfia B, Hollósi P, et al.
DNA hypermethylation and decreased mRNA expression of MAL, PRIMA1, PTGDR and SFRP1 in colorectal adenoma and cancer.
BMC Cancer. 2015; 15:736 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colorectal cancer (CRC) development is accompanied by changes in expression for several genes; but the details of the underlying regulatory procesess remain unknown. Our aims were to assess the role of epigenetic processes in tumour formation and to identify characteristic DNA methylation and miRNA alterations in the colorectal adenoma-carcinoma sequence.
METHODS: Whole genome expression profiling was performed on colonic biopsy samples (49 healthy normal, 49 colorectal adenoma (AD), 49 CRC); on laser capture microdissected (LCM) epithelial and stromal cells from 6 CRC-normal adjacent tissue (NAT) samples pairs, and on demethylated human CRC cell lines using HGU133 Plus 2.0 microarrays (Affymetrix). Methylation status of genes with gradually altering expression along the AD-CRC sequence was further analysed on 10-10 macrodissected and 5-5 LCM samples from healthy colon, from adenoma and from CRC biopsy samples using bisulfite-sequencing PCR (BS-PCR) followed by pyrosequencing. In silico miRNA prediction for the selected genes was performed with miRWALK algorithm, miRNA expression was analysed on 3 CRC-NAT sample pairs and 3 adenoma tissue samples using the Human Panel I + II (Exiqon). SFRP1 immunohistochemistry experiments were performed.
RESULTS: A set of transcripts (18 genes including MAL, SFRP1, SULT1A1, PRIMA1, PTGDR) showed decreasing expression (p < 0.01) in the biopsy samples along the adenoma-carcinoma sequence. Three of those (COL1A2, SFRP2, SOCS3) showed hypermethylation and THBS2 showed hypomethylation both in AD and in CRC samples compared to NAT, while BCL2, PRIMA1 and PTGDR showed hypermethylation only in the CRC group. miR-21 was found to be significantly (p < 0.01) upregulated in adenoma and tumour samples compared to the healthy colonic tissue controls and could explain the altered expression of genes for which DNA methylation changes do not appear to play role (e.g. BCL2, MAL, PTGS2). Demethylation treatment could upregulate gene expression of genes that were found to be hypermethylated in human CRC tissue samples. Decreasing protein levels of SFRP1 was also observed along the adenoma-carcinoma sequence.
CONCLUSION: Hypermethylation of the selected markers (MAL, PRIMA1, PTGDR and SFRP1) can result in reduced gene expression and may contribute to the formation of colorectal cancer.

Zhou W, Yin M, Cui H, et al.
Identification of potential therapeutic target genes and mechanisms in non-small-cell lung carcinoma in non-smoking women based on bioinformatics analysis.
Eur Rev Med Pharmacol Sci. 2015; 19(18):3375-84 [PubMed] Related Publications
OBJECTIVE: The study was aimed to explore the underlying mechanisms and identify the potential target genes by bioinformatics analysis for non-small-cell lung carcinoma (NSCLC) treatment in non-smoking women.
MATERIALS AND METHODS: The microarray data of GSE19804 was downloaded from Gene Expression Omnibus (GEO) database. Paired samples (from the same patient) of tumor and normal lung tissues from 60 non-smoking female NSCLC patients were used to identify differentially expressed genes (DEGs). The functional enrichment analysis was performed. Furthermore, the protein-protein interaction (PPI) network of the DEGs was constructed by Cytoscape software. The module analysis was performed.
RESULTS: Totally, 817 DEGs including 273 up- and 544 down-regulated genes were identified. The up-regulated genes were mainly enriched in extracellular matrix (ECM)-receptor interaction, focal adhesion and cell cycle functions, while down-regulated genes were mainly enriched in the cytokine-cytokine receptor interaction pathway. DEGs including hyaluronan-mediated motility receptor (HMMR), collagen, type I alpha 2 (COL1A2), cyclin A2 (CCNA2), MAD2 mitotic arrest deficient-like 1 (MAD2L1), interleukin 6 (IL6) and interleukin 1, beta (IL1B) were identified in these functions. These genes were hub nodes in PPI networks. Besides, there were 3 up-regulated modules and 1 down-regulated module. The significant pathways were ECM-receptor interaction and focal adhesion in up-regulated modules, while in down-regulated module, the significant pathway was mitogen-activated protein kinase (MAPK) signaling pathway.
CONCLUSIONS: The ECM-receptor interaction, focal adhesion, cell cycle and cytokine-cytokine receptor interaction functions may be associated with NSCLC development. Genes such as HMMR, COL1A2, CCNA2, MAD2L1, IL6 and IL1B may be potential therapeutic target genes for NSCLC.

Zhu GC, Gao L, He J, et al.
CD90 is upregulated in gastric cancer tissues and inhibits gastric cancer cell apoptosis by modulating the expression level of SPARC protein.
Oncol Rep. 2015; 34(5):2497-506 [PubMed] Related Publications
Cluster of differentiation 90 (CD90) (Thy-1) plays important roles in the oncogenesis in various types of malignancies. In the present study, we investigated the expression of CD90 in gastric cancer (GC) tissues by q-PCR, immunohistochemistry (IHC), and western blot technologies. The results showed that CD90 was overexpressed in gastric cancer tissues compared with the level in the adjacent non‑cancerous tissues. To explore the possible mechanism of CD90 in GC, we elucidated the effect of CD90 on the apoptosis of AGS gastric cancer cells, and found that a considerable decrease in apoptotic cells was observed for AGS cells with CD90 overexpression. Meanwhile, the rate of apoptotic cells was increased in the AGS cells with CD90 interference (siCD90) compared with that in the AGS cells. Cell apoptosis is closely related to a reduction in mitochondrial membrane potential (ΔΨm) and an increase in intracellular reactive oxygen species (ROS) and calcium ion (Ca2+) concentrations. Our results showed that overexpression of CD90 in the AGS gastric cancer cells led to an increase in ΔΨm and a decrease in intracellular ROS and Ca2+ concentrations. At the same time, siCD90 reduced ΔΨm and the increase in intracellular ROS and Ca2+ concentrations. Furthermore, we identified and confirmed that CD90 functions by modulating the expression level of secreted protein, acidic, cysteine‑rich (osteonectin) (SPARC) in vitro through LC‑MS/MS analyses and western blot technology. In summary, our results suggest that CD90 is upregulated in gastric cancer and inhibits gastric cancer cell apoptosis by modulating the expression level of SPARC protein.

Lin J, Goldstein L, Nesbit A, Chen MY
Influence of Hormone Receptor Status on Spinal Metastatic Lesions in Patients with Breast Cancer.
World Neurosurg. 2016; 85:42-8 [PubMed] Related Publications
OBJECTIVE: Bony metastasis predominantly affects the spinal column and has been commonly associated in patients with breast cancer. There are two types of lesions that can occur with spine cancer-osteolytic or osteoblastic. Some patients may have mixed lesions, which include lytic and blastic in one vertebra or lytic and blastic in different vertebrae. Previous studies have shown that patients with breast cancer have an increased likelihood for development of lytic spinal metastases.
METHODS: A retrospective chart review was conducted to more closely examine the association between hormone receptor status and spinal lesion type. A total of 195 patients were initially identified through the City of Hope Cancer Registry. Of the 195, only 153 patients had hormone receptor marker status available. Associations between spinal lesion and hormone receptor status were evaluated using χ(2) tests with alpha = 0.05 significance level. In a secondary analysis, the Oncomine Platform was used, which integrated The Cancer Genome Atlas (TCGA) datasets, to identify osteogenic genes that may be relevant to invasive breast cancers.
RESULTS: Contrary to previous studies, our findings revealed progesterone receptor positive (PR+) patients were significantly more likely to present with blastic than lytic or mixed lesions. Furthermore, using TCGA analysis, COL1A1 and COL1A2 were found to be up-regulated, which could provide a molecular explanation for the development of blastic metastases.
CONCLUSIONS: By integrating clinical and bioinformatic techniques, this study provides a novel discovery of the relationship between blastic and PR + breast cancers, which may have important implications for diagnostic strategies concerning vertebral metastases.

Kawabe S, Mizutani T, Ishikane S, et al.
Establishment and characterization of a novel orthotopic mouse model for human uterine sarcoma with different metastatic potentials.
Cancer Lett. 2015; 366(2):182-90 [PubMed] Related Publications
Uterine sarcomas are rare and aggressive gynecologic tumors with a poor prognosis because of recurrence and metastasis. However, the mechanisms of uterine sarcoma metastasis are largely unknown. To investigate this mechanism, we developed a novel uterine sarcoma tissue-derived orthotopic and metastatic model in KSN nude mice using a green fluorescent protein stably expressed uterine sarcoma cell line, MES-SA. Histological analysis showed that all orthotopic primary tumors were undifferentiated sarcoma. Primary tumors were characterized by high (18)F-fluorodeoxyglucose uptake with a positive correlation to the number of pulmonary metastases. In addition, we generated uterine sarcoma cell sublines with high or low metastatic potentials by serial in vivo selection. Microarray analysis between orthotopic tumors with high and low metastatic potentials revealed differential expression of genes related to cell proliferation and migration (TNNT1, COL1A2, and ZIC1). Our model would be useful to compensate for the limited clinical cases of uterine sarcoma and to investigate the molecular mechanisms of metastatic uterine sarcoma.

Park JH, Ryu SH, Choi EK, et al.
SKI2162, an inhibitor of the TGF-β type I receptor (ALK5), inhibits radiation-induced fibrosis in mice.
Oncotarget. 2015; 6(6):4171-9 [PubMed] Free Access to Full Article Related Publications
Here we demonstrated that SKI2162, a small-molecule inhibitor of the TGF-β type I receptor (ALK5), prevented radiation-induced fibrosis (RIF) in mice. SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro. In RIF a mouse model, SKI2162 reduced late skin reactions and leg-contracture without jeopardizing the acute skin reaction. Irradiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect. Thus, these findings support that SKI2162 has potential value as novel RIF-protective agent, and could be candidate for clinical trials.

Liu F, Ji F, Ji Y, et al.
Dissecting the mechanism of colorectal tumorigenesis based on RNA-sequencing data.
Exp Mol Pathol. 2015; 98(2):246-53 [PubMed] Related Publications
OBJECTIVE: This study aimed to identify the differentially expressed genes (DEGs), mutated genes and fusion genes in colorectal cancer.
MATERIALS AND METHODS: RNA-sequencing data (ID: SRP009386) from cancerous, paracancerous non-tumor and distant normal tissue from one Chinese patient with stage III colorectal cancer were downloaded from Sequence Read Archive. Quality control was checked using FastQC, followed by sequence alignment against the hg19 reference genome using TopHat v1.3.3. The expression levels were quantified using Cufflinks, followed by DEGs screening using NOISeq. Enrichment analysis was performed using DAVID. Transcription factors were screened using TRANSFA. Mutated loci were identified using SAMTools and VCFTools. Gene fusion events were detected by TopHat-fusion.
RESULTS: In total 2440, 1887 and 834 DEGs were respectively detected in cancerous vs. normal tissue, cancerous vs. paracancerous tissue and paracancerous vs. normal tissue. The up-regulated genes from cancerous and paracancerous tissue compared with normal tissue were enriched in "extracellular matrix receptor interaction" and "focal adhesion pathway" as well as some biological processes except for "negative regulation of programmed cell death" uniquely presenting in cancer. Dysregulated transcription factors including SOX4, BCL6, CEBPB and MSX2 were enriched in the unique biological process. Trp53 was identified with one mutated locus 7577142 (C → T) on chromosome 17. BCL6 also experienced missense mutation. Additionally, COL1A1-PPP2R2C and EXPH5-COL1A2 were observed fusion genes in cancer tissue.
CONCLUSIONS: The unique biological process in cancer tissue may be the cause for colorectal carcinogenesis. The screened transcription factors, mutated genes and fusion genes may contribute to the progression of colorectal cancer.

Januchowski R, Zawierucha P, Ruciński M, Zabel M
Microarray-based detection and expression analysis of extracellular matrix proteins in drug‑resistant ovarian cancer cell lines.
Oncol Rep. 2014; 32(5):1981-90 [PubMed] Related Publications
Ovarian cancer is the most lethal gynecological malignancy. Multiple drug resistance (MDR) development leads to resistance of cancer cells to chemotherapy. Microarray methods can provide information regarding new candidate genes that can play a role in resistance to cytostatic drugs. Extracellular matrix (ECM) can influence drug resistance by inhibiting the penetration of the drug into cancer tissue as well as increased apoptosis resistance. In the present study, we report changes in the ECM and related gene expression pattern in methotrexate-, cisplatin-, doxorubicin-, vincristine-, topotecan- and paclitaxel-resistant variants of the W1 ovarian cancer cell line. The resistant variants of the W1 cell line were generated by stepwise selection of cells with an increasing concentration of the indicated drugs. Affymetrix GeneChip® Human Genome U219 Array Strips were used for hybridizations. Independent t-tests were used to determinate the statistical significance of results. Genes whose expression levels were higher than the assumed threshold (upregulated, >5-fold and downregulated, <5-fold) were visualized using the scatter plot method, selected and listed in the tables. Among the investigated genes, expression of 24 genes increased, expression of 14 genes decreased and expression of three genes increased or decreased depending on the cell line. Among the increased genes, expression of 10 increased very significantly, >20-fold. These genes were: ITGB1BP3, COL3A1, COL5A2, COL15A1, TGFBI, DCN, LUM, MATN2, POSTN and EGFL6. The expression of seven genes decreased very significantly: ITGA1, COL1A2, LAMA2, GPC3, KRT23, VIT and HMCN1. The expression pattern of ECM and related genes provided the preliminary view into the role of ECM components in cytostatic drug resistance of cancer cells. The exact role of the investigated genes in drug resistance requires further investigation.

Wu D, Chen K, Bai Y, et al.
Screening of diagnostic markers for osteosarcoma.
Mol Med Rep. 2014; 10(5):2415-20 [PubMed] Related Publications
Osteosarcoma, which is the most common type of highly malignant bone tumor in children and adolescents, has poor diagnosis and 2-year survival rates of 15-20% following surgery or radiotherapy, and has therefore generated marked attention. In order to investigate the potential biomarkers for diagnosing osteosarcoma, the expression profiling data from normal and disease tissues were compared, respectively, and the differentially‑expressed genes were analyzed by three different statistical tests. Interacting proteins were determined and an interaction network was constructed by Search Tool for the Retrieval of Interacting Genes database. Subsequently, the protein interaction network was decomposed and Gene Otology annotation using Cytoscape, Mcode and Bingo, was conducted on the function modules. Finally, three differentially‑expressed genes GJA1, COL1A2 and COL5A2 were identified, and an interaction network was successfully generated with COL1A2 and COL5A2 at the core. From the results, it was observed that COL1A2 and COL5A2 interact with a number of genes of the matrix metalloprotease (MMP) family, including MMP1, MMP2, MMP3 and MMP14, TGFβ and RUNX2. Furthermore, these genes have been confirmed to be important in the tumorigenesis of osteosarcoma. It was hypothesized that the upregulation of the COL gene family may be considered as a diagnostic marker for osteosarcoma and collagen may be administered as a therapy.

Januchowski R, Zawierucha P, Ruciński M, et al.
Extracellular matrix proteins expression profiling in chemoresistant variants of the A2780 ovarian cancer cell line.
Biomed Res Int. 2014; 2014:365867 [PubMed] Free Access to Full Article Related Publications
Ovarian cancer is the leading cause of death among gynaecological malignancies. Extracellular matrix (ECM) can affect drug resistance by preventing the penetration of the drug into cancer cells and increased resistance to apoptosis. This study demonstrates alterations in the expression levels of ECM components and related genes in cisplatin-, doxorubicin-, topotecan-, and paclitaxel-resistant variants of the A2780 ovarian cancer cell line. Affymetrix Gene Chip Human Genome Array Strips were used for hybridisations. The genes that had altered expression levels in drug-resistant sublines were selected and filtered by scatter plots. The genes that were up- or downregulated more than fivefold were selected and listed. Among the investigated genes, 28 genes were upregulated, 10 genes were downregulated, and two genes were down- or upregulated depending on the cell line. Between upregulated genes 12 were upregulated very significantly--over 20-fold. These genes included COL1A2, COL12A1, COL21A1, LOX, TGFBI, LAMB1, EFEMP1, GPC3, SDC2, MGP, MMP3, and TIMP3. Four genes were very significantly downregulated: COL11A1, LAMA2, GPC6, and LUM. The expression profiles of investigated genes provide a preliminary insight into the relationship between drug resistance and the expression of ECM components. Identifying correlations between investigated genes and drug resistance will require further analysis.

Yoshida H, Miyachi M, Ouchi K, et al.
Identification of COL3A1 and RAB2A as novel translocation partner genes of PLAG1 in lipoblastoma.
Genes Chromosomes Cancer. 2014; 53(7):606-11 [PubMed] Related Publications
Lipoblastoma is a rapidly growing, benign neoplasm in children. Surgical excision is usually curative, with a recurrence rate of about 20%. Because the histology of lipoblastoma is heterogeneous and overlaps with other lipomatous tumors, some lipoblastoma cases have been difficult to diagnose. The detection of PLAG1 gene rearrangement is useful for the diagnosis of lipoblastoma. Three fusion partner genes are known in relation to PLAG1 in lipoblastoma HAS2 at 8q24.1, COL1A2 at 7q22, and RAD51L1 at 14q24. Herein, we describe another two novel fusion genes in lipoblastoma tumor specimens. We checked six tumors for the presence of two known fusion genes, HAS2-PLAG1 and COL1A2-PLAG1. Only HAS2-PLAG1 was found in one of the cases. Next, we attempted to identify potential PLAG1 fusion partners using 5'RACE. Sequence analysis revealed two novel fusion genes, COL3A1-PLAG1 in three cases and RAB2A-PLAG1 in one case, respectively. As a result of the translocations, the constitutively active promoter of the partner gene drives the ectopic expression of PLAG1. We also evaluated whether a high level of PLAG1 expression can be used to help differentiate lipomatous tumors. PLAG1 expression was evaluated by real-time PCR in five lipoblastoma tumor specimens. The expressions were 70-150 times higher in lipoblastomas than in human adipocytes. However, PLAG1 expression was low in one case of lipoma. These results demonstrate that PLAG1 overexpression is a potential marker of lipoblastoma. Our findings, in agreement with previous studies, show that lipoblastoma is a group of lipomatous tumors with PLAG1 rearrangement and overexpression. © 2014 Wiley Periodicals, Inc.

Kaleağasıoğlu F, Berger MR
Differential effects of erufosine on proliferation, wound healing and apoptosis in colorectal cancer cell lines.
Oncol Rep. 2014; 31(3):1407-16 [PubMed] Related Publications
The alkylphosphocholine, erucylphospho-N,N, N-trimethylpropanolamine (erufosine), has demonstrated anticancer effects in various cell lines, including leukemia, multiple myeloma, bladder, breast and oral squamous cell carcinoma cells. The purpose of the present study was to investigate its antiproliferative, antimigratory and pro-apoptotic effects in colorectal cancer cell lines, SW480 and CC531. The antiproliferative effect was determined by (3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide) (MTT) dye reduction assay following exposure to erufosine (3.1-100 µM) for 24-72 h. The antimigratory effect of erufosine (1.6-6 µM) was investigated by a wound healing assay for 12-48 h. Caspase-3/-7 activity was measured to detect apoptotic cell death. Erufosine inhibited cell proliferation in a dose- and time-dependent manner. The IC50 values following 72 h of incubation were 3.4 and 25.4 µM for SW480 and CC531 cells, respectively. erufosine at concentrations of 50 and 100 µM induced caspase-3/-7 activity concentration-dependently in SW480 cells, but only at 100 µM in CC531 cells. Incubation of SW480 cells with erufosine (1.56 µM) for 48 h inhibited migration into the scratched area by 54% as compared to the untreated cells; whereas in CC531 cells, the wound width in the erufosine-treated (1.56-6.25 µM) cells following 48 h was closed 2-fold slower than the rate in the untreated group. Erufosine (25 µM) attenuated osteonectin expression and abolished COL1A1 expression in CC531 cells. Erufosine appears to be a promising treatment agent for colorectal cancer. Rat CC531 cells are less sensitive to erufosine than human SW480 cells.

Zou X, Feng B, Dong T, et al.
Up-regulation of type I collagen during tumorigenesis of colorectal cancer revealed by quantitative proteomic analysis.
J Proteomics. 2013; 94:473-85 [PubMed] Related Publications
UNLABELLED: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. The discovery of non-invasive biomarker candidates for diagnosis and prognosis is important for the management of CRC. In this study, we performed proteomic profiling of serum from patients with different stages of CRC using a 2D-LC-MS/MS based approach combined with the APEX quantitative method. 917 proteins were identified and 93 were differentially expressed in normal and three patient groups (stages I, II and III). These proteins were predominantly involved in cell adhesion, immune response, coagulation process and metabolism. Importantly, we found collagen I dynamically changed from stages I to IV, with maximum expression in stage II, as detected in serum by MS analysis. Expression of collagen I was also validated in tumor tissues from the same group of CRC patients by real-time PCR and western blotting. Furthermore, we demonstrate that serum levels of collagen I degradation telopeptide (CTx) are correlated with staging and poor disease-free survival of CRC patients by ELISA analysis. These results suggest (1) serum proteomics may reflect biological changes in colorectal tumor tissues and (2) altered collagen I expression may be an early event in CRC tumorigenesis and CTx may provide additional information for prognosis of CRC.
BIOLOGICAL SIGNIFICANCE: In this work, we performed a systematic characterization of serum proteomic alterations in colorectal cancer (CRC) with different stages using a LC-MS based approach combined with the APEX quantitative method, attempting to gain overview of relevant proteins in tumorigenesis and discover non-invasive CRC-derived markers. We found a significant up-regulation of collagen I based on the proteomics data, and confirmed its expression in tissue and serum of the same group of patients. In addition, we also demonstrated that serum levels of collagen I degradation telopeptide (CTx) are correlated with the staging and poor survival rate of CRC. Those findings imply that alternation of collagen I might be an early event during tumorigenesis of CRC, and might contribute to the metastasis of CRC under the degradation regulated by some specific proteases. This work provides evidence for the clinical application of serum proteomics, and would aid the understanding of the role of the ECM in the clinical progression of CRC.

van Rooyen BA, Schäfer G, Leaner VD, Parker MI
Tumour cells down-regulate CCN2 gene expression in co-cultured fibroblasts in a Smad7- and ERK-dependent manner.
Cell Commun Signal. 2013; 11:75 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recent studies have revealed that interactions between tumour cells and the surrounding stroma play an important role in facilitating tumour growth and invasion. Stromal fibroblasts produce most of the extracellular matrix components found in the stroma. The aim of this study was to investigate mechanisms involved in tumour cell-mediated regulation of extracellular matrix and adhesion molecules in co-cultured fibroblasts. To this end, microarray analysis was performed on CCD-1068SK human fibroblast cells after direct co-culture with MDA-MB-231 human breast tumour cells.
RESULTS: We found that the expression of both connective tissue growth factor (CTGF/CCN2) and type I collagen was negatively regulated in CCD-1068SK fibroblast cells under direct co-culture conditions. Further analysis revealed that Smad7, a known negative regulator of the Smad signalling pathway involved in CCN2 promoter regulation, was increased in directly co-cultured fibroblasts. Inhibition of Smad7 expression in CCD-1068SK fibroblasts resulted in increased CCN2 expression, while Smad7 overexpression had the opposite effect. Silencing CCN2 gene expression in fibroblasts led, in turn, to a decrease in type I collagen mRNA and protein levels. ERK signalling was also shown to be impaired in CCD-1068SK fibroblasts after direct co-culture with MDA-MB-231 tumour cells, with Smad7 overexpression in fibroblasts leading to a similar decrease in ERK activity. These effects were not, however, seen in fibroblasts that were indirectly co-cultured with tumour cells.
CONCLUSION: We therefore conclude that breast cancer cells require close contact with fibroblasts in order to upregulate Smad7 which, in turn, leads to decreased ERK signalling resulting in diminished expression of the stromal proteins CCN2 and type I collagen.

Lauvrak SU, Munthe E, Kresse SH, et al.
Functional characterisation of osteosarcoma cell lines and identification of mRNAs and miRNAs associated with aggressive cancer phenotypes.
Br J Cancer. 2013; 109(8):2228-36 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Osteosarcoma is the most common primary malignant bone tumour, predominantly affecting children and adolescents. Cancer cell line models are required to understand the underlying mechanisms of tumour progression and for preclinical investigations.
METHODS: To identify cell lines that are well suited for studies of critical cancer-related phenotypes, such as tumour initiation, growth and metastasis, we have evaluated 22 osteosarcoma cell lines for in vivo tumorigenicity, in vitro colony-forming ability, invasive/migratory potential and proliferation capacity. Importantly, we have also identified mRNA and microRNA (miRNA) gene expression patterns associated with these phenotypes by expression profiling.
RESULTS: The cell lines exhibited a wide range of cancer-related phenotypes, from rather indolent to very aggressive. Several mRNAs were differentially expressed in highly aggressive osteosarcoma cell lines compared with non-aggressive cell lines, including RUNX2, several S100 genes, collagen genes and genes encoding proteins involved in growth factor binding, cell adhesion and extracellular matrix remodelling. Most notably, four genes-COL1A2, KYNU, ACTG2 and NPPB-were differentially expressed in high and non-aggressive cell lines for all the cancer-related phenotypes investigated, suggesting that they might have important roles in the process of osteosarcoma tumorigenesis. At the miRNA level, miR-199b-5p and mir-100-3p were downregulated in the highly aggressive cell lines, whereas miR-155-5p, miR-135b-5p and miR-146a-5p were upregulated. miR-135b-5p and miR-146a-5p were further predicted to be linked to the metastatic capacity of the disease.
INTERPRETATION: The detailed characterisation of cell line phenotypes will support the selection of models to use for specific preclinical investigations. The differentially expressed mRNAs and miRNAs identified in this study may represent good candidates for future therapeutic targets. To our knowledge, this is the first time that expression profiles are associated with functional characteristics of osteosarcoma cell lines.

Fang ZQ, Zang WD, Chen R, et al.
Gene expression profile and enrichment pathways in different stages of bladder cancer.
Genet Mol Res. 2013; 12(2):1479-89 [PubMed] Related Publications
Bladder cancer is a highly heterogeneous neoplasm. We examined the gene expression profile in 3 bladder cancer stages (Ta, T1, T2) using expression microarray analysis of 40 bladder tumors. Differentially expressed genes were found by the t-test, with <0.005 as the significance threshold. KEGG pathway-enrichment analysis was used to study the signaling pathways of the genes. We found 36 genes that could be used as molecular markers for predicting the transition from Ta-T1 to T1-T2. Among these, 11 overlapped between Ta-T1 and T1-T2 stages. Six genes were down-regulated at the Ta-T1 stage, but were up-regulated at the T1-T2 stage (ANXA5, ATP6V1B2, CTGF, GEM, IL13RA1, and LCP1); 5 genes were up-regulated at the Ta-T1 stage, but down-regulated at the T1-T2 stage (ACPP, GNL1, RIPK1, RAPGEF3, and ZER1). Another 25 genes changed relative expression levels at the T1-T2 stage. These genes (including COL1A1, COL1A2, FN1, ITGA5, LGALS1, SPP1, VIM, POSTN, and COL18A1) may be involved in bladder cancer progression by affecting extracellular matrix-receptor interaction and focal adhesion. The cytokine-cytokine receptor interaction, neuroactive ligand-receptor interaction, and calcium-signaling pathway were associated with bladder cancer progression at both the Ta-T1 and T1-T2 stages.

Yeh CN, Weng WH, Lenka G, et al.
cDNA microarray profiling of rat cholangiocarcinoma induced by thioacetamide.
Mol Med Rep. 2013; 8(2):350-60 [PubMed] Related Publications
Cholangiocarcinoma (CCA) is a malignant neoplasm affecting thousands of individuals worldwide. CCA develops through a multistep process. In the current study, an oral thioacetamide (TAA)‑induced model of rat CCA was established which generates the histological progression of human CCA, particularly the mass‑forming type. Seven male Sprague‑Dawley rats were treated with TAA for 24 weeks to induce CCA. Following the generation of the rat CCA model, whole rat genomic oligo microarray was performed to examine gene expression profiles in CCA and non‑cancerous liver samples. In brief, 10,427 genes were found to be differentially expressed (8,318 upregulated and 3,489 downregulated) in CCA compared with non‑tumor liver tissue. The top 50 genes (upregulated or downregulated) were selected and their functional involvement in various pathways associated with cancer progression was analyzed, including cell proliferation, apoptosis, metabolism and the cell cycle. In addition, increased expression of CLCA3, COL1A2, DCN, GLIPr2 and NID1, and decreased expression of CYP2C7 and SLC10A1 were validated by quantitative real‑time PCR. Immunohistochemical analysis was performed to determine the protein expression levels of GLIPr2 and SLC10A1. The gene expression profiling performed in this study provides a unique opportunity for understanding the carcinogenesis of TAA‑induced CAA. In addition, expression profiling of a number of specific genes is likely to provide important novel biomarkers for the diagnosis of CCA and the development of novel therapeutic strategies for CCA.

Li NY, Dailey S, Thibeault SL
Assessment of fine needle aspiration feasibility and specimen adequacy for molecular diagnostics of benign vocal fold lesions.
Laryngoscope. 2013; 123(4):960-5 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES/ HYPOTHESIS: The use of molecular testing is becoming more significant for the diagnosis and classification of disease. The application of fine-needle aspiration (FNA) biopsy as the means of sampling lesions in union with molecular testing could be a powerful combination in laryngology. The objectives of this study were to investigate 1) if FNA was feasible to sample benign vocal fold lesions; 2) if FNA samples provided sufficient RNA quality for molecular analysis; and 3) if gene expression of FNA samples matched paired surgical excised specimens.
STUDY DESIGN: Prospective cross-sectional.
METHODS: Fifteen vocal fold specimens were obtained from adult patients undergoing routine surgical removal for benign vocal fold lesions using FNA and surgical excision. Comparisons were made between FNA and excision biopsies for RNA quality. Correlative analysis was completed for RNA expression of nine genes, including decorin (DCN), connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF), collagen type VI alpha 3 (COL6A3), superoxide dismutase 1 (SOD1), glutathione S-transferase (GST2), collagen type I alpha 2 (COL1A2), ATP binding cassette (ABC), and procollagen I alpha 1 (COL1A1).
RESULTS: FNA and excision samples demonstrated similar RNA quality (P > 0.05). Per gene expression, four out of nine genes were moderately correlated between the paired samples (P < 0.05).
CONCLUSIONS: FNA of the vocal fold lamina propria is technically feasible to perform. Further improvement in the FNA technology is desirable to optimize RNA quality for reliable gene expression analysis.

Duong CV, Emes RD, Wessely F, et al.
Quantitative, genome-wide analysis of the DNA methylome in sporadic pituitary adenomas.
Endocr Relat Cancer. 2012; 19(6):805-16 [PubMed] Related Publications
DNA methylation is one of the several epigenetic modifications that together with genetic aberrations are hallmarks of tumorigenesis including those emanating from the pituitary gland. In this study, we examined DNA methylation across 27 578 CpG sites spanning more than 14 000 genes in the major pituitary adenoma subtypes. Genome-wide changes were first determined in a discovery cohort comprising non-functioning (NF), growth hormone (GH), prolactin (PRL)-secreting and corticotroph (CT) adenoma relative to post-mortem pituitaries. Using stringent cut-off criteria, we validated increased methylation by pyrosequencing in 12 of 16 (75%) genes. Overall, these criteria identified 40 genes in NF, 21 in GH, six in PRL and two in CT that were differentially methylated relative to controls. In a larger independent cohort of adenomas, for genes in which hypermethylation had been validated, different frequencies of hypermethylation were apparent, where the KIAA1822 (HHIPL1) and TFAP2E genes were hypermethylated in 12 of 13 NF adenomas whereas the COL1A2 gene showed an increase in two of 13 adenomas. For genes showing differential methylation across and between adenoma subtypes, pyrosequencing confirmed these findings. In three of 12 genes investigated, an inverse relationship between methylation and transcript expression was observed where increased methylation of EML2, RHOD and HOXB1 is associated with significantly reduced transcript expression. This study provides the first genome-wide survey of adenoma, subtype-specific epigenomic changes and will prove useful for identification of biomarkers that perhaps predict or characterise growth patterns. The functional characterisation of identified genes will also provide insight of tumour aetiology and identification of new therapeutic targets.

Lin ZY, Chuang WL
Genes responsible for the characteristics of primary cultured invasive phenotype hepatocellular carcinoma cells.
Biomed Pharmacother. 2012; 66(6):454-8 [PubMed] Related Publications
The common genes responsible for the characteristics of primary cultured invasive phenotype hepatocellular carcinoma (HCC) cells were investigated. Primary cultured HCC cells from three patients were separated by Matrigel invasion into parent and invasive cells. Whole human genome oligo microarray was applied to detect the differentially expressed genes in invasive cells. A purchased HCC cell line (HA 22T/VGH) was studied for comparison. Forty genes were consistently up-regulated and 14 genes were consistently down-regulated among primary cultured invasive cells. Among these genes, only three up-regulated genes (CNN1, PLAT, SPARC) and one down-regulated tumor suppressor gene (MDFI) had same expressions in invasive cells originated from purchased cell line. For primary cultured invasive cells, differential expressions of several groups of common genes are known to have capacities to promote proliferation (CAV1, IL6, PLAT, RRAD, SRPX), remodeling of extracellular matrix (COL1A1, COL1A2, NID2, TNC, RELN, SPARC), migration (ACTG2, CAV1, CCL2, CCL26, CDC42EP3, CNN1, PHLDB2, PLAT, RRAD, SRPX), implantation (IL6), immune escape (CD70) and angiogenesis (CCL2, IL6, IL18, PLAT, SLIT3). Two genes related to signal transduction (AXL, RASL10B) and one related to metabolism (PTGS2) also showed consistent expressions. Differential expressions of these genes are capable for tumor invasiveness. In conclusion, the characteristics of invasive phenotype HCC cells are originated from differential expressions of several groups of genes rather than few target genes. This information may give us a new insight to design new stratagems in HCC treatment. Analysis of the results from a purchased cell line may have bias due to long-term repeated in vitro cultures.

Shi H, Bevier M, Johansson R, et al.
Prognostic impact of polymorphisms in the MYBL2 interacting genes in breast cancer.
Breast Cancer Res Treat. 2012; 131(3):1039-47 [PubMed] Related Publications
MYBL2 is a transcription factor, which regulates the expression of genes involved in cancer progression. In this study, we investigated whether putative functional variants in genes regulating MYBL2 (E2F1, E2F3 and E2F4) or in genes, which are regulated by MYBL2 (BCL2, BIRC5, COL1A1, COL1A2, COL5A2, ERBB2, CLU, LIN9 and TOP2A) affect breast cancer (BC) susceptibility and clinical outcome. Twenty-eight SNPs were genotyped in a population-based series of 782 Swedish BC cases and 1,559 matched controls. BC-specific survival analysis of BIRC5 suggested that carriers of the minor allele of rs8073069 and rs1042489 have a worse survival compared with the major homozygotes (HR 2.46, 95% CI 1.39-4.36 and HR 1.81, 95% CI 1.01-3.25, respectively). The poor survival was observed especially in women with aggressive tumours. Multivariate analysis supported the role of rs8073069 as an independent prognostic marker. For BCL2, minor allele carriers of rs1564483 were more likely to have hormone receptor-positive tumours than the major homozygotes. Another SNP in BCL2, rs4987852, was associated with tumour stages II-IV and histologic grade 3. In CLU, the minor allele carriers of rs9331888 were more likely to have tumours with regional lymph node metastasis and stages II-IV than the major homozygotes. In conclusion, our study suggests a role of genetic variation in BIRC5, BCL2 and CLU as progression and prognostic markers for BC, supporting previous studies based on the expression of the genes.

Bonazzi VF, Nancarrow DJ, Stark MS, et al.
Cross-platform array screening identifies COL1A2, THBS1, TNFRSF10D and UCHL1 as genes frequently silenced by methylation in melanoma.
PLoS One. 2011; 6(10):e26121 [PubMed] Free Access to Full Article Related Publications
Epigenetic regulation of tumor suppressor genes (TSGs) has been shown to play a central role in melanomagenesis. By integrating gene expression and methylation array analysis we identified novel candidate genes frequently methylated in melanoma. We validated the methylation status of the most promising genes using highly sensitive Sequenom Epityper assays in a large panel of melanoma cell lines and resected melanomas, and compared the findings with those from cultured melanocytes. We found transcript levels of UCHL1, COL1A2, THBS1 and TNFRSF10D were inversely correlated with promoter methylation. For THBS1 and UCHL1 the effect of this methylation on expression was confirmed at the protein level. Identification of these candidate TSGs and future research designed to understand how their silencing is related to melanoma development will increase our understanding of the etiology of this cancer and may provide tools for its early diagnosis.

Zhu Z, Jiang Y, Chen S, et al.
An insertion/deletion polymorphism in the 3' untranslated region of type I collagen a2 (COL1A2) is associated with susceptibility for hepatocellular carcinoma in a Chinese population.
Cancer Genet. 2011; 204(5):265-9 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is one of the most common and severe diseases in the world. Besides the influence of environmental factors, such as viral infection, an increasing number of novel genetic components identified by genome-wide association studies have been associated with predisposition to HCC. Thus, studies focusing on functional variants in these findings are indispensable. In the present study, based on in-silico analysis, we carried out a case-control study in a Chinese population (207 cases and 245 controls) to investigate the association between HCC susceptibility with a 7 base pair (bp) insertion/deletion polymorphism (rs3917) in the 3'UTR of COL1A2. Our results showed that the ins/del + del/del genotype had an odds ratio of 1.76 (95% C.I.=1.03-3.01; P=0.028) for developing HCC compared to the ins/ins genotype. Carriers for the "del" allele of rs3917 were associated with a 1.73-fold increased risk for HCC (95% C.I.=1.06-2.84; P(trend)=0.02). Computational modeling suggests that this polymorphism is located in the hsa-let-7 g potential target sequence in the COL1A2 3' untranslated region. Our data suggest that most likely, common genetic changes in COL1A2 may influence HCC risk, at least in part by let-7 g-mediated regulation, which is possibly involved in the pathogenesis of HCC. The replication of our studies in other populations will further strengthen our understanding of this association.

Schwalbe EC, Lindsey JC, Straughton D, et al.
Rapid diagnosis of medulloblastoma molecular subgroups.
Clin Cancer Res. 2011; 17(7):1883-94 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Microarray studies indicate medulloblastoma comprises distinct molecular disease subgroups, which offer potential for improved clinical management.
EXPERIMENTAL DESIGN: Minimal mRNA expression signatures diagnostic for the Wnt/Wingless (WNT) and Sonic Hedgehog (SHH) subgroups were developed, validated, and used to assign subgroup affiliation in 173 tumors from four independent cohorts, alongside a systematic investigation of subgroup clinical and molecular characteristics.
RESULTS: WNT tumors [12% (21/173)] were diagnosed >5 years of age (peak, 10 years), displayed classic histology, CTNNB1 mutation (19/20), and associated chromosome 6 loss, and have previously been associated with favorable prognosis. SHH cases [24% (42/173)] predominated in infants (<3 years) and showed an age-dependent relationship to desmoplastic/nodular pathology; all infant desmoplastic/nodular cases (previously associated with a good outcome) were SHH-positive, but these relationships broke down in noninfants. PTCH1 mutations were common [34% (11/32)], but PTCH1 exon1c hypermethylation, chromosome 9q and REN (KCTD11) genetic loss were not SHH associated, and SMO or SUFU mutation, PTCH1 exon1a or SUFU hypermethylation did not play a role, indicating novel activating mechanisms in the majority of SHH cases. SHH tumors were associated with an absence of COL1A2 methylation. WNT/SHH-independent medulloblastomas [64% (110/173)] showed all histologies, peaked at 3 and 6 years, and were exclusively associated with chromosome 17p loss.
CONCLUSIONS: Medulloblastoma subgroups are characterized by distinct genomic, epigenomic and clinicopathologic features, and clinical outcomes. Validated array-independent gene expression assays for the rapid assessment of subgroup affiliation in small biopsies provide a basis for their routine clinical application, in strategies including molecular disease-risk stratification and delivery of targeted therapeutics.

Carén H, Djos A, Nethander M, et al.
Identification of epigenetically regulated genes that predict patient outcome in neuroblastoma.
BMC Cancer. 2011; 11:66 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Epigenetic mechanisms such as DNA methylation and histone modifications are important regulators of gene expression and are frequently involved in silencing tumor suppressor genes.
METHODS: In order to identify genes that are epigenetically regulated in neuroblastoma tumors, we treated four neuroblastoma cell lines with the demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-dC) either separately or in conjunction with the histone deacetylase inhibitor trichostatin A (TSA). Expression was analyzed using whole-genome expression arrays to identify genes activated by the treatment. These data were then combined with data from genome-wide DNA methylation arrays to identify candidate genes silenced in neuroblastoma due to DNA methylation.
RESULTS: We present eight genes (KRT19, PRKCDBP, SCNN1A, POU2F2, TGFBI, COL1A2, DHRS3 and DUSP23) that are methylated in neuroblastoma, most of them not previously reported as such, some of which also distinguish between biological subsets of neuroblastoma tumors. Differential methylation was observed for the genes SCNN1A (p < 0.001), PRKCDBP (p < 0.001) and KRT19 (p < 0.01). Among these, the mRNA expression of KRT19 and PRKCDBP was significantly lower in patients that have died from the disease compared with patients with no evidence of disease (fold change -8.3, p = 0.01 for KRT19 and fold change -2.4, p = 0.04 for PRKCDBP).
CONCLUSIONS: In our study, a low methylation frequency of SCNN1A, PRKCDBP and KRT19 is significantly associated with favorable outcome in neuroblastoma. It is likely that analysis of specific DNA methylation will be one of several methods in future patient therapy stratification protocols for treatment of childhood neuroblastomas.

Misawa K, Kanazawa T, Misawa Y, et al.
Hypermethylation of collagen α2 (I) gene (COL1A2) is an independent predictor of survival in head and neck cancer.
Cancer Biomark. 2011-2012; 10(3-4):135-44 [PubMed] Related Publications
OBJECTIVES: Collagen production plays a role in the development of tumors from cancer cells. The aim of the present study is to examine the involvement of epigenetic alteration of Collagen α2 (I) (COL1A2) gene expression in cases of head and neck squamous cell carcinoma (HNSCC).
METHODS: COL1A2 expression was examined in a panel of cell lines using RT-PCR. The methylation status of the COL1A2 promoter was studied using bisulfate sequencing and methylation-specific PCR (MSP).
RESULTS: COL1A2 expression was absent in 6 of 11 (54.5%) UM-SCC cell lines, whereas three nonmalignant cell lines had stable expressions. MSP analysis showed that 46/98 (46.9%) contained methylated alleles. COL1A2 methylation was significantly correlated with tumor size (P = 0.041), lymph node status (P = 0.008), tumor stage (P = 0.011), H-cadherin methylation (P = 0.039) and disease-free survival (P = 0.005). On multivariate Cox proportional hazard regression, which included age, sex, smoking status, and alcohol exposure, both tumor stage and COL1A2 methylation remained independent prognostic factors.
CONCLUSIONS: This study suggests that CpG hypermethylation is a likely mechanism of COL1A2 gene inactivation, supporting the hypothesis that the COL1A2 gene may play a role in the tumorigenesis of HNSCC and may serve as an important biomarker.

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