Aberrant methylation as a main mechanism of TSGs silencing in PTC

Czarnecka, Karolina; Pastuszak-Lewandoska, Dorota; Migdalska-Sęk, Monika; Nawrot, Ewa; Brzeziński, Jan; Dedecjus, Marek; Pomorski, Lech; Brzeziańska, Ewa

doi:10.2741/e228

Cited by 10 publications

(21 citation statements)

References 51 publications

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“…To our knowledge, two selected in our study markers for 1p31.2 region analysis (covering ARHI and GADD45A genes) have not been used in PCa study yet. Molecular downregulation of ARHI (including LOH) is proved to be linked with several cancer types in human, such as ovarian, breast, hepatocellular and thyroid cancer [10, 21, 22], but LOH observed by us in this loci in prostate carcinogenesis is innovative and should be continued as a new project.…”

Section: Discussionmentioning

confidence: 99%

“…Evaluation of LOH/MSI was performed by calculating the ratio of the fluorescence intensity of the alleles, originating from blood sample (N, normal, i.e., control sample) to the fluorescence intensity of the alleles originating from prostatic biopsy (T, tumor). For each informative tumor–normal DNA pair (paired T and N samples), an Allelic Imbalance Ratio (AIR) was calculated, based on the maximum allele peak heights (fluorescence intensity), as follows: normal allele 1: normal allele 2/tumor allele 1: tumor allele 2 (N1:N2/T1:T2) according to protocol [10]. When AIR was less than 0.67 or greater than 1.35, it was considered indicative of LOH in tumor samples (according to the criteria of GeneMapper Software v 4.0).…”

Section: Methodsmentioning

confidence: 99%

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Diagnostic value of DNA alteration: loss of heterozygosity or allelic imbalance—promising for molecular staging of prostate cancers

et al. 2013

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The biological behavior of prostate cancer is uncertain, and therefore, search for molecular prognostic markers associated with disease progression seems to be essential. We performed microsatellite allelotyping of DNA isolated from primary prostate tumors biopsies (prostate adenocarcinoma, PCa). We evaluated the frequency of allelic imbalance (AI), including loss of heterozygosity and/or microsatellite imbalance (LOH/MSI) as well as the association of these DNA alterations with clinicopathological variables. We assessed the significance of LOH/MSI alterations in selected imprinted and non-imprinted chromosomal regions (IR and NIR) in PCa. A total of 50 biopsies of prostate tumor (containing >75 % tumor cells) were histologically examined confirming prostate carcinoma. Microsatellite allelotyping using 16 microsatellite markers linked to the following chromosomal regions: 1p31.2, 3p21.3–25.3, 7q32.2, 9p21.3, 11p15.5, 12q23.2, and 16q22.1 was performed. The incidence of LOH/MSI alterations in prostate tumor cells was the highest for chromosomal regions 7q32.2 and 16q22.1 (31.25 and 26.60 %, respectively), followed by 1p31.2 and 3p21.3–25.3 (26.50 and 17.40 %, respectively). Statistically significant increase in LOH/MSI alterations has been observed for markers: D1S2137 (1p region; p = 0.00032), D9S974 (9p region; p = 0.0017), and D16S3025 (16q region; p = 0.0017). Statistically significant differences in frequency of LOH/MSI alterations in particular chromosomal regions have been found for 1p31.2, 7q32.2 and 16q22.1 (p = 0.027, p = 0.012 and p = 0.031, respectively). We documented statistically significant association between Fractional Allele Loss (FAL) index and advanced tumor stage (p < 0.05). We suggest that genomic instability of LOH/MSI type is a frequent event in prostate carcinogenesis and assessed as FAL index has clinical value for the molecular staging of prostate cancer in (TRUS)-guided prostate biopsy material.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Diagnostic value of DNA alteration: loss of heterozygosity or allelic imbalance—promising for molecular staging of prostate cancers

et al. 2013

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“…Evaluation of LOH/MSI was performed by calculating the ratio of the fluorescence intensity of the alleles from unchanged lung tissue sample (N, normal, that is, control sample) to the fluorescence intensity of the alleles from NSCLC sample (T, tumor). For each informative tumor–normal DNA pair (paired T and N samples), an allelic imbalance ratio (AIR) was calculated, based on the maximum allele peak heights (fluorescence intensity), as follows: normal allele 1:normal allele 2/tumor allele 1:tumor allele 2 (N1:N2/T1:T2), according to the previously published protocol [24]. LOH in tumor samples was considered indicative when AIR value was less than 0.67 or greater than 1.35 (according to the criteria of GeneMapper Software v 4.0).…”

Section: Methodsmentioning

confidence: 99%

Significant frequency of allelic imbalance in 3p region covering RARβ and MLH1 loci seems to be essential in molecular non-small cell lung cancer diagnosis

et al. 2013

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The aim of the study was to investigate the influence of allelic imbalance (AI) in several loci of tumor suppressor genes in 3p region on the non-small cell lung cancer (NSCLC) development. We evaluated the frequency of loss of heterozygosity and/or microsatellite imbalance (LOH/MSI) and assessed their association with patients’ characteristics (age, gender, tobacco addiction) and NSCLC classification according to TNM/AJCC staging. To analyze the potential role of AI involved in NSCLC pathogenesis, we allelotyped a group of 74 NSCLC patients using 7 microsatellite markers. The highest frequency of LOH/MSI, however, not statistically significant, was observed in RARβ and MLH1 (p = 0.104 and p = 0.216, respectively) loci. The association between high LOH/MSI frequency in 3p region with male gender (p = 0.041) as well as with age (especially >60 years) for RARβ and MLH1 genes (p = 0.0001 and p = 0.020, respectively) was documented. Statistically significant increased frequency of MLH1 allelic loss in squamous cell carcinoma (SCC) versus non-squamous cell carcinoma (non-SCC) was observed (p = 0.01). Significant increase in LOH/MSI frequency in 3p region (mainly in FHIT and MLH1loci) in correlation with cigarette addiction in a lifetime (≥40 years and ≥40 Pack Years) was also documented (p < 0.05). The highest LOH/MSI was revealed in RARβ locus in IA tumors (p = 0.0001), while the similarly high allelic loss of MLH1 correlated with III A/B tumors (p = 0.0002), according to AJCC staging. The obtained results demonstrate that AI is influenced by tobacco smoking and seems to be vital in the molecular diagnosis of NSCLC, especially of SCC subtype.

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“…CMTM4 is the most conserved member of this family and forms a gene cluster with CKLF and CMTM1-3 on chromosome 16q22.1, a locus that is frequently deleted or modified in multiple tumours and that harbours a number of tumour suppressor genes [ 26 – 33 ]. CMTM4 encodes three transcript variants, CMTM4-v1, −v2 and -v3.…”

Section: Introductionmentioning

confidence: 99%

CMTM4 is frequently downregulated and functions as a tumour suppressor in clear cell renal cell carcinoma

Cheng

Wang

et al. 2015

J Exp Clin Cancer Res

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BackgroundChemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family (CMTM) is a gene family involved in multiple malignancies. CMTM4 is a member of this family and is located at chromosome 16q22.1, a locus that harbours a number of tumour suppressor genes. It has been defined as a regulator of cell cycle and division in HeLa cells; however, its roles in tumourigenesis remain poorly studied.MethodsAn integrated bioinformatics analysis based on the array data from the GEO database was conducted to view the differential expression of CMTM4 across multiple cancers and their corresponding control tissues. Primary clear cell renal cell carcinoma (ccRCC) and the paired adjacent non-tumour tissues were then collected to examine the expression of CMTM4 by western blotting, immunohistochemistry, and quantitative RT-PCR. The ccRCC cell lines A498 and 786-O and the normal renal tubular epithelial cell line HK-2 were also tested for CMTM4 expression by western blotting. Cell Counting Kit-8 (CCK-8) and viable cell counting assays were used to delineate the growth curves of 786-O cells after CMTM4 overexpression or knockdown. Wound healing and transwell assays were performed to assess the cells’ ability to migrate. The effects of CMTM4 on cellular apoptosis and cell cycle progression were analysed by flow cytometry, and cell cycle hallmarks were detected by western blotting and RT-PCR. The xenograft model in nude mice was used to elucidate the function of CMTM4 in tumourigenesis ex vivo.ResultsBy omic data analysis, we found a substantial downregulation of CMTM4 in ccRCC. Western blotting then confirmed that CMTM4 was dramatically reduced in 86.9 % (53/61) of ccRCC tissues compared with the paired adjacent non-tumour tissues, as well as in the 786-O and A498 ccRCC cell lines. Restoration of CMTM4 significantly suppressed 786-O cell growth by inducing G2/M cell cycle arrest and p21 upregulation, and cell migration was also inhibited. However, knockdown of CMTM4 led to a completely opposite effect on these cell behaviours. Overexpression of CMTM4 also markedly inhibited the tumour xenograft growth in nude mice.ConclusionsCMTM4 is downregulated and exhibits tumour-suppressor activities in ccRCC, and could be exploited as a target for ccRCC treatment.

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Aberrant methylation as a main mechanism of TSGs silencing in PTC

Cited by 10 publications

References 51 publications

Diagnostic value of DNA alteration: loss of heterozygosity or allelic imbalance—promising for molecular staging of prostate cancers

Diagnostic value of DNA alteration: loss of heterozygosity or allelic imbalance—promising for molecular staging of prostate cancers

Significant frequency of allelic imbalance in 3p region covering RARβ and MLH1 loci seems to be essential in molecular non-small cell lung cancer diagnosis

CMTM4 is frequently downregulated and functions as a tumour suppressor in clear cell renal cell carcinoma

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