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| 2. |
- Dmitriev, Alexey A, et al.
(författare)
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Genetic and epigenetic analysis of non-small cell lung cancer with NotI-microarrays
- 2012
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Ingår i: Epigenetics. - : Landes Bioscience. - 1559-2294 .- 1559-2308. ; 7:5, s. 502-513
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to clarify genetic and epigenetic alterations that occur during lung carcinogenesis and to design perspective sets of newly identified biomarkers. The original method includes chromosome 3 specific NotI-microarrays containing 180 NotI clones associated with genes for hybridization with 40 paired normal/tumor DNA samples of primary lung tumors: 28 squamous cell carcinomas (SCC) and 12 adenocarcinomas (ADC). The NotI-microarray data were confirmed by qPCR and bisulfite sequencing analyses. Forty-four genes showed methylation and/or deletions in more than 15% of non-small cell lung cancer (NSCLC) samples. In general, SCC samples were more frequently methylated/deleted than ADC. Moreover, the SCC alterations were observed already at stage I of tumor development, whereas in ADC many genes showed tumor progression specific methylation/deletions. Among genes frequently methylated/deleted in NSCLC, only a few were already known tumor suppressor genes: RBSP3 (CTDSPL), VHL and THRB. The RPL32, LOC285205, FGD5 and other genes were previously not shown to be involved in lung carcinogenesis. Ten methylated genes, i.e., IQSEC1, RBSP3, ITGA9, FOXP1, LRRN1, GNAI2, VHL, FGD5, ALDH1L1 and BCL6 were tested for expression by qPCR and were found downregulated in the majority of cases. Three genes (RBSP3, FBLN2 and ITGA9) demonstrated strong cell growth inhibition activity. A comprehensive statistical analysis suggested the set of 19 gene markers, ANKRD28, BHLHE40, CGGBP1, RBSP3, EPHB1, FGD5, FOXP1, GORASP1/TTC21, IQSEC1, ITGA9, LOC285375, LRRC3B, LRRN1, MITF, NKIRAS1/RPL15, TRH, UBE2E2, VHL, WNT7A, to allow early detection, tumor progression, metastases and to discriminate between SCC and ADC with sensitivity and specificity of 80-100%.
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| 3. |
- Schwarz, J., et al.
(författare)
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F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort
- 2013
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 19:1, s. 113-118
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Tidskriftsartikel (refereegranskat)abstract
- Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in haemophilia A. It has been suggested that differences in the distribution of FVIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Data from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1 + H2) and inhibitor risk among individuals of genetically determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and human leucocyte antigen (HLA) were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Haplotype 3 was associated with higher inhibitor risk among those genetically identified (N = 49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N = 223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Haplotype 3 was not an independent predictor of inhibitor risk. Furthermore, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual.
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| 6. |
- Haraldson, Klas, et al.
(författare)
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LRRC3B gene is frequently epigenetically inactivated in several epithelial malignancies and inhibits cell growth and replication
- 2012
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Ingår i: Biochimie. - : Elsevier. - 0300-9084 .- 1638-6183. ; 94:5, s. 1151-1157
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Tidskriftsartikel (refereegranskat)abstract
- Chromosome 3 specific NotI microarrays containing 180 NotI linking clones associated with 188 genes were hybridized to NotI representation probes prepared using matched tumor/normal samples from major epithelial cancers: breast (47 pairs), lung (40 pairs) cervical (43 pairs), kidney (34 pairs of clear cell renal cell carcinoma), colon (24 pairs), ovarian (25 pairs) and prostate (18 pairs). In all tested primary tumors (compared to normal controls) methylation and/or deletions was found. For the first time we showed that the gene LRRC3B was frequently methylated and/or deleted in breast carcinoma - 32% of samples, cervical - 35%, lung - 40%, renal - 35%, ovarian - 28%, colon - 33% and prostate cancer - 44%. To check these results bisulfite sequencing using cloned PCR products with representative two breast, one cervical, two renal, two ovarian and two colon cancer samples was performed. In all cases methylation was confirmed. Expression analysis using RT-qPCR showed that LRRC3B is strongly down-regulated at the latest stages of RCC and ovarian cancers. In addition we showed that LRRC3B exhibit strong cell growth inhibiting activity (more than 95%) in colony formation experiments in vitro in KRC/Y renal cell carcinoma line. All these data suggest that LRRC3B gene could be involved in the process of carcinogenesis as a tumor suppressor gene.
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| 7. |
- Kashuba, Vladimir, et al.
(författare)
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NotI Microarrays: Novel Epigenetic Markers for Early Detection and Prognosis of High Grade Serous Ovarian Cancer
- 2012
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 13:10, s. 13352-13377
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Tidskriftsartikel (refereegranskat)abstract
- Chromosome 3-specific NotI microarray (NMA) containing 180 clones with 188 genes was used in the study to analyze 18 high grade serous ovarian cancer (HGSOC) samples and 7 benign ovarian tumors. We aimed to find novel methylation-dependent biomarkers for early detection and prognosis of HGSOC. Thirty five NotI markers showed frequency of methylation/deletion more or equal to 17%. To check the results of NMA hybridizations several samples for four genes (LRRC3B, THRB, ITGA9 and RBSP3 (CTDSPL)) were bisulfite sequenced and confirmed the results of NMA hybridization. A set of eight biomarkers: NKIRAS1/RPL15, THRB, RBPS3 (CTDSPL), IQSEC1, NBEAL2, ZIC4, LOC285205 and FOXP1, was identified as the most prominent set capable to detect both early and late stages of ovarian cancer. Sensitivity of this set is equal to (72 +/- 11)% and specificity (94 +/- 5)%. Early stages represented the most complicated cases for detection. To distinguish between Stages I + II and Stages III + IV of ovarian cancer the most perspective set of biomarkers would include LOC285205, CGGBP1, EPHB1 and NKIRAS1/RPL15. The sensitivity of the set is equal to (80 +/- 13)% and the specificity is (88 +/- 12)%. Using this technique we plan to validate this panel with new epithelial ovarian cancer samples and add markers from other chromosomes.
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| 9. |
- Astermark, Jan, et al.
(författare)
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The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort.
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 121:8, s. 1446-1454
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Tidskriftsartikel (refereegranskat)abstract
- Studies of determinants of development of inhibitory antibodies to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study Combined Cohort was formed to extend understanding of the genetic background of risk. The study group contains 833 subjects from three independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status. Using an Illumina iSelect platform, 13,331 SNPs from 1,081 genes, primarily immune response and immune modifier genes, were typed. Each cohort was analyzed separately with results combined using a meta-analytic technique. After adjustment for potential confounders, 53 SNPs were significant predictors of inhibitor status using the criteria of odds ratios (OR) in the same direction in all cohorts, or allowing for a 20% interval around an OR of 1 in one of the three, and significant in at least two. Of the 53, 13 markers had meta p-values of <0.001. Eight of the 53 were significant predictors among the discordant pairs. Results support the complexity of the immune response, and encourage further research with the goal of understanding the pathways involved.
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