For many high-dimensional studies, additional information on the variables, like (genomic) annotation or external p-values, is available. In the context of binary and continuous prediction, we ...develop a method for adaptive group-regularized (logistic) ridge regression, which makes structural use of such 'co-data'. Here, 'groups' refer to a partition of the variables according to the co-data. We derive empirical Bayes estimates of group-specific penalties, which possess several nice properties: i) they are analytical; ii) they adapt to the informativeness of the co-data for the data at hand; iii) only one global penalty parameter requires tuning by cross-validation. In addition, the method allows use of multiple types of co-data at little extra computational effort. We show that the group-specific penalties may lead to a larger distinction between `near-zero' and relatively large regression parameters, which facilitates post-hoc variable selection. The method, termed GRridge, is implemented in an easy-to-use R-package. It is demonstrated on two cancer genomics studies, which both concern the discrimination of precancerous cervical lesions from normal cervix tissues using methylation microarray data. For both examples, GRridge clearly improves the predictive performances of ordinary logistic ridge regression and the group lasso. In addition, we show that for the second study the relatively good predictive performance is maintained when selecting only 42 variables.
Abstract
Deregulated expression of microRNAs (miRNAs) is common and biologically relevant in cervical carcinogenesis and appears only partly related to chromosomal changes. We recently identified 34 ...miRNAs showing decreased expression in cervical high-grade precursor lesions and carcinomas not associated with a chromosomal loss, 6 of which were located within a CpG island. This study aimed to investigate to what extent these miRNAs are subject to DNA methylation-mediated silencing in cervical carcinogenesis.
Methylation-specific PCR (MSP) analysis on a cell line panel representing different stages of human papillomavirus (HPV) induced transformation revealed an increase in methylation of hsa-miR-149, -203, and -375 with progression to malignancy, whereas expression of these miRNAs was restored upon treatment with a demethylating agent. All three miRNAs showed significantly increased levels of methylation in cervical carcinomas, whereas methylation levels of hsa-miR-203 and -375 were also significantly increased in high-grade cervical intraepithelial neoplasia (CIN). A pilot analysis showed that increased hsa-miR-203 methylation was also detectable in HPV-positive cervical scrapes of women with high-grade CIN compared to controls. Similar to recent findings on hsa-miR-375, ectopic expression of hsa-miR-203 in cervical cancer cells decreased both the proliferation rate and anchorage independent growth.
We found evidence for methylation-mediated silencing of hsa-miR-149, -203 and -375 in cervical cancer. Methylation of the latter two was already apparent in precancerous lesions and represent functionally relevant events in HPV-mediated transformation. In addition, as demonstrated for hsa-miR-203, these methylated miRNAs may provide valuable markers for assessment of the presence of (pre)cancerous cervical lesions in HPV-positive women.
Citation Format: Saskia Marije Wilting, Wina Verlaat, Annelieke Jaspers, Nour A. Makazaji, Reuven Agami, Chris JLM Meijer, Peter JF Snijders, Renske DM Steenbergen. Methylation-mediated silencing of microRNAs during cervical carcinogenesis. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2971. doi:10.1158/1538-7445.AM2013-2971
Compared with other types of tumours, malignant melanomas are highly refractory to radio- or chemotherapy. To support the search for possible sensitizers, we explored the effects of the cellular ...oncoproteins c-Myc and N-Ras, which can decrease the clonogenic potential of irradiated p53-negative IGR39D melanoma cells. Using stable transfectants of this cell line, we showed that mutant N-Ras decreased the proliferation rate by inducing a prolonged cell cycle arrest. In contrast, c-Myc made these melanoma cells more prone to radiation-induced cell death. Membrane blebbing, the formation of apoptotic bodies and caspase activation, as measured by cleavage of Asp-Glu-Val-Asp (DEVD) substrate and poly(ADP-ribose) polymerase (PARP), indicate that these cells die by an apoptotic process. c-Myc also sensitized these p53-deficient melanoma cells to treatment with various cytotoxic drugs and heat shock. Similar results were obtained in inducible c-Myc models of IGR39D and in another melanoma cell line, 9007, which expresses functional p53. Together, these findings indicate that c-Myc is capable of sensitizing typically resistant tumour cells and that this occurs irrespective of the functional status of the p53 protein. Our results should facilitate the identification of factors that can be exploited for the treatment of aggressive cancers.
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