This study aimed to clarify epigenetic and genetic alterations that occur during renal carcinogenesis. The original method includes chromosome 3 specific NotI-microarrays containing 180 NotI-clones associated with 188 genes for hybridization with 23 paired normal/tumor DNA samples of primary clear cell renal cell carcinomas (ccRCC). Twenty-two genes showed methylation and/or deletion in 17–57% of tumors. These genes include tumor suppressors or candidates (VHL, CTDSPL, LRRC3B, ALDH1L1, and EPHB1) and genes that were not previously considered as cancer-associated (e.g., LRRN1, GORASP1, FGD5, and PLCL2). Bisulfite sequencing analysis confirmed methylation as a frequent event in ccRCC. A set of six markers (NKIRAS1/RPL15, LRRN1, LRRC3B, CTDSPL, GORASP1/TTC21A, and VHL) was suggested for ccRCC detection in renal biopsies. The mRNA level decrease was shown for 6 NotI-associated genes in ccRCC using quantitative PCR: LRRN1, GORASP1, FOXP1, FGD5, PLCL2, and ALDH1L1. The majority of examined genes showed distinct expression profiles in ccRCC and papillary RCC. The strongest extent and frequency of downregulation were shown for ALDH1L1 gene both in ccRCC and papillary RCC. Moreover, the extent of ALDH1L1 mRNA level decrease was more pronounced in both histological types of RCC stage III compared with stages I and II (P = 0.03). The same was observed for FGD5 gene in ccRCC (P < 0.06).
Dedicated to thememory of Eugene R. Zabarovsky
Background: Large-scale screening methods are widely used to reveal cancer-specific DNA methylation markers. We previously identified non-satellite 3.3-kb repeats associated with facioscapulohumeral muscular dystrophy (FSHD) as hypermethylated in cervical cancer in genomewide screening. To determine whether hypermethylation of 3.3-kb repeats is a tumor-specific event and to evaluate frequency of this event in tumors, we investigated the 3.3-kb repeat methylation status in human papilloma virus (HPV)-positive cervical tumors, cancer cell lines, and normal cervical tissues. Open reading frames encoding DUX family proteins are contained within some 3.3-kb repeat units. The DUX mRNA expression profile was also studied in these tissues.
High-risk human papillomavirus (HR-HPV) persistent infection is responsible for the development of the majority of cervical cancers. The therapy against HPV-associated cancer requires knowledge of the viral gene expression mechanisms. In this study, the polyadenylated polycistronic transcripts containing full-size E1ORF and produced from the early P14 promoter were detected for the first time in cervical tumors with episomal forms of the HPV16 genome. P14-initiated mRNAs were revealed also in precancerous lesions. The amount of P14-initiated transcripts was significantly less compared to transcripts initiated from the major P97 HPV16 promoter in cervical intraepithelial neoplasms and squamous cell carcinomas. The ratios of P97/P14-transcripts determined by qRT-PCR were unique for each clinical sample and varied in quite wide ranges independent of disease progression stages or tumor grade. These data suggest that the levels of P14- and P97-transcripts are regulated independently from each other in cervical neoplasms.
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