Reticular basement membrane thickness is associated with growth : and fibrosis-promoting airway transcriptome profile-study in asthma patients

Airway remodeling in asthma is characterized by reticular basement membrane (RBM) thickening, likely related to epithelial structural and functional changes. Gene expression profiling of the airway epithelium might identify genes involved in bronchial structural alterations. We analyzed bronchial wall geometry (computed tomography (CT)), RBM thickness (histology), and the bronchial epithelium transcriptome profile (gene expression array) in moderate to severe persistent (n = 21) vs. no persistent (n = 19) airflow limitation asthmatics. RBM thickness was similar in the two studied subgroups. Among the genes associated with increased RBM thickness, the most essential were those engaged in cell activation, proliferation, and growth (e.g., CDK20, TACC2, ORC5, and NEK5) and inhibiting apoptosis (e.g., higher mRNA expression of RFN34, BIRC3, NAA16, and lower of RNF13, MRPL37, CACNA1G). Additionally, RBM thickness correlated with the expression of genes encoding extracellular matrix (ECM) components (LAMA3, USH2A), involved in ECM remodeling (LTBP1), neovascularization (FGD5, HPRT1), nerve functioning (TPH1, PCDHGC4), oxidative stress adaptation (RIT1, HSP90AB1), epigenetic modifications (OLMALINC, DNMT3A), and the innate immune response (STAP1, OAS2). Cluster analysis revealed that genes linked with RBM thickness were also related to thicker bronchial walls in CT. Our study suggests that the pro-fibrotic profile in the airway epithelial cell transcriptome is associated with a thicker RBM, and thus, may contribute to asthma airway remodeling

The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2–4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases

Detection of viral DNA sequences in sporadic colorectal cancers in relation to CpG island methylation and methylator phenotype

There is evidence that insertion of viral DNA into a mammalian genome can lead to alterations of methylation patterns. The aim of the present study was to examine the presence of DNA sequences of five human DNA viruses (assessed by PCR): JC polyoma virus (JCV), human adenovirus (AdV), Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV/HHV8) and human papillomavirus (HPV) in a cohort of 186 sporadic colorectal cancers (CRCs) and related these data with the methylation status of six CIMP-specific genes (MLH1, CACNA1G, NEUROG1, IGF2, SOCS1, RUNX3) and seven cancer-related genes markers (p16, MINT1, MINT2, MINT31, EN1, SCTR and INHBB) assessed by methylationspecific PCR in 186 and 134 CRC cases, respectively. The AdV, KSHV and HPV were detected in 4 (2%), 2 (1%) and 0 CRC cases, respectively and thus were excluded from further analyses. Althought, 19% and 9% of the CRCs were positive for EBV and JCV respectively, no associations between virus presence and CpG island methylation were found after correction for multiple testing. Our results demonstrate that the presence of DNA sequences of JCV and EBV in CRC is unrelated to the methylation of the 13 cancer-related CpG islands and CIMP

FANCM and RECQL genetic variants and breast cancer susceptibility: relevance to South Poland and West Ukraine

Abstract Background FANCM and RECQL have recently been reported as breast cancer susceptibility genes and it has been suggested that they should be included on gene panel tests for breast cancer predisposition. However, the clinical value of testing for mutations in RECQL and FANCM remains to be determined. In this study, we have characterised the spectrum of FANCM and RECQL mutations in women affected with breast or ovarian cancer from South-West Poland and West Ukraine. Methods We applied Hi-Plex, an amplicon-based enrichment method for targeted massively parallel sequencing, to screen the coding exons and proximal intron-exon junctions of FANCM and RECQL in germline DNA from unrelated women affected with breast cancer (n = 338) and ovarian cancer (n = 89) from Poland (n = 304) and Ukraine (n = 123). These women were at high-risk of carrying a genetic predisposition to breast and/or ovarian cancer due to a family history and/or early-onset disease. Results Among 427 women screened, we identified one carrier of the FANCM:c.1972C > T nonsense mutation (0.23%), and two carriers of the frameshift insertion FANCM:c.1491dup (0.47%). None of the variants we observed in RECQL were predicted to be loss-of-function mutations by standard variant effect prediction tools. Conclusions Our study of the Polish and Ukrainian populations has identified a carrier frequency of truncating mutations in FANCM consistent with previous reports. Although initial reports suggesting that mutations in RECQL could be associated with increased breast cancer risk included women from Poland and identified the RECQL:c.1667_1667 + 3delAGTA mutation in 0.23–0.35% of breast cancer cases, we did not observe any carriers in our study cohort. Continued screening, both in research and diagnostic settings, will enable the accumulation of data that is needed to establish the clinical utility of including RECQL and FANCM on gene panel tests

Additional file 1: Table S1. of FANCM and RECQL genetic variants and breast cancer susceptibility: relevance to South Poland and West Ukraine

FANCM and RECQL truncating mutations characterized by case-control analyses, following their initial involvement in breast cancer susceptibility via a whole-exome sequencing approach. List of FANCM and RECQL truncation mutations identified by case-control analyses and corresponding references. (DOCX 19 kb

Polymorphisms in methyl-group metabolism genes and risk of sporadic colorectal cancer with relation to the CpG island methylator phenotype .

The CpG island methylator phenotype (CIMP), together with extensive promoter methylation, is regarded as one of the mechanisms involved in colorectal carcinogenesis (CRC). The mechanisms underlying the presence of CIMP in sporadic colorectal cancer are poorly understood. Genes involved in methyl-group metabolism are likely to affect DNA methylation and thereby influence an individual's susceptibility to CIMP. To test this hypothesis, we examined the potential association between the polymorphisms of MTHFR 677C>T, TS 5’UTR 2R/3RG>C, TS 3’UTR 1494del6, MTHFD1 401G>A, DNMT3B -149C>T and DNMT3B -283T>C and the presence of CIMP in a group of 186 sporadic CRC cases and 100 controls. The CIMP status of the tumors was determined by a panel of five markers (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1), which was also followed by analysing hMLH1 methylation and BRAF V600E mutation. Individuals with TS 3R/3R had an increased risk of CIMP- colorectal cancer (OR = 2.38, 95% CI = 1.0-5.7; P = 0.042, Fisher's exact test) when compared with 2R/2R homozygotes. Individuals with DNMT3B -283 CC reduced risk of CIMP+ colorectal cancer (OR = 0.220, 95% CI = 0.0226-1.07; P = 0.046, Fisher's exact test) when compared to -283 TT carriers. This study provides some support to the hypothesis that methyl-group metabolism plays a role in the etiology of both CIMP+ and CIMP - colorectal cancers