NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.

• MeSH
• B-buněčný lymfom metabolismus   MeSH
• buněčné jádro metabolismus   MeSH
• chromozomální aberace MeSH
• chronická lymfatická leukemie genetika   metabolismus   MeSH
• cytoplazma metabolismus   MeSH
• delece genu MeSH
• kinasa I-kappa B genetika   fyziologie   MeSH
• kohortové studie MeSH
• lidé MeSH
• lymfom z B-buněk marginální zóny metabolismus   MeSH
• lymfom z plášťových buněk metabolismus   MeSH
• mutační analýza DNA MeSH
• NF-kappa B metabolismus   MeSH
• posunová mutace MeSH
• receptory antigenů B-buněk metabolismus   MeSH
• regulace genové exprese u leukemie * MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• signální transdukce MeSH
• stanovení celkové genové exprese MeSH
• viabilita buněk MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

The incidence of renal cell carcinoma (RCC) is increasing worldwide, and its prevalence is particularly high in some parts of Central Europe. Here we undertake whole-genome and transcriptome sequencing of clear cell RCC (ccRCC), the most common form of the disease, in patients from four different European countries with contrasting disease incidence to explore the underlying genomic architecture of RCC. Our findings support previous reports on frequent aberrations in the epigenetic machinery and PI3K/mTOR signalling, and uncover novel pathways and genes affected by recurrent mutations and abnormal transcriptome patterns including focal adhesion, components of extracellular matrix (ECM) and genes encoding FAT cadherins. Furthermore, a large majority of patients from Romania have an unexpected high frequency of A:T>T:A transversions, consistent with exposure to aristolochic acid (AA). These results show that the processes underlying ccRCC tumorigenesis may vary in different populations and suggest that AA may be an important ccRCC carcinogen in Romania, a finding with major public health implications.

• MeSH
• dospělí MeSH
• fokální adheze metabolismus   MeSH
• fosfatidylinositol-3-kinasy genetika   MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genetická variace * MeSH
• genom lidský genetika   MeSH
• genomika * MeSH
• karcinom z renálních buněk genetika   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• mutační rychlost MeSH
• regulace genové exprese u nádorů MeSH
• sekvenční analýza DNA MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sestřih RNA genetika   MeSH
• signální transdukce genetika   MeSH
• stanovení celkové genové exprese MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH