Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.
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ABSTRACT:
SUBMITTER: Speedy HE
PROVIDER: S-EPMC5271173 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma.
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Project description:Purpose of reviewFamilies with multiple individuals affected with chronic lymphocytic leukemia (CLL) and other related B-cell tumors have been described in the literature and strong familial aggregation has been seen in population studies. However, predisposing germline mutations have not been identified. We will discuss the spectrum of conditions associated with CLL in families and the advances in identifying the underlying susceptibility genes.Recent findingsFamilial CLL does not appear to differ substantially from sporadic CLL in terms of prognostic markers and clinical outcome, although it may be associated with more indolent disease. The precursor condition, monoclonal B-cell lymphocytosis, also aggregates in CLL families. Linkage studies have been conducted in high-risk CLL families to screen the whole genome for susceptibility loci but no gene mutations have yet been identified by this method. Association studies of candidate genes have implicated several genes as being important in CLL but more studies are needed. Results from whole-genome association studies are promising.SummaryThe ability to conduct large-scale genomic studies in unrelated CLL patients and in high-risk CLL families will play an important role in detecting susceptibility genes for CLL over the next few years and thereby help to delineate causal pathways.
| S-EPMC2891437 | biostudies-literature
Project description:The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families. Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF 2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with χ(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction). Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma. Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility.
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Project description:Chronic lymphocytic leukemia (CLL) is the most frequent leukemia type in which the genetic alterations influencing the clinico-biological course are not entirely understood. CLL has a heterogeneous course, with some patients showing an indolent course and others experiencing an aggressive course. Whole-genome sequencing and whole-exome sequencing studies identified recurrently mutated genes in CLL and profiled its clonal evolution patterns. However, more recent whole-genome sequencing studies also identified variants in non-coding sequences of the CLL genome, revealing important lesions outside the protein-coding regions. Here we describe the most representative non-coding lesion of the CLL genome, including lesions in the 3'-UTR region of NOTCH1 which result in the truncation of the NOTCH1 protein PEST domain, and non-coding mutations in an enhancer region on chromosome 9p13 which result in reduced expression of the PAX5 transcription factor. In addition, we describe the role of microRNA in CLL, in particular the miR15a/miR16-1 microRNA recurrently affected by deletions of chromosome 13q14. Together, new findings in non-coding genome genetic lesions provide a more complete portrait of the genomic landscape of CLL with clinical implications.
| S-EPMC6322188 | biostudies-other
Project description:BACKGROUND: NOTCH1 PEST domain mutations in chronic lymphocytic leukemia have recently been shown to be of prognostic relevance. Both NOTCH1 and NOTCH2 are constitutively activated in B-cell CLL but not expressed in normal B cells and may be involved in survival and resistance to apoptosis in CLL. We screened for mutations in different parts of both NOTCH1 and NOTCH2 genes and related the changes to survival and other known risk factors. METHODS: In a cohort of 209 CLL patients, we used single strand conformation analysis to determine which of the samples carrying the NOTCH mutations and direct dideoxy sequencing was used to determine the exact nucleotide changes. Kaplan-Meier curves and log rank test were used to determine overall survival for NOTCH1 mutated cases and Cox regression analysis was used to calculate hazardous ratios. RESULTS: In the present study, we found NOTCH1 PEST domain mutations in 6.7% of the cases. A shorter overall survival was found in patients with NOTCH1 mutations compared to wildtype (p = 0.049). Further, we also examined the extracellular and the heterodimerisation domains of the NOTCH1 gene and the PEST domain and heterodimerisation domain of the NOTCH2 gene, but no mutations were found in these regions. NOTCH1 mutations were most commonly observed in patients with unmutated IGHV gene (10/14), and associated with a more aggressive disease course. In addition, NOTCH1 mutations were almost mutually exclusive with TP53 mutations. In the combined group of NOTCH1 (6.7%) or TP53 (6.2%) mutations, a significant difference in overall survival compared to the wildtype NOTCH1 and TP53 was found (p = 0.002). CONCLUSIONS: Both NOTCH1 and TP53 mutations seem to be independent predictive markers for worse outcome in CLL-patients and this study emphasizes the contention that NOTCH1 mutations is a novel risk marker.
| S-EPMC3679784 | biostudies-literature
Project description:Recent studies of chronic lymphocytic leukemia (CLL) have reported recurrent mutations in the RPS15 gene, which encodes the ribosomal protein S15 (RPS15), a component of the 40S ribosomal subunit. Despite some evidence about the role of mutant RPS15 (mostly obtained from the analysis of cell lines), the precise impact of RPS15 mutations on the translational program in primary CLL cells remains largely unexplored. Here, using RNA sequencing and ribosome profiling, a technique that involves measuring translational efficiency, we sought to obtain global insight into changes in translation induced by RPS15 mutations in CLL cells. To this end, we evaluated primary CLL cells from patients with wild-type or mutant RPS15 as well as MEC1 CLL cells transfected with mutant or wild-type RPS15. Our data indicate that RPS15 mutations rewire the translation program of primary CLL cells by reducing their translational efficiency, an effect not seen in MEC1 cells. In detail, RPS15 mutant primary CLL cells displayed altered translation efficiency of other ribosomal proteins and regulatory elements that affect key cell processes, such as the translational machinery and immune signaling, as well as genes known to be implicated in CLL, hence highlighting a relevant role for RPS15 in the natural history of CLL.
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| S-EPMC3650490 | biostudies-literature
Project description:BackgroundExportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood.MethodsWe performed a large, multi-center retrospective analysis of CLL cases (N = 1286) to correlate nonsynonymous mutations in XPO1 (predominantly E571K or E571G; n = 72) with genetic and epigenetic features contributing to the overall outcomes in these patients. We then established a mouse model with over-expression of wildtype (wt) or mutant (E571K or E571G) XPO1 restricted to the B cell compartment (Eµ-XPO1). Eµ-XPO1 mice were then crossed with the Eµ-TCL1 CLL mouse model. Lastly, we determined crystal structures of XPO1 (wt or E571K) bound to several selective inhibitors of nuclear export (SINE) molecules (KPT-185, KPT-330/Selinexor, and KPT-8602/Eltanexor).ResultsWe report that nonsynonymous mutations in XPO1 associate with high risk genetic and epigenetic features and accelerated CLL progression. Using the newly-generated Eµ-XPO1 mouse model, we found that constitutive B-cell over-expression of wt or mutant XPO1 could affect development of a CLL-like disease in aged mice. Furthermore, concurrent B-cell expression of XPO1 with E571K or E571G mutations and TCL1 accelerated the rate of leukemogenesis relative to that of Eµ-TCL1 mice. Lastly, crystal structures of E571 or E571K-XPO1 bound to SINEs, including Selinexor, are highly similar, suggesting that the activity of this class of compounds will not be affected by XPO1 mutations at E571 in patients with CLL.ConclusionsThese findings indicate that mutations in XPO1 at E571 can drive leukemogenesis by priming the pre-neoplastic lymphocytes for acquisition of additional genetic and epigenetic abnormalities that collectively result in neoplastic transformation.
| S-EPMC7809770 | biostudies-literature
Project description:Chronic lymphocytic leukemia (CLL) is a biologically heterogeneous illness that primarily afflicts the elderly. For many decades, the initial therapy for most patients requiring treatment was limited to single-agent alkylator therapy. Within the last two decades, we have seen remarkable progress in understanding the biology of CLL and the development of more effective treatment strategies that have employed monoclonal antibodies, such as rituximab (anti-CD20). Furthermore, recognition of the synergy between fludarabine, cyclophosphamide, and rituximab (FCR) prompted investigators to explore the clinical activity of FCR in Phase II and III trials in patients with relapsed/refractory or previously untreated CLL. On the basis of these findings, the US Food and Drug Administration (FDA) recently approved rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with relapsed/refractory or previously untreated CD20-postive CLL. Recent data from a randomized Phase III trial has confirmed improved overall survival with FCR in patients with previously untreated CLL. However, FCR is not for everyone. More tolerable regimens using rituximab for the elderly and less fit patients are being pursued in clinical trials. Recent Phase II trials have explored potentially less myelosuppressive approaches by using lower doses of fludarabine and cyclophosphamide, replacing fludarabine with pentostatin, and combining rituximab with chlorambucil. Furthermore new biomarkers predictive of early disease progression have prompted investigators to explore the benefits of early treatment with rituximab combined with other agents. In addition to the proven utility of rituximab as a frontline agent for CLL, rituximab has a favorable toxicity profile both as a single agent and in combination with chemotherapy. The majority of adverse events are Grade 1 and 2 infusion-related reactions (fevers, chills, and rigors) and occur with the first dose of rituximab. The improved tolerability observed with second and subsequent infusions allows for shorter infusion times. Rituximab's proven activity and favorable toxicity profile has made it an ideal agent for expanding treatment options for patients with CLL, the majority of whom are elderly.
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