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Novel Mutation Hotspots within Non-Coding Regulatory Regions of the Chronic Lymphocytic Leukemia Genome.

ABSTRACT: Mutations in non-coding DNA regions are increasingly recognized as cancer drivers. These mutations can modify gene expression in cis or by inducing high-order chormatin structure modifications with long-range effects. Previous analysis reported the detection of recurrent and functional non-coding DNA mutations in the chronic lymphocytic leukemia (CLL) genome, such as those in the 3' untranslated region of NOTCH1 and in the PAX5 super-enhancer. In this report, we used whole genome sequencing data produced by the International Cancer Genome Consortium in order to analyze regions with previously reported regulatory activity. This approach enabled the identification of numerous recurrently mutated regions that were frequently positioned in the proximity of genes involved in immune and oncogenic pathways. By correlating these mutations with expression of their nearest genes, we detected significant transcriptional changes in genes such as PHF2 and S1PR2. More research is needed to clarify the function of these mutations in CLL, particularly those found in intergenic regions.

SUBMITTER: Mosquera Orgueira A

PROVIDER: S-EPMC7015923 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Novel Mutation Hotspots within Non-Coding Regulatory Regions of the Chronic Lymphocytic Leukemia Genome.

Mosquera Orgueira Adrián A Rodríguez Antelo Beatriz B Díaz Arias José Ángel JÁ Díaz Varela Nicolás N Alonso Vence Natalia N González Pérez Marta Sonia MS Bello López José Luis JL

Scientific reports 20200212 1

Mutations in non-coding DNA regions are increasingly recognized as cancer drivers. These mutations can modify gene expression in cis or by inducing high-order chormatin structure modifications with long-range effects. Previous analysis reported the detection of recurrent and functional non-coding DNA mutations in the chronic lymphocytic leukemia (CLL) genome, such as those in the 3' untranslated region of NOTCH1 and in the PAX5 super-enhancer. In this report, we used whole genome sequencing data ...[more]

PMID: 32051441

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Project description:The targeting of mutations by Activation-Induced Deaminase (AID) is a key step in generating antibody diversity at the Immunoglobulin (Ig) loci but is also implicated in B-cell malignancies such as chronic lymphocytic leukemia (CLL). AID has previously been shown to preferentially deaminate WRC (W = A/T, R = A/G) hotspots. WGCW sites, which contain an overlapping WRC hotspot on both DNA strands, mutate at much higher frequency than single hotspots. Human Ig heavy chain (IGHV) genes differ in terms of WGCW numbers, ranging from 4 for IGHV3-48*03 to as many as 12 in IGHV1-69*01. An absence of V-region mutations in CLL patients ("IGHV unmutated", or U-CLL) is associated with a poorer prognosis compared to "IGHV mutated" (M-CLL) patients. The reasons for this difference are still unclear, but it has been noted that particular IGHV genes associate with U-CLL vs M-CLL. For example, patients with IGHV1-69 clones tend to be U-CLL with a poor prognosis, whereas patients with IGHV3-30 tend to be M-CLL and have a better prognosis. Another distinctive feature of CLL is that ~30% of (mostly poor prognosis) patients can be classified into "stereotyped" subsets, each defined by HCDR3 similarity, suggesting selection, possibly for a self-antigen. We analyzed >1000 IGHV genes from CLL patients and found a highly significant statistical relationship between the number of WGCW hotspots in the germline V-region and the observed mutation frequency in patients. However, paradoxically, this correlation was inverse, with V-regions with more WGCW hotspots being less likely to be mutated, i.e., more likely to be U-CLL. The number of WGCW hotspots in particular, are more strongly correlated with mutation frequency than either non-overlapping (WRC) hotspots or more general models of mutability derived from somatic hypermutation data. Furthermore, this correlation is not observed in sequences from the B cell repertoires of normal individuals and those with autoimmune diseases.

Project description:Previous studies have shown increased familial risk for chronic lymphocytic leukemia. In the most comprehensive study to date, we evaluated risk of chronic lymphocytic leukemia and lymphoproliferative disorders among first-degree relatives of chronic lymphocytic leukemia cases compared to first-degree relatives of controls.Population-based registry data from Sweden were used to evaluate outcomes in 26,947 first-degree relatives of 9,717 chronic lymphocytic leukemia patients (diagnosed 1958-2004) compared with 107,223 first-degree relatives of 38,159 matched controls. Using a marginal survival model, we calculated relative risks (RR) and 95% confidence intervals as measures of familial aggregation.Compared to relatives of controls, relatives of chronic lymphocytic leukemia patients had an increased risk for chronic lymphocytic leukemia (RR=8.5, 6.1-11.7) and other non-Hodgkin's lymphomas (NHLs) (RR=1.9, 1.5-2.3). Evaluating NHL subtypes, we found a striking excess of indolent B-cell NHL, specifically lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and hairy cell leukemia. No excesses of aggressive B-cell or T-cell lymphomas were found. There was no statistical excess of Hodgkin's lymphoma, multiple myeloma, or the precursor condition, monoclonal gammopathy of undetermined significance, among chronic lymphocytic leukemia relatives.These familial aggregations are striking and provide novel clues to research designed to uncover early pathogenetic mechanisms in chronic lymphocytic leukemia including studies to identify germ line susceptibility genes. However, clinicians should counsel their chronic lymphocytic leukemia patients emphasizing that because the baseline population risks are low, the absolute risk for a first-degree relative to develop chronic lymphocytic leukemia or another indolent lymphoma is low. At this time, an increased medical surveillance of first-degree relatives of chronic lymphocytic leukemia patients has no role outside research studies.

Dataset Information

Novel Mutation Hotspots within Non-Coding Regulatory Regions of the Chronic Lymphocytic Leukemia Genome.

Publications

Novel Mutation Hotspots within Non-Coding Regulatory Regions of the Chronic Lymphocytic Leukemia Genome.

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