Genetic Variation in DNA Repair Pathways and Risk of Non-Hodgkin's Lymphoma

Genetic studies of diffuse large B-cell lymphomas (DLBCLs) in humans have revealed numerous targets of somatic mutations and an increasing number of potentially relevant germline alterations. The latter often affect genes involved in DNA repair and/or immune function. In general, defects in these genes also predispose to other conditions. Knowledge of these mutations can lead to disease-preventing measures in the patient and relatives thereof. Conceivably, these germline mutations will be taken into account in future therapy of the lymphoma. In other hematological malignancies, mutations originally found as somatic aberrations have also been shown to confer predisposition to these diseases, when occurring in the germline. Further interrogations of the genome in DLBCL patients are therefore expected to reveal additional hereditary predisposition genes. Our review shows that germline mutations have already been described in over one-third of the genes that are somatically mutated in DLBCL. Whether such germline mutations predispose carriers to DLBCL is an open question. Symptoms of the inherited syndromes associated with these genes range from anatomical malformations to intellectual disability, immunodeficiencies and malignancies other than DLBCL. Inherited or de novo alterations in protein-coding and non-coding genes are envisioned to underlie this lymphoma.

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“… 66 For lymphomas, such an epistatic interaction was suggested for variants in the DNA repair genes MRE11A and NBS1 . 91 …”

Section: Genes With Less Obvious Causalitymentioning

confidence: 99%

Germline mutations predisposing to diffuse large B-cell lymphoma

Leeksma

Miranda

Veelken

2017

Blood Cancer Journal

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“…Strikingly, at least nine polymorphisms out of 23 known SNPs in the human POLQ gene are predicted to alter protein function [32]. Several POLQ SNPs have also been associated with a risk of different tumors, such as breast cancer, esophageal cancer, and Non-Hodgkin’s Lymphoma [28,37,38,39,40]. While only some of the breast cancer studies included rs3218649, no significant association was detected [28,38,40] and none of the other associated SNPs were found in the linkage disequilibrium with our selected SNPs.…”

Section: Discussionmentioning

confidence: 99%

Functional Polymorphisms in DNA Repair Genes Are Associated with Sporadic Colorectal Cancer Susceptibility and Clinical Outcome

Jirásková

Hughes

Brezina

et al. 2018

IJMS

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DNA repair processes are involved in both the onset and treatment efficacy of colorectal cancer (CRC). A change of a single nucleotide causing an amino acid substitution in the corresponding protein may alter the efficiency of DNA repair, thus modifying the CRC susceptibility and clinical outcome. We performed a candidate gene approach in order to analyze the association of non-synonymous single nucleotide polymorphisms (nsSNPs) in the genes covering the main DNA repair pathways with CRC risk and clinical outcome modifications. Our candidate polymorphisms were selected according to the foremost genomic and functional prediction databases. Sixteen nsSNPs in 12 DNA repair genes were evaluated in cohorts from the Czech Republic and Austria. Apart from the tumor-node-metastasis (TNM) stage, which occurred as the main prognostic factor in all of the performed analyses, we observed several significant associations of different nsSNPs with survival and clinical outcomes in both cohorts. However, only some of the genes (REV3L, POLQ, and NEIL3) were prominently defined as prediction factors in the classification and regression tree analysis; therefore, the study suggests their association for patient survival. In summary, we provide observational and bioinformatics evidence that even subtle alterations in specific proteins of the DNA repair pathways may contribute to CRC susceptibility and clinical outcome.

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“…Finally, 20 case-control studies were discerned. However, three studies were excluded because of insufficient data (Barroso et al, 2009;Rendleman et al, 2014;Hayashi et al, 2015). Two studies used the same data, so only one of them was included (Pharoah et al, 2007;Yang et al, 2014).…”

Section: Extraction Process and Study Characteristicmentioning

confidence: 99%