Germline mutations predisposing to diffuse large B-cell lymphoma

Abstract

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.

Characterization of DNA double‐strand break repair pathways in diffuse large B cell lymphoma

“…However, expression of low levels of NHEJ proteins such as Ligase IV and KU80 were consistent with compromised NHEJ in DLBCL cells. Consistent to this, previous sequencing studies of DNA DSB repair genes have identified many mutations in c‐NHEJ genes in DLBCL . In a recent study, we observed that although treatment with SCR7, an inhibitor of NHEJ, alone was less sensitive, its combination with radiation resulted in enhanced cytotoxicity in SUDHL8 cells…”

“…Consistent to this, previous sequencing studies of DNA DSB repair genes have identified many mutations in c-NHEJ genes in DLBCL. 22,26,27 In a recent study, we observed that although treatment with SCR7, an inhibitor of NHEJ, alone was less sensitive, its combination with radiation resulted in enhanced cytotoxicity in SUDHL8 cells. 50 Previous studies have suggested that different cancer cells have varying levels of c-NHEJ.…”

“…and NHEJ proteins (LIGASE IV, XLF, Artemis) have also been reported in studies using targeted capture sequencing. 26 Furthermore, there are reports of overexpressed DNA repair proteins (particularly the nucleotide excision repair proteins) in CHOP (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) resistant DLBCL samples. 27 However, there are no studies characterizing DSB repair pathways in DLBCL.…”

Lymphoma in Australian Border Collies: survey results and pedigree analyses

“…Understanding of the mechanisms in lymphoma predisposition is limited in people. Using techniques such as targeted sequencing or whole exome/genome sequencing, germline variants in 49 genes have been associated with diffuse large B‐cell lymphoma . Most of these genes are involved in DNA repair or immune function and are suspected to contribute to the pathogenesis of lymphoma.…”

“…Using techniques such as targeted sequencing 60 or whole exome/genome sequencing, 61-63 germline variants in 49 genes have been associated with diffuse large B-cell lymphoma. 64 Most of these genes are involved in DNA repair or immune function 60,64 and are suspected to contribute to the pathogenesis of lymphoma. Similarly, knowledge of germline mutation in dogs is limited.…”