Exploring the genetic landscape of HCV-related B-cell lymphomas using whole exome sequencing

Chronic Hepatitis C Virus Infection, Extrahepatic Disease and the Impact of New Direct-Acting Antivirals

“…Following HCV autoimmune and lymphoproliferative activity, it is well documented that the overall risk of developing B-cell lymphoma is higher when compared with the general population, and even more so when HCV-CV is present; approximately 8–10% of those patients develop lymphoproliferative disorders [ 15 , 20 , 23 ]. The predominant types are non-Hodgkin lymphoma (NHL), particularly low-grade marginal zone lymphoma (MZL), representing about 12% of B-cell lymphomas, followed by diffuse large B-cell lymphoma (DLBCL) [ 23 , 24 ]. HCV-MZL mainly originates from the spleen and occurs after a course of more than 15 years of HCV chronic infection, with an indolent development independent from liver fibrosis and diagnosed in older patients, about 65 years old [ 23 , 24 , 25 ].…”

“…The predominant types are non-Hodgkin lymphoma (NHL), particularly low-grade marginal zone lymphoma (MZL), representing about 12% of B-cell lymphomas, followed by diffuse large B-cell lymphoma (DLBCL) [ 23 , 24 ]. HCV-MZL mainly originates from the spleen and occurs after a course of more than 15 years of HCV chronic infection, with an indolent development independent from liver fibrosis and diagnosed in older patients, about 65 years old [ 23 , 24 , 25 ]. As with HCV-mixed cryoglobulinemia (HCV-MC), it is proposed that HCV lymphomas develop after chronic antigenic stimulation by HCV, leading to B-cell mutation and/or bcl rearrangement [ 15 , 24 ].…”

“…Furthermore, chronic antigen simulation leads to B-cell clonal expansion; B-cells in both HCV-MC and lymphomas use the VH1-69 gene and VkA27 segment, which are at the same time used by anti-E2 antibodies elicited by HCV, supporting the theory of an antigenic selection-driven process underlying lymphoma development. In addition, HCV-MC immunoglobulins and RF are associated with other NHLs such as MALT lymphoma, and immunoglobulins may be a result of somatic hypermutation [ 20 , 24 , 25 , 26 ]. In the case of MZL, HCV’s antigenic stimulation of B-cells in the spleen by the E2 viral protein binds to the CD81 receptor of the B-cell, inducing somatic hypermutation [ 20 , 25 , 26 ].…”

Deciphering molecular complexity of HCV‐associated lymphoproliferation

“…9,10 Finally, another fundamental piece of this multifaceted puzzle was provided by the evaluation of mutational signatures of HCV-positive LPD, which have been recently explored. 10,11 Interestingly, it was shown that patients exhibiting stereotyped KCDR3 were enriched in mutations involving pathways regulating epigenetics, NF-kB, BCR and NOTCH signalling, compared with those carrying non-stereotyped KCDR3. 10 This may suggest that a subset of patients may harbour distinct mutational and immunogenetic signatures associated with pronounced sensitivity to HCV eradication.…”

Molecular characterization of diffuse large B‐cell lymphomas associated with hepatitis C virus infection

“…20,21 Finally, a recent study evaluated a cohort of HCV-positive lymphoma, including eight cases of DLBCL, by whole exome sequencing (WES) and described novel putative genes with pronounced specificity for HCV-associated DLBCL. 22 In this study, we performed a comprehensive characterization of the COO and molecular landscape of a well-annotated series of HCV-associated DLBCL cases and applied the LymphGen classification for the first time in this setting. 17 Histological diagnosis of DLBCL was established by expert pathologists at each participating institution and reviewed in accordance with the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours.…”