Targeted deep sequencing of gastric marginal zone lymphoma identified alterations of TRAF3 and TNFAIP3 that were mutually exclusive for MALT1 rearrangement

Abstract

Gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is a distinct entity in that Helicobacter pylori infection plays the most important causative role in the development of the disease. To investigate the genomic alteration in gastric marginal zone lymphoma that was resistant to the H. pylori eradication therapy, we analyzed 19 cases of the gastric marginal zone lymphoma using fluorescence in situ hybridization for MALT1, BCL10 rearrangement, and targeted sequencing using an Illumina platform. Major genetic alterations affected genes involved in nuclear factor (NF)-κB pathway activation and included MALT1 rearrangement (39%), and somatic mutations of TRAF3 (21%), TNFAIP3 (16%), and NOTCH1 (16%). In the MALT1 rearrangement-negative group, disruptive somatic mutations of TRAF3 were the most common alterations (4/12, 33%), followed by somatic mutations of TNFAIP3 (3/12, 25%), and NOTCH1 (3/12, 25%). The present study confirms that genes involved in activation of NF-κB-signaling pathways are a major driver in oncogenesis of H. pylori eradication-resistant gastric marginal zone lymphoma and revealed that TRAF3 mutation is a major contributor in MALT1 rearrangement-negative gastric marginal zone lymphoma.

Genetic Alterations of TRAF Proteins in Human Cancers

“…Interestingly however, a subgroup among the 279 cases of HNSCC cataloged in TCGA, the human papilloma virus-positive (HPV+) HNSCC tumors, has much higher frequency (22%, 8/36) of deep deletions and truncations of TRAF3 than the HPV- HNSCC tumors (Figure 1B ) ( 113 ). Notably, although not cataloged in TCGA, deletions and mutations of TRAF3 are recognized as one of the most frequent genetic alterations in a variety of B cell malignancies ( 153 ), including gastric marginal zone lymphoma (MZL, 21%) ( 154 ), multiple myeloma (MM, 17%) ( 155 , 156 ), HL (15%) ( 157 ), DLBCL (14.3%) ( 158 ), splenic MZL (10%) ( 159 ), and Waldenstrom's macroglobulinemia (WM, 5.3%) ( 160 ) (Figure 1B ). Furthermore, somatic mutations of TRAF3 are also frequently detected in human nasopharyngeal cancer (NPC, 8.6%) ( 161 ) (Figure 1B ).…”

Mutational analysis of extranodal marginal zone lymphoma using next generation sequencing

“…Although the analyzed sample size was small, genetic mutations for rare gastrointestinal MALT lymphoma were identified. Various mutations or genetic alterations identified in previous studies using NGS of MALT lymphoma (54,55) were confirmed, and several variations affecting the development of MALT lymphoma for which the exact mechanisms have not yet been elucidated were identified. Hyeon et al (54) analyzed 19 cases of gastric MALT lymphoma using targeted sequencing and the majority of genes affected by genetic alterations were involved in NF-κB pathway activation and included MALT1 rearrangement and somatic mutations of TNF receptor associated factor 3, TNFAIP3 and NOTCH1.…”

“…Various mutations or genetic alterations identified in previous studies using NGS of MALT lymphoma (54,55) were confirmed, and several variations affecting the development of MALT lymphoma for which the exact mechanisms have not yet been elucidated were identified. Hyeon et al (54) analyzed 19 cases of gastric MALT lymphoma using targeted sequencing and the majority of genes affected by genetic alterations were involved in NF-κB pathway activation and included MALT1 rearrangement and somatic mutations of TNF receptor associated factor 3, TNFAIP3 and NOTCH1. Cascione et al (55) analyzed 72 cases of MALT lymphoma derived from different anatomic sites using a large panel of previously known genes and reported genetic mutations or alterations (SNVs and CNVs) that code for proteins involved in chromatin remodeling and transcription regulation, the breakpoint cluster region protein/NF-κB signaling pathway, immune escape and the NOTCH singaling pathway [trisomy 3, TNFAIP3, CREBBP, lysine methyltransferase 2C, tet methylcytosine dioxygenase 2, spen family transcriptional repressor (SPEN), trisomy 18, lysine methyltransferase 2D, LDL receptor related protein 1B, PR/SET domain 1, baculoviral IAP repeat containing 3-MALT, E1A binding protein p300 (EP300), TNFRSF14, NOTCH1/NOTCH2, β-2-microglobulin and 6p gains, in common order].…”

Real-world data on the survival outcome of patients with newly diagnosed Waldenström macroglobulinemia

“…We also gathered the results of targeted sequencing from the data registry of our prospective cohort after written informed consent (ClinicalTrials.gov Identifier: NCT01877109). Targeted sequencing was performed with paraffin-embedded tissue samples using the He-maSCAN containing 425 genes related to hematological malignancies (Supplementary Table 1) [14]. Thus, we retrospectively analyzed the mutation profiles of two representative cases to compare the distribution of mutations between good and poor prognoses.…”

“…Thus, we retrospectively analyzed the mutation profiles of two representative cases to compare the distribution of mutations between good and poor prognoses. Detailed methods have been described previously [14,15]. Briefly, genomic DNA was extracted using a QIAamp DNA Mini www.kjim.org https://doi.org/10.3904/kjim.2019.367 kit (Qiagen, Valencia, CA, USA).…”