Mutational analyses are predictive in malignant lymphomas

Mutational profiles are predictive for transformation in patients with follicular lymphoma and for overall survival in patients with gastrointestinal diffuse large B-cell lymphoma (DLBCL), 2 presentations showed.

Follicular lymphoma is an indolent but mainly incurable disease. Histological transformation to DLBCL is associated with rapid progression, treatment resistance, and poor prognosis. Prior research showed a prognostic signature for transformation [1]. Dr Ismael Fernández-Miranda (Institute of Sanitary Investigation Puerta de Hierro, Spain) now reported on the validation of a previously identified, prognostic, genetic signature (DTX1, HIST1H1E, UBE2A, NOTCH2) [2].

A targeted massive parallel sequencing was performed on new diagnostic samples from 21 pre-transformed and 30 non-transformed patients. Additionally, the previously published cohort of 42 samples (22 pre-transformed and 20 non-transformed patients) was included to enable risk analysis. In this validation sample, the detection of mutations in HIST1H1E, NOTCH2, UBE2A, and IRF8 were statistically (P<0.05) associated with transformation by the multivariate Cox analysis. Inclusion of the Follicular Lymphoma International Prognostic Index (FLIPI) with alterations in HIST1H1E, NOTCH2, UBE2A, and IRF8 into the multivariate Cox model rendered a classification of the samples into 3 risk groups, with distinct transformation probabilities at 5 years (P<0.0001).

“Genomic analysis on follicular lymphoma samples have enabled the association of mutated genes with higher risk of transformation,” concluded Dr Fernández-Miranda. “Integration of the mutational status with clinical risk factors into a predictive model improves the risk stratification and could be useful for identifying patients at higher risk of transformation.”

About 10% of DLBCL cases primarily occur in the gastrointestinal tract. Previous reports have revealed that primary gastrointestinal DLBCL harbours different genetic mutations from other nodal or extranodal DLBCL [3]. However, the exonic mutation profile of primary gastrointestinal DLBCL has not been fully addressed. Therefore, Chinese investigators now performed whole-exome sequencing of 53 matched tumour and normal samples from primary gastrointestinal DLBCL patients. Dr Shan-Shan Li (Hospital of Sun Yat-sen University, China) presented the results [4]. A total of 6,848 protein-altering events were found in the primary gastrointestinal DLBCL cohort, and among these mutations, the 5 most frequent mutated genes were IGLL5 (47%), TP53 (42%), BTG2 (28%), IGHV2-70 (26%), and P2RY5 (26%). Compared with the nodal DLBCL, significantly less mutations were found within MYD88 (0%), EZH2 (0%), or BCL2 (2%) genes in primary gastrointestinal DLBCL. The top 50 mutated genes of primary gastrointestinal DLBCL were mostly enriched in pathways related to complement activation, immunoglobulin receptor binding, and positive regulation of B-cell activation. Moreover, the nucleotide mutational signature analysis revealed that the primary gastrointestinal DLBCL mutation pattern was fitted with COSMIC signature 3, which has been implicated with the activation-induced cytidine deaminase during the pathogenesis of chronic lymphocytic leukaemia. In addition, survival analysis demonstrated that primary gastrointestinal DLBCL patients with wildtype P2RY8 gene, an orphan Gα13-coupled receptor promoting the clustering of activated B cells, had a significantly longer overall survival time compared with those harbouring its mutation after receiving tumour resection surgery plus rituximab-based therapy.

“Our study provides a comprehensive view of the exonic mutational landscape of primary gastrointestinal DLBCL, within which a specific gene cluster was mutated relating to humoral immunity activation and P2RY8 mutation was associated with patient prognosis,” concluded Dr Li.

1. González-Rincón J, et al. PLoS One. 2019;14(2):e0212813.
2. Fernandez-Miranda I, et al. A gene signature to predict risk of transformation in patients with follicular lymphoma. Abstract 829MO, ESMO Congress 2021, 16–21 September.
3. Ye H, et al. Int J Clin Exp Pathol. 2015;8(10):13043–13050.
4. Li S, et al. Exonic mutation profile of primary gastrointestinal diffuse large B-cell lymphoma. Abstract 828MO, ESMO Congress 2021, 16–21 September.

 

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Posted on 19 November, 202115 February, 2024