Missense Mutations in the KAT Domain of CREBBP Gene in Patients with Follicular Lymphoma: Implications for Differential Diagnosis and Prognosis

TL;DR

This study shows that specific mutations in the CREBBP gene can help distinguish between different types of follicular lymphoma and predict patient outcomes.

Contribution

The study identifies the prognostic and diagnostic significance of CREBBP KAT domain missense mutations in follicular lymphoma.

Findings

Patients with a single missense mutation in the CREBBP KAT domain had better survival and fewer adverse events.

FL 3A–3B (14;18)-negative cases lacked CREBBP KAT domain mutations and may represent a distinct high-risk variant.

HDCT/auto-HSCT improved outcomes for (14;18)-positive FL without CREBBP KAT mutations.

Abstract

Follicular lymphoma (FL) is one of the most common types of non-Hodgkin’s lymphomas. The tumor is characterized by a wide range of clinical manifestations, ranging from indolent forms to early transformation and progression with a poor prognosis. The search for clinically significant genetic changes is essential for personalized risk assessment and treatment selection. The CREBBP gene is frequently mutated in this type of lymphoma, with changes occurring at the level of the earliest tumor precursor cells. However, the prognostic and diagnostic significance of the CREBBP gene mutation status in FL has not been fully established. In this study, we analyzed sequencing data of exons 22–30 of the CREBBP gene in 86 samples from patients with different grades of FL (1–3B), including those in the 3A–3B subgroup without the t(14;18) translocation. We also investigated the prognostic significance of CREBBP gene mutations in relation to the treatment options, namely high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT/auto-HSCT) and conventional chemotherapy programs (CCT). It was found that FL patients with a single missense mutation in the KAT domain of the CREBBP gene experienced an extremely low number of early adverse events related to lymphoma and had better long-term survival rates, regardless of treatment option. In contrast, when comparing patients with FL without a missense mutation in the KAT domain or those with multiple mutations in the CREBBP gene, overall and progression free survival were worse, and early progression and histological transformation were more common. Compared to standard therapy, patients who underwent HDCT/auto-HSCT in the FL 1–3B (14;18)-positive group without a single missense mutation in the KAT domain had better survival rates and lower rates of transformation and early progression. In addition, among patients with FL 3A–3B (14;18)-negative, we found that there were no cases of a missense mutation in the KAT domain of the CREBBP gene. This suggests that a single missense mutation in the CREBBP gene may be a feature that discriminates 14;18-positive FL with a favorable prognosis from a high-risk disease. FL 3A–3B (14;18)-negative may represent a distinct variant with different biology and underlying mechanisms of development compared to classical FL.

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