Most follicular lymphomas harbor the BCL2 chromosomal translocation, but not everyone with this translocation develops the cancer, which diminishes its predictive value. To find the other mutations that cooperate with BCL2 translocation to initiate follicular lymphoma (FL), researchers led by Ludwig Stanford’s Ash Alizadeh and Joseph Schroers-Martin conducted ultra-sensitive sequencing of prediagnostic blood, saliva and tissue samples from 48 people who ultimately developed the cancer among thousands enrolled in two early cancer detection studies. The researchers reported in Cancer Discovery in March that mutations to the lysine acetyltransferase (KAT) domain of CREB binding protein (CREBBP), a tumor suppressor, were the most common precursor lesions identified. They largely distinguished patients developing FL (14/48, 29%) from healthy adults with or without detected BCL2 rearrangements. Mutational variants of CREBBP could be detected nearly six years before FL diagnosis and were clonally selected in the cancers. The findings suggest that mutations of the CREBBP KAT domain are common in precancerous cells destined to become follicular lymphomas. Ash and his colleagues suggest such founder mutations might help identify people with BCL2 translocations likely to develop FL, and serve as a specific marker of common progenitor cells and residual disease following treatment.
Tracing founder mutations in circulating and tissue-resident follicular lymphoma precursors
Cancer Discovery, 2023 March 20