Tracing Founder Mutations in Circulating and Tissue-Resident Follicular Lymphoma Precursors - Aix-Marseille Université
Article Dans Une Revue Cancer Discovery Année : 2023

Tracing Founder Mutations in Circulating and Tissue-Resident Follicular Lymphoma Precursors

Joseph G Schroers-Martin
Joanne Soo
Florian Scherer
David M Kurtz
Brian J Sworder
Michael S Khodadoust
Michael C Jin
Agnès Bru
Chih Long Liu
Henning Stehr
Paolo Vineis
Yasodha Natkunam
Lauren R Teras

Résumé

Follicular lymphomas (FL) are characterized by BCL2 translocations, often detectable in blood years before FL diagnosis, but also observed in aging healthy individuals, suggesting additional lesions are required for lymphomagenesis. We directly characterized early cooperating mutations by ultradeep sequencing of prediagnostic blood and tissue specimens from 48 subjects who ultimately developed FL. Strikingly, CREBBP lysine acetyltransferase (KAT) domain mutations were the most commonly observed precursor lesions, and largely distinguished patients developing FL (14/48, 29%) from healthy adults with or without detected BCL2 rearrangements (0/13, P = 0.03 and 0/20, P = 0.007, respectively). CREBBP variants were detectable a median of 5.8 years before FL diagnosis, were clonally selected in FL tumors, and appeared restricted to the committed B-cell lineage. These results suggest that mutations affecting the CREBBP KAT domain are common lesions in FL cancer precursor cells (CPC), with the potential for discriminating subjects at risk of developing FL or monitoring residual disease. Significance: Our study provides direct evidence for recurrent genetic aberrations preceding FL diagnosis, revealing the combination of BCL2 translocation with CREBBP KAT domain mutations as characteristic committed lesions of FL CPCs. Such prediagnostic mutations are detectable years before clinical diagnosis and may help discriminate individuals at risk for lymphoma development. This article is highlighted in the In This Issue feature, p. 1275
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hal-04542707 , version 1 (11-04-2024)

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Joseph G Schroers-Martin, Joanne Soo, Gabriel Brisou, Florian Scherer, David M Kurtz, et al.. Tracing Founder Mutations in Circulating and Tissue-Resident Follicular Lymphoma Precursors. Cancer Discovery, 2023, 13 (6), pp.1310-1323. ⟨10.1158/2159-8290.CD-23-0111⟩. ⟨hal-04542707⟩

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