Table of Contents

Overview

Somatic mutations in FBXO11 are common in BL1 and appear in a small number of DLBCLs.2 This gene has some recurrent sites of mutations (hot spots). Mutations lead to stabilization of BCL6, an important transcriptional repressor involved in lymphomagenesis. These mutations present a potential novel target for therapeutic intervention, particularly through strategies aimed at degrading BCL6 or inhibiting its function.

Experimental Evidence

Driver mutations affecting this gene in DLBCL/BL have been experimentally demonstrated to cause a reduction or loss of function (LOF).3

Relevance tier by entity

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Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity Collection N mutated Incidence 95% CI
DLBCL GAMBL without Reddy 1,089 31 0.0285 [0.0186,0.0383]
DLBCL GAMBL with Reddy 2,088 52 0.0249 [0.0182,0.0316]
DLBCL BC 231 5 0.0216 [0.0029,0.0404]
DLBCL Dana-Farber 303 9 0.0297 [0.0106,0.0488]
DLBCL NCI 470 10 0.0213 [0.0082,0.0343]
DLBCL Reddy 999 21 0.0210 [0.0121,0.0299]
DLBCL DLBCL_ICGC 85 7 0.0824 [0.0239,0.1408]

BL

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Mutation pattern and selective pressure estimates

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FBXO11 hot spots

Chromosome Coordinate Mutation HGVSp
chr2 48040426 T>A N725I
chr2 48040427 T>C N725D
chr2 48040427 T>G N725H
chr2 48040427 T>A N725Y
chr2 48040488 TA>GC I704S
chr2 48040489 A>C I704R
chr2 48040495 T>A N702I
chr2 48040495 T>C N702S
chr2 48040496 T>C N702D
chr2 48040496 T>A N702Y
chr2 48040500 T>A E700D
chr2 48040500 T>G E700D
chr2 48040501 T>A E700V
chr2 48040510 C>T G697D
chr2 48040511 C>G G697R

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Expression

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References

1.
Richter J, Schlesner M, Hoffmann S, Kreuz M, Leich E, Burkhardt B, Rosolowski M, Ammerpohl O, Wagener R, Bernhart SH, Lenze D, Szczepanowski M, Paulsen M, Lipinski S, Russell RB, Adam-Klages S, Apic G, Claviez A, Hasenclever D, Hovestadt V, Hornig N, Korbel JO, Kube D, Langenberger D, Lawerenz C, Lisfeld J, Meyer K, Picelli S, Pischimarov J, Radlwimmer B, Rausch T, Rohde M, Schilhabel M, Scholtysik R, Spang R, Trautmann H, Zenz T, Borkhardt A, Drexler HG, Möller P, MacLeod RAF, Pott C, Schreiber S, Trümper L, Loeffler M, Stadler PF, Lichter P, Eils R, Küppers R, Hummel M, Klapper W, Rosenstiel P, Rosenwald A, Brors B, Siebert R, ICGC MMML-Seq Project. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nat Genet. 2012 Dec;44(12):1316–1320.
2.
Hübschmann D, Kleinheinz K, Wagener R, Bernhart SH, López C, Toprak UH, Sungalee S, Ishaque N, Kretzmer H, Kreuz M, Waszak SM, Paramasivam N, Ammerpohl O, Aukema SM, Beekman R, Bergmann AK, Bieg M, Binder H, Borkhardt A, Borst C, Brors B, Bruns P, Carrillo de Santa Pau E, Claviez A, Doose G, Haake A, Karsch D, Haas S, Hansmann ML, Hoell JI, Hovestadt V, Huang B, Hummel M, Jäger-Schmidt C, Kerssemakers JNA, Korbel JO, Kube D, Lawerenz C, Lenze D, Martens JHA, Ott G, Radlwimmer B, Reisinger E, Richter J, Rico D, Rosenstiel P, Rosenwald A, Schillhabel M, Stilgenbauer S, Stadler PF, Martín-Subero JI, Szczepanowski M, Warsow G, Weniger MA, Zapatka M, Valencia A, Stunnenberg HG, Lichter P, Möller P, Loeffler M, Eils R, Klapper W, Hoffmann S, Trümper L, ICGC MMML-Seq consortium, ICGC DE-Mining consortium, BLUEPRINT consortium, Küppers R, Schlesner M, Siebert R. Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas. Leukemia. 2021 Jul;35(7):2002–2016. PMCID: PMC8257491
3.
Duan S, Cermak L, Pagan JK, Rossi M, Martinengo C, di Celle PF, Chapuy B, Shipp M, Chiarle R, Pagano M. FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas. Nature. 2011 Nov;
4.
Arthur SE, Jiang A, Grande BM, Alcaide M, Cojocaru R, Rushton CK, Mottok A, Hilton LK, Lat PK, Zhao EY, Culibrk L, Ennishi D, Jessa S, Chong L, Thomas N, Pararajalingam P, Meissner B, Boyle M, Davidson J, Bushell KR, Lai D, Farinha P, Slack GW, Morin GB, Shah S, Sen D, Jones SJM, Mungall AJ, Gascoyne RD, Audas TE, Unrau P, Marra MA, Connors JM, Steidl C, Scott DW, Morin RD. Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma. Nat Commun. 2018 Oct 1;9(1):4001. PMCID: PMC6167379
5.
Parry M, Rose-Zerilli MJJ, Gibson J, Ennis S, Walewska R, Forster J, Parker H, Davis Z, Gardiner A, Collins A, Oscier DG, Strefford JC. Whole exome sequencing identifies novel recurrently mutated genes in patients with splenic marginal zone lymphoma. PLoS One. 2013;8(12):e83244. PMCID: PMC3862727

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