Aggressive morphologic variants of mantle cell lymphoma characterized with high genomic instability showing frequent chromothripsis, CDKN2A/B loss, and TP53 mutations: A multi-institutional study

Lukas Streich, Madina Sukhanova, Xinyan Lu, Yi Hua Chen, Girish Venkataraman, Stephanie Mathews, Shanxiang Zhang, Katalin Kelemen, Jeremy Segal, Juehua Gao, Leo Gordon, Qing Chen, Amir Behdad*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Aggressive morphologic variants of mantle cell lymphoma (MCL), including blastoid and pleomorphic (B/P-MCL), are rare and associated with poor clinical outcomes. The genomic landscape of these variants remains incompletely explored. In this multi-institutional study, we describe recurrent mutations and novel genomic copy number alterations (CNAs) in B/P-MCL, using next generation sequencing and SNP-array. Chromothripsis, a recently described phenomenon of massive chromosomal rearrangements, was identified in eight of 13 (62%) B/P MCL cases, and a high degree of genomic complexity with frequent copy number gains and losses was also seen. In contrast, a comparative cohort of nine cases of conventional MCL (C-MCL) showed no chromothripsis and less complexity. Twelve of 13 (92%) B/P-MCL cases showed loss of CDKN2A/B (6 biallelic and 6 monoallelic losses); while only one C-MCL showed monoallelic CDKN2A/B loss. In B/P-MCL, TP53 was the most commonly mutated gene, with mutations present in eight cases (62%), six of which showed concurrent loss of chromosome 17p. Of the eight cases with chromothripsis, six (85%) harbored TP53 mutations. Other recurrent mutations in B/P-MCL included ATM (7, 53%), CCND1 (5, 38%), NOTCH1 (2, 18%), NOTCH2, and BIRC3 (each in 3, 23%). Here, we describe high genomic instability associated with chromothripsis and a high frequency of CDKN2A/B and TP53 alterations in the aggressive variants of MCL. The nonrandom chromothripsis events observed in B/P-MCL may be an indicator of clinically aggressive MCL. In addition, frequent CDKN2A deletion and high genomic instability may provide potential targets for alternative treatment.

Original languageEnglish (US)
Pages (from-to)484-494
Number of pages11
JournalGenes Chromosomes and Cancer
Volume59
Issue number8
DOIs
StatePublished - Aug 1 2020

Keywords

  • blastoid
  • chromothripsis
  • mantle cell lymphoma
  • next generation sequencing
  • pleomorphic

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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