4.8 Article

Genomic and transcriptomic profiling reveals distinct molecular subsets associated with outcomes in mantle cell lymphoma

期刊

JOURNAL OF CLINICAL INVESTIGATION
卷 132, 期 3, 页码 -

出版社

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI153283

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资金

  1. National Nature Science Foundation of China [81970187, 82170193, 81920108006, 81900203]
  2. Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences [2019-I2M-2-009, 2016-I2M-3-013, 2017-I2M-3-018]
  3. National Science and Technology Major Project from China [2017ZX09304024]
  4. NIH (National Cancer Institute [NCI]) [R01CA240910, R01CA21623, R01CA244576]
  5. Spanish Ministerio de Ciencia e Innovacion [RTI2018-094274-B-I00]
  6. NIH [1P01CA229100]
  7. Generalitat de Catalunya Suport Grups de Recerca AGAUR [2017-SGR-709, 2017-SGR-1142]
  8. Fondo de Investigaciones Sanitarias
  9. Instituto de Salud Carlos III
  10. European Regional Development Fund Una manera de hacer Europa [PI17/01061]
  11. Lymphoma Society Scholar Award
  12. Lymphoma Research Foundation Larry and Denise Mason Clinical Investigator Career Development Award
  13. City of Hope

向作者/读者索取更多资源

This study identified four distinct genetic subsets of mantle cell lymphoma (MCL) and demonstrated the impact of clonal evolution on clinical outcomes. These findings provide valuable insights into the heterogeneity of MCL and its genetic determinants.
Mantle cell lymphoma (MCL) is a phenotypically and genetically heterogeneous malignancy in which the genetic alterations determining clinical indications are not fully understood. Here, we performed a comprehensive whole-exome sequencing analysis of 152 primary samples derived from 134 MCL patients, including longitudinal samples from 16 patients and matched RNA-Seq data from 48 samples. We classified MCL into 4 robust clusters (C1-C4). C1 featured mutated immunoglobulin heavy variable (IGHV), CCND1 mutation, amp(11q13), and active B cell receptor (BCR) signaling. C2 was enriched with del(11q)/ATM mutations and upregulation of NF-kappa B and DNA repair pathways. C3 was characterized by mutations in SP140, NOTCH1, and NSD2, with downregulation of BCR signaling and MYC targets. C4 harbored del(17p)/TP53 mutations, del(13q), and del(9p), and active MYC pathway and hyperproliferation signatures. Patients in these 4 clusters had distinct outcomes (5-year overall survival [OS] rates for C1-C4 were 100%, 56.7%, 48.7%, and 14.2%, respectively). We also inferred the temporal order of genetic events and studied clonal evolution of 16 patients before treatment and at progression/relapse. Eleven of these samples showed drastic clonal evolution that was associated with inferior survival, while the other samples showed modest or no evolution. Our study thus identifies genetic subsets that clinically define this malignancy and delineates clonal evolution patterns and their impact on clinical outcomes.

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