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Genomic alterations important for the prognosis in patients with follicular lymphoma treated on SWOG study S0016

Xiaoyu Qu, Hongli Li, Rita M. Braziel, Verena Passerini, Lisa M. Rimsza, Eric D. Hsi, John P. Leonard, Sonali M. Smith, Robert Kridel, Oliver Press, Oliver Weigert, Michael LeBlanc, Jonathan W. Friedberg and Min Fang

Key points

  • Assessing pretreatment genomic aberrations improves risk stratification of follicular lymphoma independent of clinical/mutation markers.

  • Gain or cnLOH of 2p is correlated with 2-year progression; CDKN2A/B deletion with worse PFS; CREBBP and TP53 deletions predict worse OS.

Abstract

Although recent advances in molecular genetics have enabled improved risk classification of follicular lymphoma (FL) using, for example, the m7-FLIPI score, the impact on treatment has been limited. We aimed to assess the prognostic significance of copy number aberrations (CNAs) and copy neutral loss of heterozygosity (cnLOH) identified by chromosome genomic array testing (CGAT) at FL diagnosis using prospectively collected clinical trial specimens from 255 patients enrolled in SWOG S0016. The impact of genomic aberrations was assessed for early progression (progressed or died within 2 years after registration), progression free survival (PFS), and overall survival (OS). We showed that increased genomic complexity (i.e., the total number of aberration calls) was associated with poor outcome in FL. Certain chromosome arms were critical for clinical outcome. Prognostic CNAs/cnLOH were identified: while early progression was correlated with 2p gain [P=0.007, OR=2.55 (1.29, 5.03)] and 2p cnLOH [P=0.005, OR=10.9 (2.08, 57.2)], 2p gain specifically encompassing VRK2 and FANCL predicted PFS [P=0.01, HR=1.80 (1.14, 2.68)] as well as OS [P=0.005, 2.40 (1.30, 4.40)]; CDKN2A/B (9p) deletion correlated with worse PFS [P=0.004, 3.50 (1.51, 8.28)]; whereas CREBBP (16p) [P<0.001, 6.70 (2.52, 17.58)] and TP53 (17p) [P<0.001, 3.90 (1.85, 8.31)] deletion predicted worse OS. An independent cohort from the m7-FLIPI study was explored, and the prognostic significance of aberration count, and TP53 and CDKN2A/B deletion were further validated. In conclusion, assessing genomic aberrations at FL diagnosis with CGAT improves risk stratification independent of known clinical parameters, and provides a framework for development of future rational targeted therapies.

  • Submitted July 24, 2018.
  • Accepted November 6, 2018.