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

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

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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 the SWOG study 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 (ie, 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: whereas early progression was correlated with 2p gain (P5.007; odds ratio [OR]52.55 [1.29, 5.03]) and 2p cnLOH (P5.005; OR510.9 [2.08, 57.2]), 2p gain specifically encompassing VRK2 and FANCL predicted PFS (P 5 .01; hazard ratio51.80 [1.14, 2.68]) as well as OS (P5.005; 2.40 [1.30, 4.40]); CDKN2A/B (9p) deletion correlated with worse PFS (P 5 .004, 3.50 [1.51, 8.28]); whereas CREBBP (16p) (P < .001; 6.70 [2.52, 17.58]) and TP53 (17p) (P < .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.

Original languageEnglish (US)
Pages (from-to)81-93
Number of pages13
JournalBlood
Volume133
Issue number1
DOIs
StatePublished - Jan 3 2019

Fingerprint

Follicular Lymphoma
Aberrations
Loss of Heterozygosity
Disease-Free Survival
Chromosomes
Survival
Molecular Biology
Odds Ratio
Clinical Trials
Testing
Hazards
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Genomic alterations important for the prognosis in patients with follicular lymphoma treated in SWOG study S0016. / Qu, Xiaoyu; Li, Hongli; Braziel, Rita; Passerini, Verena; Rimsza, Lisa M.; His, Eric D.; Leonard, John P.; Smith, Sonali M.; Kridel, Robert; Press, Oliver; Weigert, Oliver; LeBlanc, Michael; Friedberg, Jonathan W.; Fang, Min.

In: Blood, Vol. 133, No. 1, 03.01.2019, p. 81-93.

Research output: Contribution to journalArticle

Qu, X, Li, H, Braziel, R, Passerini, V, Rimsza, LM, His, ED, Leonard, JP, Smith, SM, Kridel, R, Press, O, Weigert, O, LeBlanc, M, Friedberg, JW & Fang, M 2019, 'Genomic alterations important for the prognosis in patients with follicular lymphoma treated in SWOG study S0016', Blood, vol. 133, no. 1, pp. 81-93. https://doi.org/10.1182/blood-2018-07-865428
Qu, Xiaoyu ; Li, Hongli ; Braziel, Rita ; Passerini, Verena ; Rimsza, Lisa M. ; His, Eric D. ; Leonard, John P. ; Smith, Sonali M. ; Kridel, Robert ; Press, Oliver ; Weigert, Oliver ; LeBlanc, Michael ; Friedberg, Jonathan W. ; Fang, Min. / Genomic alterations important for the prognosis in patients with follicular lymphoma treated in SWOG study S0016. In: Blood. 2019 ; Vol. 133, No. 1. pp. 81-93.
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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 the SWOG study 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 (ie, 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: whereas early progression was correlated with 2p gain (P5.007; odds ratio [OR]52.55 [1.29, 5.03]) and 2p cnLOH (P5.005; OR510.9 [2.08, 57.2]), 2p gain specifically encompassing VRK2 and FANCL predicted PFS (P 5 .01; hazard ratio51.80 [1.14, 2.68]) as well as OS (P5.005; 2.40 [1.30, 4.40]); CDKN2A/B (9p) deletion correlated with worse PFS (P 5 .004, 3.50 [1.51, 8.28]); whereas CREBBP (16p) (P < .001; 6.70 [2.52, 17.58]) and TP53 (17p) (P < .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.",
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AU - Braziel, Rita

AU - Passerini, Verena

AU - Rimsza, Lisa M.

AU - His, Eric D.

AU - Leonard, John P.

AU - Smith, Sonali M.

AU - Kridel, Robert

AU - Press, Oliver

AU - Weigert, Oliver

AU - LeBlanc, Michael

AU - Friedberg, Jonathan W.

AU - Fang, Min

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N2 - 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 the SWOG study 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 (ie, 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: whereas early progression was correlated with 2p gain (P5.007; odds ratio [OR]52.55 [1.29, 5.03]) and 2p cnLOH (P5.005; OR510.9 [2.08, 57.2]), 2p gain specifically encompassing VRK2 and FANCL predicted PFS (P 5 .01; hazard ratio51.80 [1.14, 2.68]) as well as OS (P5.005; 2.40 [1.30, 4.40]); CDKN2A/B (9p) deletion correlated with worse PFS (P 5 .004, 3.50 [1.51, 8.28]); whereas CREBBP (16p) (P < .001; 6.70 [2.52, 17.58]) and TP53 (17p) (P < .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.

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