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. 2017 Apr 25;8(17):28008-28020.
doi: 10.18632/oncotarget.15883.

An extensive molecular cytogenetic characterization in high-risk chronic lymphocytic leukemia identifies karyotype aberrations and TP53 disruption as predictors of outcome and chemorefractoriness

Gian Matteo Rigolin  1 , Luca Formigaro  1 , Maurizio Cavallari  1 , Francesca Maria Quaglia  1 , Enrico Lista  1 , Antonio Urso  1 , Emanuele Guardalben  1 , Sara Martinelli  1 , Elena Saccenti  1 , Cristian Bassi  2 , Laura Lupini  2 , Maria Antonella Bardi  1 , Eleonora Volta  1 , Elisa Tammiso  1 , Aurora Melandri  1 , Massimo Negrini  2 , Francesco Cavazzini  1 , Antonio Cuneo  1
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An extensive molecular cytogenetic characterization in high-risk chronic lymphocytic leukemia identifies karyotype aberrations and TP53 disruption as predictors of outcome and chemorefractoriness

Gian Matteo Rigolin et al. Oncotarget. .

Abstract

We investigated whether karyotype analysis and mutational screening by next generation sequencing could predict outcome in 101 newly diagnosed chronic lymphocytic leukemia patients with high-risk features, as defined by the presence of unmutated IGHV gene and/or 11q22/17p13 deletion by FISH and/or TP53 mutations. Cytogenetic analysis showed favorable findings (normal karyotype and isolated 13q14 deletion) in 30 patients, unfavorable (complex karyotype and/or 17p13/11q22 deletion) in 34 cases and intermediate (all other abnormalities) in 36 cases. A complex karyotype was present in 21 patients. Mutations were detected in 56 cases and were associated with unmutated IGHV status (p = 0.040) and complex karyotype (p = 0.047). TP53 disruption (i.e. TP53 mutations and/or 17p13 deletion by FISH) correlated with the presence of ≥ 2 mutations (p = 0.001) and a complex karyotype (p = 0.012). By multivariate analysis, an advanced Binet stage (p < 0.001) and an unfavorable karyotype (p = 0.001) predicted a shorter time to first treatment. TP53 disruption (p = 0.019) and the unfavorable karyotype (p = 0.028) predicted a worse overall survival. A shorter time to chemorefractoriness was associated with TP53 disruption (p = 0.001) and unfavorable karyotype (p = 0.025). Patients with both unfavorable karyotype and TP53 disruption presented a dismal outcome (median overall survival and time to chemorefractoriness of 28.7 and 15.0 months, respectively). In conclusion, karyotype analysis refines risk stratification in high-risk CLL patients and could identify a subset of patients with highly unfavorable outcome requiring alternative treatments.

Keywords: chronic lymphocytic leukemia; gene somatic mutations; karyotype: prognosis; next generation sequencing.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare that they have no potential conflicts of interests.

Figures

Figure 1
Figure 1
TTFT (in A), OS (in B) and TTCR (in C) according to karyotype abnormalities.
Figure 2
Figure 2
TTFT (in A), OS (in B) and TTCR (in C) according to TP53 disruption status and karyotype abnormalities.
See this image and copyright information in PMC

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