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On the way towards a ‘CLL prognostic index’: focus on TP53, BIRC3, SF3B1, NOTCH1 and MYD88 in a population-based cohort

Leukemia volume 28, pages 710–713 (2014)Cite this article

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Considering the clinical and biological heterogeneity observed among patients with chronic lymphocytic leukemia (CLL), a ‘CLL prognostic index’ aimed at accurately predicting outcome at the individual patient level is highly warranted.1 Through the past decades, numerous molecular markers have proven informative with regards to predicting the disease course and thus facilitating treatment decisions.1 The most reliable of these, and those offered in routine diagnostics, include the use of fluorescence in situ hybridization for the detection of genomic aberrations, namely del(17p), del(11q), trisomy 12 and del(13q), and assessment of the immunoglobulin heavy-chain variable (IGHV) gene mutational status.2, 3, 4 In addition, the presence of TP53 mutations has recently been demonstrated as an independent high-risk marker, irrespective of the presence or absence of del(17p), and has also been associated with a short time to progression as well as therapy resistance.5, 6, 7 Aside from the more traditional biomarkers, deep sequencing technologies have identified novel genomic markers, several of which exhibit prognostic value,8, 9, 10, 11 with the current key players being NOTCH1, SF3B1, BIRC3 and MYD88. All of these genes, with the exception of MYD88, have been associated with shorter time-to-treatment (TTT) as well as overall survival (OS).7, 8, 9, 10, 11, 12, 13

Mutations within the NOTCH1 gene (8–12%) and the SF3B1 gene (8–15%) were repeatedly shown to be associated with a worse outcome.7, 8, 9, 10, 11, 12, 13, 14 The majority of NOTCH1 mutations (>90%) concern a 2-bp deletion (exon 34) within the PEST domain, whereas mutations within SF3B1 were found to be located primarily within three hotspot exons (14–16).10, 11, 13, 15 Compared with the mutational frequencies reported in the initial studies, we recently demonstrated lower frequencies of mutations within both the SF3B1 and NOTCH1 genes (3.6% and 4.7%, respectively) following the analysis of an unselected, population-based Scandinavian CLL cohort.13 Nevertheless, in line with previous studies, mutations within both these genes were significantly associated with a poor outcome and remained as independent factors in multivariate analysis.13

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Acknowledgements

This research project was supported by the Nordic Cancer Union, the Swedish Cancer Society, the Swedish Medical Research Council and Lion’s Cancer fund, Uppsala.

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Author notes

  1. L Mansouri and R Rosenquist: These authors contributed equally as senior authors to this work.

Authors and Affiliations

  1. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    D Cortese, L-A Sutton, N Cahill, R Gunnarsson, L Mansouri & R Rosenquist

  2. Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden

    K E Smedby

  3. Department of Hematology, Leukemia Laboratory, Rigshospitalet, Copenhagen, Denmark

    C Geisler

  4. Department of Laboratory Medicine, Stem Cell Center, Hematology and Transplantation, Lund University, Lund, Sweden

    G Juliusson

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  1. D Cortese
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Correspondence to R Rosenquist.

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Cortese, D., Sutton, LA., Cahill, N. et al. On the way towards a ‘CLL prognostic index’: focus on TP53, BIRC3, SF3B1, NOTCH1 and MYD88 in a population-based cohort. Leukemia 28, 710–713 (2014). https://doi.org/10.1038/leu.2013.333

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