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Clinical relevance of MYD88 mutations in B-NHL
of resistance.134 To our knowledge, currently no clinical trials are underway to investigate this intriguing treat- ment concept.
Liquid biopsy
Until now, comprehensive genomic analysis for accu- rate diagnosis and classification of B-NHL has been based on DNA isolated from lymphoma tissues. For most patients, the collection of this tissue is a highly invasive procedure with the risk of severe complications.135 An alternative and less invasive method of sampling is the so-called ‘liquid biopsy’, using blood plasma or cere- brospinal fluid, instead of lymphoma tissue. These fluids contain circulating tumor DNA (ctDNA) that is secreted or released during apoptosis or necrosis of the tumor cells, and may harbor somatic mutations, such as MYD88(L265P). Besides being a less invasive method of sampling, ctDNA allows detection of spatial differences between lymphoma cells spread throughout the body, which is not possible with tissue biopsies.
The high frequency of MYD88(L265P) in several B-NHL subtypes make this mutation perfectly appropriate for screening by ctDNA, as already demonstrated in DLBCL,136 primary DLBCL of the central nervous system,137 and intravascular large B-cell lymphoma.95 With the highly sen- sitive and specific method of digital droplet PCR (ddPCR), even low amounts of ctDNA can be detected, potentially providing information about minimal residual disease, clonal evolution over time, and spatial differences between the lymphoma cells. As demonstrated in patients with DLBCL and WM, ddPCR analysis of liquid biopsies can aid in monitoring the disease course, because of the highly sensitive identification and quantification of the variant allele frequency of MYD88(L265P).31,138
An alternative technique for ctDNA analysis is targeted
next-generation sequencing. The benefit of this technique over ddPCR is the possibility of identifying multiple vari- ants at the same time, as was shown by Bohers et al.139 and Kurtz et al.140 in liquid biopsies from 30 and 217 DLBCL patients, respectively. The mutational burden of most of their patients, with a median of 117 variants per patient, was sufficient for disease monitoring. This novel way of disease monitoring could enhance evaluation of treatment responses (Figure 3). In their studies, the tumor burden, as measured by positron emission tomography- computed tomography scans, was significantly correlated with the variant allele frequency of ctDNA both during and after treatment.139,140 Given this recent progress in ctDNA analysis, liquid biopsies are a minimally invasive method for evaluation of the molecular profile and can be used for analysis of tumor burden, disease progression, and treatment efficacy in patients with B-NHL.
Conclusions and future perspectives
Routine diagnostics in B-NHL are moving forward from classical morphology and immunohistochemistry towards the implementation of genetic analysis. In sever- al subtypes of B-NHL subtype, MYD88(L265P) plays a crucial role as a driver of lymphomagenesis and can be used as a diagnostic classifier, as well as a prognostic fac- tor and predictive biomarker. B-NHL with MYD88(L265P) can be (in)directly targeted by several novel therapeutic strategies and prospective clinical trials investigating these strategies are ongoing. We expect that that these theranostic strategies will be guided by analy- sis of MYD88(L265P) in liquid biopsies to monitor disease progression and determine response to therapy. Altogether, given the significant clinical relevance of MYD88(L265P), we advocate evaluation of MYD88 mutational status in routine diagnostics of B-NHL.
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