Whole Exome Sequencing in Patients With Hematologic Malignancies: Ready for Real-Time Precision Medicine?

In the last decade the landscape in hematological diseases has been newly defined. New platforms and assays in research have been used, new pathways, variations in genes and targets for precision medicine have been detected. Next generation sequencing (NGS) contributed a lot to these important achievements. In parallel, NGS has emerged from a research tool to a diagnostic tool and is increasingly applied in routine diagnostic laboratories. Today, NGS techniques are capable of facilitating diagnostics to detect mutations, many variants of uncertain significance, translocations but also gains and losses of chromosomal material. We now have to define, which scenario will be useful for daily routine, which application should still be considered research and how we can improve in the next few years. For sure, NGS is able to reproduce findings from Sanger sequencing to detect variants in single genes as well as to apply gene panels. The latter approach is increasingly used. It will substitute Sanger sequencing in many cases. Also the investigation of gene fusions and translocations will soon be available by NGS based assays in a routine setting. So far, whole exome sequencing (WES) studies have been published from several groups on AML, MDS, CML, ALL, lymphoma entities, CLL or myeloma, in a total ~ 1,500 cases. However, the investigation by WES or even whole genome sequencing so far is not a method of choice in routine diagnostics in hematology. The drawbacks are not only the technical applicability or costs but much more important: data handling and interpretation, and data storage. This is especially true as curated data is still limited and easy-to-use software applications are needed for routine application. If big data sets shall contribute in a routine diagnostic approach, significant bioinformatic processing is mandatory. Further, in many circumstances today WES is hampered as germline material is often missing and data have to be calculated from the "tumor only" sample. Therefore, the routine use of WES to define targets for precision medicine in hematology in a timely manner has only been established in very few places worldwide. The technique itself, instruments, assays and bioinformatic tools will however have the chance to be included in routine workflows at a reasonable turn-around-time within the next 5 years. This will shift or abolish several of today´s standard techniques.