Genomics and Diagnostics in Acute Myeloid Leukaemia

Abstract

Cancers can be best described as genetic diseases, where mutations typically accumulate over a protracted period of time, leading to a cellular shift from normalcy to malignancy and an ever-evolving tumour and its microenvironment. The tools at our disposal to characterise the genetic landscape(s) of these tumours and our appreciation of their complexity have fundamentally changed over the last 10 years, following the first whole-genome sequencing (WGS) of a case of acute myeloid leukaemia (AML) in 2008 and the introduction of global initiatives (e.g. The Cancer Genome Atlas (TCGA)), both with an overarching goal of improving diagnosis, treatment and cancer prevention by setting out to systematically explore the entire spectrum of genomic changes involved in human disease. While this journey is far from complete, modern diagnosis of cancers now relies on the integration of morphological and molecular information that, together, offer the potential to refine classification, establish prognosis and determine the most appropriate treatment for groups of patients. In this chapter, we examine how genomics has revolutionised our understanding of the diagnosis of blood cancers, using the exemplar of AML, and how this new knowledge is set to inform and direct treatment in the near future.

Nordic Guidelines for Germline Predisposition to Myeloid Neoplasms in Adults: Recommendations for Genetic Diagnosis, Clinical Management and Follow-up

“…There was consensus in the working group about the potential value of annual blood testing for somatic gene mutations with an NGS gene panel targeting myeloid genes with high coverage and reading depth. This recommendation is based on recent reports which highlight the emergence of clonal hematopoiesis associated with increased risk for the development of MDS or AML in hereditary conditions, mainly those related to germline GATA2 and RUNX1 mutations 49,6,47,48 . The frequency of testing for somatic mutations and the clinical implications are however, undefined in most other patients with germline predisposition to MDS or AML.…”

“…Nevertheless, appearance in the blood of a new somatic mutation or a persistent or steep increase in variant allele frequency of an already existing clone should lead to further investigations including a bone marrow aspirate/biopsy in exactly the same way as emerging cytopenia (see “Complete blood count” above). The emergence of a clone should not solely be an indication for clinical action 6 . The gene, the VAF, the number of pathogenic variants as well as the dynamics over time should be taken into account.…”

“…Estimates suggest that about 5% to 15% of adults and 4% to 13% of pediatric patients with MDS or AML carry germline pathogenic variants in cancer susceptibility genes 1–4 . At the same time, several new genes associated with familial MDS or AML, with or without syndromic features, have been recently discovered, such as GATA2 , ETV6 , DDX41 , SAMD9, and SAMD9L 5–20 …”