Universal genetic testing for inherited susceptibility in children and adults with myelodysplastic syndrome and acute myeloid leukemia: are we there yet?

Abstract

Comprehensive genomic profiling of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cases have enabled the detection and differentiation of driver and subclonal mutations, informed risk prognostication, and defined targeted therapies. These insights into disease biology, and management have made multigene-acquired mutation testing a critical part of the diagnostic assessment of patients with sporadic MDS and AML. More recently, our understanding of the role of an increasing number of inherited genetic factors on MDS/AML risk and management has rapidly progressed. In recognition of the growing impact of this field, clinical guidelines and disease classification systems for both MDS and AML have recently incorporated familial MDS/AML predisposition syndromes into their diagnostic algorithms. In this perspective piece, we contemplate the advantages, disadvantages, and barriers that would need to be overcome to incorporate inherited MDS/AML genetic testing into the upfront molecular diagnostic work-up of every MDS/AML patient. For centers already performing panel-based tumor-only testing, including genes associated with familial forms of MDS/AML (e.g., RUNX1, CEBPA, GATA2, TP53), we advocate optimizing these tests to detect all types of germline variants in these genes and moving toward upfront paired tumor/germline testing to maximize detection and streamline patient care.

ETV6: A Candidate Gene for Predisposition to “Blend Pedigrees”? A Case Report from the NEXT-Famly Clinical Trial

“…e identi cation of some genes involved in inheritance of hematological malignancies allowed to recognition of an independent entity in last revision of WHO classi cation and also represents a further step toward the precision and personalized therapy [15,24].…”

“…e implication of some of them in the pathogenesis of genetic predisposition to neoplasia is still a matter of debate. Recent evidences highlighted the importance of sequencing by NGS in these patients and also of investigating the regulatory and intragenic portions instead of the only coding regions which are conventionally queried [17,24]. is approach is still mandatory for the study of ANKRD26 since the known mutations associated with MDS/ AML pedigrees a ect the 5′UTR of the gene [45].…”

“…In parallel with these well-established evidences, there is a group of four genes still considered as associated with a "possible tumor risk" that must be confirmed. PTPN11 is not included in the ones recognized by the WHO classification, while DDX41, GATA2, and ETV6 have been already linked with defined familial MDS/AML [24].…”

Heterozygous loss of Srp72 in mice is not associated with major hematological phenotypes

“…The overall prevalence of predisposing germline mutations is not well established, but multiple studies have shown that 4%‐13% of pediatric/young adults and 5% of adult MDS/AML patients are carriers of inherited cancer susceptibility mutations . However, the contribution of hereditary cases is most likely underestimated, especially those in which the inherited genetic lesion is associated with diseases diagnosed later in life.…”

“…3 The overall prevalence of predisposing germline mutations is not well established, but multiple studies have shown that 4%-13% of pediatric/young adults and 5% of adult MDS/AML patients are carriers of inherited cancer susceptibility mutations. 4 However, the contribution of hereditary cases is most likely underestimated, especially those in which the inherited genetic lesion is associated with diseases diagnosed later in life. Over the last two decades, genomic sequencing efforts of individuals belonging to families with a history of hematological malignancies have revealed several new susceptibility loci, including CEBPA, 5 GATA2, 6 ETV6, 7 DDX41, 8 RUNX1, 9 ANKRD26, 10 and SRP72.…”