Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia

Abstract

• Known pathogenic germ line variants in 12 genes can explain nearly 30% of families with inherited predisposition to MDS/AML. • Asymptomatic carriers of germ line RUNX1 mutations develop detectable clonal hematopoiesis with a cumulative risk of .80% by age 50 years.Familial clustering of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) can be caused by inherited factors. We screened 59 individuals from 17 families with 2 or more biological relatives with MDS/AML for variants in 12 genes with established roles in predisposition to MDS/AML, and identified a pathogenic germ line variant in 5 families (29%). Extending the screen with a panel of 264 genes that are recurrently mutated in de novo AML, we identified rare, nonsynonymous germ line variants in 4 genes, each segregating with MDS/AML in 2 families. Somatic mutations are required for progression to MDS/AML in these familial cases. Using a combination of targeted and exome sequencing of tumor and matched normal samples from 26 familial MDS/AML cases and asymptomatic carriers, we identified recurrent frameshift mutations in the cohesin-associated factor PDS5B, co-occurrence of somatic ASXL1 mutations with germ line GATA2 mutations, and recurrent mutations in other known MDS/AML drivers. Mutations in genes that are recurrently mutated in de novo AML were underrepresented in the familial MDS/AML cases, although the total number of somatic mutations per exome was the same. Lastly, clonal skewing of hematopoiesis was detected in 67% of young, asymptomatic RUNX1 carriers, providing a potential biomarker that could be used for surveillance in these high-risk families. (Blood. 2015;126(22):2484-2490

Myeloid neoplasms with germ line RUNX1 mutation

“…However, CDC25C mutations were not identified in this study [43]. CDC25C mutations were also not detected in the two affected patients with FPD/AML from the Ireland group [44] and 13 individuals of FPD/AML families from the United States [45]. The difference of ethnic origin of FPD/AML patients is suggested.…”

“…Several hematological malignancyrelated mutations (such as DNMT3A, TET2, and ASXL1) were identified in around 10-20% of healthy individuals >65-70 years of age, while the detectable mutations were very rare in a younger cohort <40 years of age. On the other hand, a recent analysis of familial MDS/AML revealed that clonal hematopoiesis was detected in 67% of asymptomatic RUNX1 mutant carriers <50 years of age [45]. Further study with a larger cohort will be required to determine whether detecting clonally skewed clones could predict a risk for leukemic transformation.…”

Myeloid neoplasms with germline DDX41 mutation

“…Firstly, the age of MDS onset in carriers of germline DDX41 mutations is similar to the diagnosis age of sporadic MDS, (median age of myeloid HM diagnosis of all published germline DDX41 cases to date is 65 years (range . This is unlike other predisposition syndromes which often have an early age of onset [29] (reviewed in [30]). However, we have observed that families with point mutations in the helicase C domain of DDX41 (R525H and G530D) have a significantly younger age of onset of HM than frameshift mutations, suggesting a different mechanism of action of these mutations [20].…”

“…Clonal hematopoiesis is observed in individuals of advanced age without germline predisposition and is associated with increased risk of myeloid HM development [35]. Early clonal hematopoiesis may be a common feature of FHM, as it is also found at an early age in FHM individuals with germline RUNX1 mutations [29].…”

Germline Genetic Predisposition to Hematologic Malignancy

“…The clinical implications of clonal cytogenetic abnormalities or somatic mutations with clonal hematopoiesis may differ in the context of these syndromes, and additional studies are needed. 3,4 In addition, many syndromes are associated with bone marrow failure (BMF), which responds poorly to standard treatment with antithymocyte globulin and cyclosporine and, thus, would require a different treatment approach compared with the patient with acquired aplastic anemia. Similarly, some germline disorders conditioning regimens may require reduced-intensity conditioning approaches for hematopoietic stem cell transplant.…”