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

Abstract

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.

Figure 1

Familial MDS/AML pedigrees. (A) Partial pedigrees of families 1001 and 1002 with GATA2-associated MDS/AML; complete pedigrees are provided in supplemental Figure 1. Subjects who provided samples for sequencing are indicated by numerals. GATA2 genotypes are provided in Table 1. Two individuals with MDS acquired somatic ASXL1 mutations, as shown. (B) Partial pedigree of family 1015 with RUNX1-associated MDS/AML (left); complete pedigree is provided in supplemental Figure 1. The number of somatic variants (SNVs, indels) detected by exome sequencing in the 3 individuals (indicated by numerals in the pedigree) is shown in the circles (right). The size of the circles is proportional to the median VAFs of somatic SNVs in each case. NOS, not otherwise specified.

Figure 2

Somatic variants in familial MDS/AML vs de novo AML. (A) Targeted sequencing of known RMGs demonstrated fewer mutations in familial cases compared to de novo cases (median, 2.0 vs 5.0; P = .0013 by 2-tailed Mann-Whitney). (B) Somatic mutation VAFs detected by exome sequencing in asymptomatic RUNX1 carriers and familial MDS and AML cases from GATA2 or RUNX1 families are shown. Age at sample collection is indicated by the x-axis labels (black, RUNX1 carrier; red, GATA2 carrier). Clonal hematopoiesis was detectable in 6 of 9 asymptomatic RUNX1 carriers.

Figure 3

Clonal evolution in RUNX1 carriers. Asymptomatic carriers of pathogenic germ line RUNX1 variants develop early-onset clonal hematopoiesis (cumulative risk of 81% by age 50 years). As depicted in the model, this finding provides a rationale for testing the hypothesis that clonal hematopoiesis may provide a biomarker for early detection of disease progression in high-risk families.