RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML

Abstract

First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.

Graphical abstract

Figure 1.

Pedigrees showing the genotypes and phenotypes detected in the new families with germline RUNX1 mutations and inherited HMs. Family 1: RUNX1 ΔP1Ex1-2 (A); family 2: RUNX1 ΔEx3-5 (B); family 3: RUNX1 L112Cfs*9 (C); family 4: RUNX1 R169I (D); family 5: RUNX1 D198V (E); family 6: RUNX1 G199E (F); family 7: RUNX1 R204Q (G); family 8: RUNX1 R320* (H); family 9: RUNX1 R320* (I); family 10: RUNX1 c.968-10C>A (J). Δ indicates a partial gene deletion; *, stop-gain mutation; amino acid changes (p.) are mentioned for missense variants, and the splice-site variant is annotated to the cDNA position. a, age at last date of contact; BM, bone marrow; BMT, bone marrow transplant; BrCa, breast cancer; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; d, age at death; dx, age at diagnosis; fs, frameshift mutation; MUD, matched unrelated donor; Panc cancer, pancreatic cancer; sAML, secondary AML; SCT, stem cell transplant; T-ALL, T-cell acute lymphoblastic leukemia; tMDS, therapy-related MDS; T-NHL, T-cell non-Hodgkin lymphoma.

Figure 2.

Schematic representation of RUNX1 showing the known germline genetic alterations associated with FPD-MM spectrum phenotypes. Shown are all mutations reported in this study, combined with published RUNX1 single-nucleotide variants (SNVs), small insertions and deletions (Indels), and CNVs annotated to RUNX1C; NM_001754.4; LRG_482. Full-mutation annotations can be found in supplemental Table 1. The numbers of the coding exons and known functional domains are shown within the protein, and the number of amino acids are shown below the diagram. The frequency of recurrent mutations is indicated by (N). For all mutations, the protein changes (p.) are shown, unless specified as splice-site variants (SA or SD). SA, splice acceptor; SD, splice donor.

Figure 3.

Somatic mutation differences in inherited (germline) and sporadic (somatic) RUNX1 mutated AML. Aggregation of somatic mutations in germline RUNX1 carriers who developed AML as identified through literature review (right). Comparison of the frequency of somatic mutation in myeloid genes in individuals with inherited or sporadic AML (left). *Somatic mutations identified in samples from this study.

Figure 4.

The spectrum of hematological phenotypes reported with different germline RUNX1 mutations. The protein (p.) changes are shown, for frameshift (fs), stop-gain (*), and missense variants. Splice-site variants are shown with the cDNA change (c.), and (partial) gene deletions are abbreviated. CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; CMMoL, chronic myelomonocytic leukemia; Del, deletion; DLBCL, diffuse large B-cell lymphoma; Dup, duplication; Ex, Exon; HCL, hairy cell leukemia; MF, myelofibrosis; SCC, squamous cell carcinoma.