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

Blood. 2015 Nov 26;126(22):2484-90. doi: 10.1182/blood-2015-04-641100. Epub 2015 Oct 22.

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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Base Sequence
  • Child
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins / genetics
  • Exome*
  • Female
  • Genetic Diseases, Inborn / genetics*
  • Germ-Line Mutation*
  • Hematopoiesis / genetics
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Myelodysplastic Syndromes / genetics*
  • Neoplasm Proteins / genetics*
  • Repressor Proteins / genetics
  • Transcription Factors / genetics

Substances

  • ASXL1 protein, human
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • PDS5B protein, human
  • RUNX1 protein, human
  • Repressor Proteins
  • Transcription Factors

Associated data

  • PIR/116897
  • PIR/601399