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

Jane E. Churpek, Khateriaa Pyrtel, Krishna Latha Kanchi, Jin Shao, Daniel Koboldt, Christopher A. Miller, Dong Shen, Robert Fulton, Michelle O'Laughlin, Catrina Fronick, Iskra Pusic, Geoffrey L. Uy, Evan M. Braunstein, Mark Levis, Julie Ross, Kevin Elliott, Sharon Heath, Allan Jiang, Peter Westervelt, John F. DiPersioDaniel C. Link, Matthew J. Walter, John Welch, Richard Wilson, Timothy J. Ley, Lucy A. Godley, Timothy A. Graubert

Research output: Contribution to journalArticle

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/AMLfor 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 novoAMLwere 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.

Original languageEnglish (US)
Pages (from-to)2484-2490
Number of pages7
JournalBlood
Volume126
Issue number22
DOIs
StatePublished - Nov 26 2015

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Churpek, J. E., Pyrtel, K., Kanchi, K. L., Shao, J., Koboldt, D., Miller, C. A., Shen, D., Fulton, R., O'Laughlin, M., Fronick, C., Pusic, I., Uy, G. L., Braunstein, E. M., Levis, M., Ross, J., Elliott, K., Heath, S., Jiang, A., Westervelt, P., ... Graubert, T. A. (2015). Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood, 126(22), 2484-2490. https://doi.org/10.1182/blood-2015-04-641100