Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia.
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.
Section of Hematology/Oncology, Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL;
Jane E
JE
Churpek
Siteman Cancer Center.
Khateriaa
K
Pyrtel
The Genome Institute, and.
Krishna-Latha
KL
Kanchi
Siteman Cancer Center.
Jin
J
Shao
Siteman Cancer Center, The Genome Institute, and Division of Oncology, Department of Medicine, Washington University, St Louis, MO;
Daniel
D
Koboldt
The Genome Institute, and.
Christopher A
CA
Miller
Medimmune/AstraZeneca, Gaithersburg, MD;
Dong
D
Shen
The Genome Institute, and.
Robert
R
Fulton
The Genome Institute, and.
Michelle
M
O'Laughlin
The Genome Institute, and.
Catrina
C
Fronick
Division of Oncology, Department of Medicine, Washington University, St Louis, MO;
Iskra
I
Pusic
Division of Oncology, Department of Medicine, Washington University, St Louis, MO;
Geoffrey L
GL
Uy
Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD;
Evan M
EM
Braunstein
Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD;
Mark
M
Levis
Department of Medicine, University of Minnesota, Minneapolis, MN; and.
Julie
J
Ross
Siteman Cancer Center.
Kevin
K
Elliott
Siteman Cancer Center.
Sharon
S
Heath
Division of Oncology, Department of Medicine, Washington University, St Louis, MO;
Allan
A
Jiang
Siteman Cancer Center, Division of Oncology, Department of Medicine, Washington University, St Louis, MO;
Peter
P
Westervelt
Siteman Cancer Center, Division of Oncology, Department of Medicine, Washington University, St Louis, MO;
John F
JF
DiPersio
Siteman Cancer Center, Division of Oncology, Department of Medicine, Washington University, St Louis, MO;
Daniel C
DC
Link
Siteman Cancer Center, Division of Oncology, Department of Medicine, Washington University, St Louis, MO;
Matthew J
MJ
Walter
Siteman Cancer Center, Division of Oncology, Department of Medicine, Washington University, St Louis, MO;
John
J
Welch
Siteman Cancer Center, The Genome Institute, and.
Richard
R
Wilson
Siteman Cancer Center, The Genome Institute, and Division of Oncology, Department of Medicine, Washington University, St Louis, MO;
Timothy J
TJ
Ley
Section of Hematology/Oncology, Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL;
Lucy A
LA
Godley
Massachusetts General Hospital Cancer Center, Boston, MA.
Timothy A
TA
Graubert
D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D002648:Child; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D018095:Germ-Line Mutation; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
C473949:ASXL1 protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C118660:PDS5B protein, human; C493728:RUNX1 protein, human; D012097:Repressor Proteins; D014157:Transcription Factors