TY - JOUR
T1 - Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia
AU - Churpek, Jane E.
AU - Pyrtel, Khateriaa
AU - Kanchi, Krishna Latha
AU - Shao, Jin
AU - Koboldt, Daniel
AU - Miller, Christopher A.
AU - Shen, Dong
AU - Fulton, Robert
AU - O'Laughlin, Michelle
AU - Fronick, Catrina
AU - Pusic, Iskra
AU - Uy, Geoffrey L.
AU - Braunstein, Evan M.
AU - Levis, Mark
AU - Ross, Julie
AU - Elliott, Kevin
AU - Heath, Sharon
AU - Jiang, Allan
AU - Westervelt, Peter
AU - DiPersio, John F.
AU - Link, Daniel C.
AU - Walter, Matthew J.
AU - Welch, John
AU - Wilson, Richard
AU - Ley, Timothy J.
AU - Godley, Lucy A.
AU - Graubert, Timothy A.
N1 - Publisher Copyright:
© 2015 by The American Society of Hematology.
PY - 2015/11/26
Y1 - 2015/11/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84948976984&partnerID=8YFLogxK
U2 - 10.1182/blood-2015-04-641100
DO - 10.1182/blood-2015-04-641100
M3 - Article
C2 - 26492932
AN - SCOPUS:84948976984
SN - 0006-4971
VL - 126
SP - 2484
EP - 2490
JO - Blood
JF - Blood
IS - 22
ER -