Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia
Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia
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DOI：
10.1182/blood-2015-04-641100
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发表时间：
2015-11-26
期刊：
影响因子：
20.3
通讯作者：
Graubert, Timothy A.
中科院分区：
文献类型：
--
作者：
Churpek, Jane E.;Pyrtel, Khateriaa;Graubert, Timothy A.
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, potential biomarker that could be used for surveillance in these high-risk families.
