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Researchers Report on Recurrent Mutations in Down Syndrome-related Myeloid Condition, Blood Cancer

NEW YORK (GenomeWeb News) – A single gene appears to be the main culprit in a myeloid proliferation complication called transient abnormal myelopoiesis, or TAM, that's sometimes seen in individuals with Down syndrome, according to a study online yesterday in Nature Genetics, which used sequencing to characterize the alterations associated with TAM and a related blood cancer.

A team led by investigators at the University of Tokyo, Kyoto University, and Hirosaki University used genome sequencing, exome sequencing, and targeted genomic assessments to tally up genetic changes involved in the often-temporary myeloid condition most akin to acute megakaryoblastic leukemia.

The researchers also generated sequence data for individuals whose TAM had progressed to a Down syndrome-related form of AMKL blood cancer that does not disappear on its own, comparing both to forms of AMKL that occur in individuals without Down syndrome.

Sifting through this sequence data, they saw that alterations affecting the GATA1 gene were enough to cause TAM in those with Down syndrome. In those who went on to develop Down syndrome-associated acute megakaryoblastic leukemia, or DS-AMKL, meanwhile, investigators detected an accumulation of additional mutations affecting several other potential driver genes, including members of epigenetic and signaling pathways.

Together, such changes can produce a condition that shares features with acute megakaryoblastic leukemia, the study's authors noted, though their comparisons with sequence data representing non-Down syndrome-related AMKL cases points to molecular differences between DS-AMKL and non-DS-AMKL that may explain some of the clinical differences described in AMKL patients with or without Down syndrome.

"DS-AMKL and non-DS-AMKL showed similar phenotypes," co-corresponding authors Seishi Ogawa, a researcher affiliated with the University of Tokyo and Kyoto University, and Hirosaki University's Etsuro Ito, and co-authors wrote, "but had distinct genetic features, which may underlie their different clinical characteristics."

Ogawa, Ito, and colleagues used Illumina's HiSeq 2000 to do whole-genome sequencing on samples from members of four parent-child trios. Within these families were children with Down syndrome who had experienced TAM, AMKL, and/or remission.

The research team added whole-exome sequence, targeted deep sequence, and/or RT-PCR data on more than 100 samples from individuals with TAM, DS-AMKL, or non-DS-AMKL.

Within all of TAM and DS-AMKL samples tested, the team saw mutations affecting GATA1, a gene implicated in TAM in past studies, but relatively few somatic changes involving other genes or non-coding sequences.

Additional genetic glitches turned up in samples from individuals whose conditions had progressed to DS-AMKL, researchers reported. The suite of mutations found at that stage was much more heterogeneous than that detected in TAM samples, they noted. Even so, genes from a few pathways appeared particularly prone to recurrent mutation in DS-AMKL.

For instance, genes comprising the cohesin complex were mutated in more than half of the DS-AMKL cases tested. Mutations in similar sorts of genes were far less common in non-Down syndrome-associated forms of the blood cancer, the study's authors found, and were not detected in TAM samples from Down syndrome-affected individuals.

In the DS-AMKL samples, the team also unearthed recurrent mutations in the CTCF and EZH2 genes and genes coding for epigenetic regulators or for members of the RAS signaling pathway.

"[D]own syndrome-related myeloid proliferation is shaped by multiple rounds of acquisition of new mutations and clonal selection," Ogawa, Ito, and co-authors wrote, "which are initiated by a GATA1 mutation in the TAM phase and further driven by mutation in cohesin or CTCF, EZH2, or other epigenetic regulators, and RAS or signal-transducing molecules, leading to AMKL."

Again, mutations to those genes and pathways tended to be much less pronounced in samples from individuals whose AMKL was not Down syndrome-related. In the latter condition, the group detected recurrent gene fusions that did not characterize forms of the blood cancer occurring in those with Down syndrome.