NEW YORK (GenomeWeb) – Looking at the gene sequences that have gone awry in patients with myelodysplastic syndrome (MDS) can offer clues to the cases most likely to progress to bone marrow failure after allogeneic hematopoietic stem cell transplant treatment, a new study has found.
Researchers from the US and Germany used targeted sequencing to profile mutation patterns in pre-treatment samples taken from more than 1,500 individuals with MDS. Their results suggest that mutations in genes such as TP53, JAK2, or genes in the RAS pathway coincide with better or worse outcomes after treatment with bone marrow, peripheral blood stem cell, or cord blood transplants, though the conditioning treatment applied prior to transplantation sometimes contributed to the equation as well.
The team published its results online today in the New England Journal of Medicine.
"[O]ur findings show that analysis of mutations in patients with MDS at the time of transplantation can predict outcomes and identify subgroups of patients who will derive the most benefit from particular conditioning regimens," corresponding author Benjamin Ebert, a hematology researcher affiliated with the Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, and his co-authors wrote.
The team sequenced a set of 129 genes with suspected roles in MDS development or progression in archived blood samples from 1,514 individuals with MDS who had joined the Center for International Blood and Marrow Transplant Research Repository, a National Institutes of Health-supported center based in Milwaukee and Minneapolis.
The samples had been collected and frozen prior to the conditioning treatment that preceded each individual's allogeneic hematopoietic stem cell transplantation, the researchers noted.
At least 1,196 of the MDS samples had mutations in one or more of the genes targeted. And when the investigators searched for ties to patient outcomes, focusing on 32 recurrently mutated genes, they identified a handful of genes that were mutated in those with poorer outcomes.
The team saw reduced survival times and quicker progression to relapse in individuals with TP53 mutations before treatment, for example. TP53 mutations, which turned up in 19 percent of cases, coincided with poor outcomes across individuals with different types of pre-treatment conditioning regimens.
Among the 423 individuals with TP53 mutations, the researchers noted that those with more severe mutations, such as truncating alterations, tended to have shorter survival times than those with missense changes to the gene.
Mutations affecting genes in the RAS signaling pathway seemed to have the most pronounced effect on survival in the TP53 mutation-free individuals over the age of 40, on the other hand, but only for individuals who had reduced-intensity condition regimens.
In the over-40, TP53 mutation-free group, average survival time was more than two years in individuals without RAS pathway mutations, but less than a year in those with mutations in the pathway. But the survival difference between cases with or without RAS pathway mutations disappeared when more aggressive, myeloablative conditioning was used before hematopoietic stem cell transplantation.
Still other patients — with mutations in the JAK2 gene — tended to have shorter overall survival times without a corresponding dip in the time to relapse, the authors noted, suggesting that "strategies that are focused on minimizing toxic effects would be useful in older patients with JAK2 mutations."
Based on the overrepresentation of PPM1D gene mutations in individuals with therapy-induced rather than spontaneously occurring MDS, meanwhile, the group speculated that this gene might contribute to the development of the condition. Mutations in PPM1D and several other genes occurred in individuals who developed MDS after their 40th birthdays.