NEW YORK (GenomeWeb) – Two new studies published online Monday in Nature Genetics have narrowed in on recurrent mutations and gene fusions in pediatric T cell acute lymphoblastic leukemia (T-ALL), including alterations with apparent ties to pediatric T-ALL patient outcomes.
For one of the studies, St. Jude Children's Research Hospital pathology researcher Charles Mullighan led a group of collaborators from the St. Jude-Washington University Pediatric Cancer Genome Project, Children's Oncology Group (COG), and National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatments project that used exome sequencing, array-based genotyping, and RNA sequencing to profile diagnostic tumor and/or remission samples from 264 children or young adults enrolled in a COG trial between 2007 and 2011.
Those data — coupled with whole genome sequences for 25 of the cases — unearthed more than 100 apparent driver genes, along with 10 pathways that were prone to recurrent coding or non-coding alterations such as the JAK-STAT, Ras, and PTEN-PI3 kinase signaling pathways. These included genes and processes not implicated in pediatric T-ALL in the past as well as alterations that appeared to be specific to a particular T-ALL subtype or disease stage.
"Although many of the most frequent mutations in T-ALL have been described previously," Mullighan and co-authors wrote, "our integrated genomic analysis of a large cohort of T-ALL cases identified a large number of unrecognized targets of mutation and demonstrated stage- and subtype-specific associations among genes, cellular pathways, and outcomes."
Using their integrated genomic data and targeted sequencing, members of that team also considered everything from risky germline mutations in the T-ALL patients to frequent gene fusions, regulatory changes, or prognostically informative tumor alterations.
"The multi-modality genomic analysis conducted for all cases enabled a detailed analysis of associations between mutated genes and subtypes of ALL that are considered to arise at defined stages of thymic development," authors of that study concluded, noting that the "detailed portrait of the T-ALL genomic landscape offers a rational foundation for the design of genetic models of T-ALL that faithfully mirror the human disease."
For their part, investigators from the University of Tokyo, Hiroshima University Graduate School of Biomedical Sciences, and other centers in Japan brought together targeted capture sequencing, RNA sequencing, RT-PCR, and/or copy number data for 181 T-ALL cases classified as treatment refractory or relapsed.
Based on the transcriptome sequencing data for 121 cases, the team tracked down recurrent fusions involving the SPI1 transcription factor-coding gene. Those included fusions between the STMN1 gene and SPI1, which were initially found in two cases, and a TCF7-SPI1 fusion that turned up in three of the pediatric T-ALLs.
Using targeted RT-PCR on another 60 pediatric T-ALL cases, the researchers found two more STMN1-SPI1 fusions, bringing the tally of SPI1 gene fusions up to seven cases or nearly 4 percent of the pediatric T-ALLs profiled. And by adding in expression, copy number, and sequence data spanning 158 cancer-related genes, they got a clearer look at the other changes accompanying these fusions.
For example, the team noted that cases marked by SPI1 gene fusions tended to fall into T-ALL subtypes with poorer-than-usual survival patterns, and had gene expression patterns hinting at altered T cell development.
"To the best of our knowledge, these are the first genetic lesions associated with a very poor prognosis in pediatric T-ALL, although their impact on survival needs to be confirmed in additional cases," Kyoto University researcher Junko Takita and the University of Tokyo's Seishi Ogawa, the study's co-corresponding authors, and their colleagues concluded. "T-ALL in patients with SPI1 fusions seems to be incurable with standard chemotherapy, which underscores the importance of detecting this subset of patients so that they may receive more intensive or alternative therapies."