Variants Mapped in Therapy-Related Myeloid Cancer May Help Guide Treatment

Variants Mapped in Therapy-Related Myeloid Cancer May Help Guide Treatment
Nearly one-quarter (24%) of the 422 patients screened in the Pediatric Molecular Analysis for Therapy Choice (Pediatric MATCH) trial are eligible for treatment with at least one drug being tested in the study, the National Cancer Institute (NCI) and the NCI-supported Children’s Oncology Group (COG) said. []

Genomic abnormalities in therapy-related myeloid neoplasms (tMN) in children have been characterized by scientists at St. Jude Children’s Research Hospital. They analyzed 84 myeloid neoplasms for somatic and germline genomic alterations using whole exome (WES), whole genome (WGS), and/or RNA sequencing.  Their data show that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53, and KMT2A rearrangements are frequent somatic drivers of tMN in children.  They also identified cases with aberrant MECOM expression secondary to enhancer hijacking—a specific type of gene regulation.

The data for this study came from patients with leukemia, solid tumors, or brain tumors, who had developed tMN after chemotherapy. The researchers suggest their study could help identify treatments to slow or prevent such cancers.  A notable finding was that unlike what is seen in adults with tMN, pediatric cases show no evidence of pre-existing minor tMN clones. The study was published in Nature Communications Feb. 12.

“One thing that we’ve known for a long time is once kids develop this secondary tumor, the outcome is really poor,” said co-corresponding author Jeffery Klco, MD, PhD, St. Jude Pathology. “The alterations that drive these tumors are different in children than they are in adults, underscoring the need to study these tumors specifically in pediatrics.”

Therapeutic regimens for pediatric cancer have improved over the years, leading to a decrease in the incidence of tMN in children. However, approximately 0.5–1.0% of pediatric cancer patients continue to develop tMN after therapy for hematological, solid, and CNS malignancies. Such malignancies are particularly hard to treat: Children with tMN do worse than those with de novo MDS/AML. The 5-year survival rate is 6–11% in patients not treated with hematopoietic cell transplant (HCT).

The pathogenesis of tMN in children overall is poorly understood. However, there are well-described associations of this condition with alkylating agents (e.g., cyclophosphamide), topoisomerase II inhibitors (e.g., the epipodophyllotoxins etoposide and teniposide), radiation therapy, and HCT. Further, epipodophyllotoxin-associated tMN is strongly associated with KMT2Ar.

This study of comprehensive sequencing of pediatric tMN reveals that KMT2Ar was the most common driver alteration in this particular cohort, along with Ras/MAPK pathway mutations. Somatic TP53 or RUNX1 alterations were also frequent, but these mutations appeared to arise after chemotherapy, unlike those seen in adults with tMN. Further, the researchers found that overexpression of the transcription factor MECOM was frequent. In some of those cases the overexpression was driven by enhancer hijacking.

Finally, they found that pediatric tMN-defining variants arise most commonly as a consequence of cytotoxic therapy, and that these malignant clones can be identified, on average, >1 year before morphologic evidence of neoplasm. The researchers note that while their findings are from just a single institution, they “highlight the diverse nature of genomic alterations in pediatric tMN and suggest that genomic screening approaches may be able to identify at risk patients prior to tMN development.”

This research benefited from computational tools developed at St. Jude that were designed to reduce error rates, including CleanDeepSeq and SequencErr. These approaches help to discriminate between true mutations and sequencing errors.  These tools allowed the researchers to trace the mutations back as far as two years before a tMN developed, which means early interventions could potentially help such patients.

“This work indicates that we can detect this type of malignancy early, to study if preventative therapies could benefit patients,” said co-senior author Xiaotu Ma, Ph.D., St. Jude Computational Biology.