Multimodal Molecular Profiles Offer Clinically Valuable Information to Oncologists

Expanding the profiling ordered for central nervous system (CNS) tumors may meaningfully impact diagnosis and treatment.

Prajwal Rajappa, MD, MS, a physician-scientist and principal investigator for the Steve and Cindy Rasmussen Institute for Genomic Medicine (IGM) at Nationwide Children’s Hospital, has long advocated for a more robust use of precision medicine approaches to improve clinicians’ understanding of CNS tumors. His latest research, published in Neuro-Oncology Advances, demonstrates the added clinical value of a multimodal approach to molecular profiling for pediatric patients with CNS tumors — some of the most histologically diverse and therapeutically challenging tumors in pediatric oncology.

The study included 53 pediatric patients with CNS tumors, all of whom underwent whole-exome sequencing (WES). A subset of tumors also underwent RNA sequencing (28 patients) and/or methylation array analysis (27 patients). This study is one of the first to examine the combined clinical utility of using multiple profiling methods in a large cohort of pediatric patients with CNS tumors.

“Whole exome sequencing was quite useful for identifying mutations, some of which were targetable, and bulk RNA sequencing revealed clinically relevant prognostic fusions,” says Dr. Rajappa, who directs the Translational Neuro- Oncology Laboratory at IGM. “Methylation profiling helped reclassify certain diagnoses, which had downstream treatment implications. Overall, we observed a meaningful clinical utility in combining a multimodal approach with each of the three next-generation sequencing platforms.”

In seven cases, RNA sequencing identified either the tumor driver or a targetable fusion, and in 23 cases it revealed potential treatment options based on outlier gene expression. Methylation profiling increased diagnostic confidence in eight cases and subclassification based on World Health Organization criteria in 10 cases.

WES revealed clinically important variant information in 36 out of the 53 samples, including 10 that would have gone undetected using only conventional targeted panels. Several children treated based on findings from the broad profiling experienced complete response to targeted treatment paradigms.

“Taken together, the data gave us a more comprehensive picture of the behavior and molecular characteristics of these disparate CNS tumor entities,” says Dr. Rajappa. “Multimodal profiling can be a valuable addition to the standard of care for children with some of the most difficult diagnoses.”

For initial clinical evaluation of CNS tumors, Dr. Rajappa recommends use of a panel of complementary assays, such as a targeted DNA or RNA panel and methylation profiling. If these do not yield information with respect to oncogenic drivers, he suggests incorporating WES and RNA-based fusion detection studies to increase the breadth of the sequencing efforts, given the clinical utility of these precision medicine approaches.

This feature was published in the Fall/Winter 2022 issue. Download the full issue. 

Reference:

Rajappa P, Eng KW, Bareja R, Bander ED, Yuan M, Dua A, Bhanu Maachani U, Snuderl M, Pan H, Zhang T, Tosi U, Ivasyk I, Souweidane MM, Elemento O, Sboner A, Greenfield JP, Pisapia DJ. Utility of multimodality molecular profiling for pediatric patients with central nervous system tumors. Neuro-Oncology Advances. 2022 Mar 10;4(1):vdac031.

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