Defining pre-cancerous potential of Persistent Rhombic Lip (PeRL) to develop biomarkers for Group 3/4 Medulloblastoma

ASPIRE Award (2023-Present)

Sriram Venneti, MD, PhD, University of Michigan, Ann Arbor; Michael Taylor, MD, PhD, Texas Children's Hospital; Elaine Mardis, PhD, Nationwide Children's Hospital

Sriram Venneti, MD, PHD

Michael Taylor, MD, PhD

Elaine Mardis, PhD

Medulloblastomas are tumors which arise during fetal development of the cerebellum and represent the most common type of childhood brain cancer. Extensive molecular heterogeneity exists among medulloblastomas, and genomic and transcriptomic analyses have identified four main subtypes, each displaying distinct clinical and prognostic characteristics. Among these subtypes, group-3 and group-4 medulloblastomas are particularly challenging to treat and often develop resistance, leading to high morbidity and fatality rates. These outcomes emphasize the critical need to gain a deeper understanding of the developmental changes that give rise to these tumor types.

Recent breakthrough work has identified that group-3 and group-4 medulloblastomas arise from aberrant/arrested brain tissue in the rhombic lip, an embryonic structure in the developing cerebellum. The human rhombic lip normally develops into a structure called the nodulus shortly after birth, but rare atypical cells, termed heterotopias, that morphologically resemble medulloblastomas, have been found in the noduli of some patients in studies dating as far back as the 1940s. Collaborating investigators Sriram Venneti, Elaine Marids, and Michael Taylor propose a new designation for these nodulus heterotopias, calling them Persistent Rhombic Lips (PeRLs), and aim to test the hypothesis that PeRLs represent premalignant lesions for group-3 and group-4 medulloblastomas. To achieve this, they will evaluate autopsy brain tissue to determine the frequency of PeRLs, identify associated co-morbidities, and assess the potential for PeRLs to transform into malignant tumors. Next-generation sequencing techniques will be employed to investigate the molecular characteristics of PeRLs in comparison to normal cerebellar tissue. This project represents one of the first studies aiming to establish the prevalence of PeRLs in the general population and evaluate their potential for progression to malignancy. The findings will determine whether there is a unique opportunity to detect pre-cancerous lesions in the developing cerebellum and may lay the foundation for the development of screening biomarkers for these deadly childhood brain cancers.