International symposium on inheritable central nervous system (CNS) cancer predisposition: A prologue Open Access

When childhood cancer physicians were asked, around 20 years ago, what proportion of childhood brain cancer was inheritable, the response would have been perhaps 5%, and examples of neurofibromatosis types I and II, tuberous sclerosis, and bilateral retinoblastoma would have been cited.

Over the ensuing years, we have come to recognize a growing number of diagnoses with specific germline alterations and genetic polymorphisms representing varying degrees of cancer susceptibility penetrance, many of which specifically associated with the development of primary brain cancer. The classic example of this situation is the individuals carrying germline TP53 mutations, associated with the Li-Fraumeni cancer predisposition syndrome (LFS). In this setting, whilst malignant gliomas were recognized early on as associated with the LFS, the recognition that choroid plexus carcinoma is often the earliest cancer to develop in these individuals has emerged over the last decade.

Other advances in our identification and understanding of inheritable cancer predisposition alterations have continued in recent years, especially with advances in nucleic acid sequencing technologies and associated computational analysis. Such examples include mismatch repair deficiency (MMRD) in both medulloblastomas and malignant gliomas, Noonan’s syndrome in low-grade gliomas, PATCH1 and SUFU germline mutations in childhood medulloblastomas, the rhabdoid tumor predisposition syndrome with brain and extra-central nervous system rhabdoid tumor primary cancers.

Accordingly, neuroscientists and pediatric neuro-oncology practitioners are being increasingly challenged with questions as to how to improve early diagnosis of such tumors in susceptible populations, through genomic screening methodologies that include liquid biopsy sampling of blood and cerebral spinal fluid. Most critically, the pursuit of how to prevent cancer from developing in individuals with germline predisposition represents the “holy grail” of the field.

In 2018, with the intention to address these emergent questions, several of us formulated the plan to assemble a small forum of leading neuroscientists, neuro-geneticists, cancer genomicists, and pediatric neuro-oncologists to “brainstorm” these important issues during a 2.5-day meeting held in Columbus, Ohio. Based upon the quality of scientific presentations and thoughtful discussions, we planned a follow-up meeting in 2 years—delayed due to the onset of the COVID-19 pandemic. Ultimately, our second meeting was held in Pismo Beach, California, in June 2023, attended by some 70 invited researchers and physician-scientists from the United States, Canada, Germany, France, the United Kingdom, Israel, and Sweden. This meeting left us determined to produce brief, manuscripted “position statements,” written by many of the principal presenters, which are now presented in this special issue of “Neuro-oncology Advances.”

We hope that this series of brief articles will serve to inform, sensitize, and stimulate the neuro-oncology community, both those in the clinical field as well as those in fundamental and translational neurosciences research. In aggregate, we hope these manuscripts will encourage others to consider addressing some of the challenges in diagnosis, prevention and treatment that our families with such predisposition syndromes confront.