Researchers discover two classes of genetic causes for childhood chordoma

Little is known about the genetics and biology of chordoma, a rare and aggressive bone tumor. Chordomas occur in about one in a million people in the US each year, and only 5% of those are in children. These tumors can appear anywhere along the spine in adults. However, in children these tumors occur mainly at the base of the skull, making complete surgical removal difficult or impossible. Any tumor remnants are treated with high doses of radiation—which can cause significant damage to the developing brain.

A team of researchers led by Xiaowu Gai, PhD, and Jaclyn Biegel, PhD, FACMG, at the Center for Personalized Medicine at Children’s Hospital Los Angeles, recently published a genomic study that revealed two classes of genetic causes for chordoma in children. genomic detective

Finding the causes that drive the different chordoma subtypes could lead to the development of better treatment strategies for children. Previous studies have been conducted mainly in adults, and we know that children’s tumors can appear and behave differently.”

Katrina O’Halloran, MD, MS, pediatric neuro-oncologist and first author of the study

For example, pediatric solid tumors are more likely to be due to underlying germline changes—alterations that can be passed on to future generations—that increase cancer risk.

Some genetic clues

Previous studies of chordoma revealed that the primary genetic defect in a subtype of the disease, poorly differentiated pediatric chordoma, is the loss of SMARCB1, a gene that encodes a key member of the SWI/SNF chromatin remodeling complex, which is a group of proteins that work together to remodel how DNA is packaged inside the cell. While additional genetic risk factors and somatic (acquired) mutations have been identified in tumors from other subtypes, there was no common biological mechanism linking all these variants. Furthermore, previous genomic studies of the chordoma focused only on the nuclear DNA genome, completely neglecting the mitochondrial DNA genome.

Looking beyond the nuclear DNA genome and nuclear-encoded genes

The CHLA research group has previously identified and published strong causative and contributory roles of mitochondrial DNA variants in a variety of pediatric cancers. In the present study, they performed a genome-wide investigation by sequencing the coding regions (exons) of all genes in the nuclear DNA genome, as well as the entire mitochondrial DNA genome, of 29 chordoma tumor samples from 23 pediatric patients. Because of the rarity of chordoma, these samples were contributed from six different academic medical centers across the country. To determine whether their findings were unique to pediatric chordoma, first author Hesamedin Hakimjavadi, PhD, clinical bioinformatics scientist at CHLA, analyzed whole-genome sequencing datasets from 93 chordomas and their matched normal tissues derived from a cohort 80 adult skull- base chordoma patients.

Aberrant indels and wireframe mitochondria

Tumors from five of 23 pediatric chordoma patients (22%) appeared to carry short in-frame insertions and deletions (indels) in ARID1B gene. The same mutations were found in normal tissue from one of the five patients. Computational studies showed a high probability that they were of vegetative origin in the remaining patients, implicating them as risk factors for pediatric chordoma.

A significant fraction of adult chordoma patients (5%) carried comparable inherited ARID1B indels. While this was a smaller number than that of pediatric chordoma patients, it was still significantly higher than that reported in the general population. The ARID1B gene encodes a member of the SWI/SNF complex, similar to SMARCB1.

“These findings implicate a common disease pathway in different chordoma subtypes that may alter gene expression through defects in the SWI/SNF chromatin remodeling complex,” says Dr. Jaclyn Biegel, Director of the Center for Personalized Medicine and senior author of the study. . The research team also discovered a significant number of mitochondrial DNA (mtDNA) mutations in the pediatric chordoma samples. These mutations were particularly enriched in NADH (Mitochondrial Complex 1) genes. Analysis of data from the adult chordoma cohort revealed similar mtDNA changes in cluster 1 genes.

“This study implicates a possible interplay of chromatin remodeling and mitochondrial metabolism in chordoma genesis,” says Dr. Gai, Director of Bioinformatics, Center for Personalized Medicine and senior author of the study. “Therefore, it will be extremely interesting to understand how this may lead to the development of these tumors. Unraveling this could be the critical first step in developing more targeted and effective treatments for chordoma in both pediatric and adult patients.”