This article is more than 5 years old. Information may no longer be current.
Genomic maps could improve pediatric adrenocortical tumor identification, treatment
Click Here to Manage Email Alerts
Genomic maps of pediatric adrenocortical tumors have revealed aberrant genetic and chromosomal changes that drive cancer, along with the sequence of changes that trigger it, according to research published in Nature Communications.
“Pediatric adrenocortical tumors had never been analyzed on a genomic scale before,” Gerard P. Zambetti, PhD, of the department of biochemistry, St. Jude Children’s Research Hospital, Memphis, Tennessee said in a news release.
The advance could improve identification of the rare childhood tumors and ultimately lead to better treatment.
“We haven’t had any good markers to establish a prognosis,” Raul Ribeiro, MD, in the department of oncology, said in the release. “The only characteristic that was somewhat consistent was tumor size, with larger tumors having a worse outcome than smaller ones. But even then, we would have cases where patients with large tumors would have good prognoses, and those with smaller tumors would do poorly.”
Researchers from St. Jude analyzed 37 adrenocortical tumors from patients with early- to late-stage disease using whole-genome, whole-exome and/or transcriptome sequencing.
The team identified key mutations involved in the tumors and their timing in cancer development. A mutation was detected in TP53, which is found on chromosome 17 and halts cell division under stress conditions. A molecular event occurred on chromosome 11, which harbors the IGF2 gene that promotes cell growth.
“With the chromosome 11 abnormality plus the TP53 mutation, you’ve lost the brakes and stepped on the accelerator at the same time,” Zambetti said.
Bioinformaticists involved in the genomic analysis determined that both chromosomal abnormalities occur early in tumor development, which suggests a fundamental role for the alterations in triggering tumor development, according to the release.
The investigators hope to confirm, in a larger group of patients, that a combination of mutations in genes ATRX and TP53 do lead to more aggressive tumors with poorer prognosis.
“Our focus now will be to determine whether the genomic abnormalities we have distinguished have clinical value in determining the prognosis for these tumors,” Ribeiro said.
The research could provide insight into other childhood cancers that show deregulation of chromosome 11 and over-activity of IGF2, including rhabdomyosarcoma, Wilms tumor and hepatoblastoma, and hold promise for improving the treatment of adrenocortical tumors .
“Collectively, these findings demonstrate the nature, timing and potential prognostic significance of key genetic alterations in pediatric (adrenocortical tumors) and outline a hypothetical model of pediatric adrenocortical tumorigenesis,” the researchers wrote.
Disclosure: The researchers report no relevant financial disclosures.
Perspective
Back to Top
Tobias Else, MD
Adrenal cancer is a rare endocrine malignancy, and several recent efforts have shed light into its molecular make-up. Clinically there are significant differences between pediatric and adult ACC. Inherited predisposition accounts for more than 50% of pediatric cases, but only 10% to 15% of adult cases. Adrenal cancer in children follows different pathologic criteria of diagnosis and has a better overall prognosis than in adults.
Pinto and colleagues undertook a detailed molecular analysis of pediatric adrenal tumors as has been done recently by a French consortium and the NCI-sponsored The Cancer Genome Atlas enterprise for adult cancers. Pinto’s study provided more details on the molecular pathogenesis shared by adult and pediatric ACCs: Tumors almost invariably show alterations in the known suspects, the IGF2 locus and either TP53 or CTNNB1 (β-catenin). It also revealed another pathway impacting telomere maintenance in tumors with mutations in ATRX (approximately 30% of tumors).
Most interestingly, some of the findings unique to pediatric ACCs might be used in risk stratifications: There is a striking difference in survival of patients with TP53 and ATRX mutations (80% recurrence or death) as opposed to those with only one of these mutations or none (less than 10% death or recurrence). This might allow for prediction of patient outcome and therefore individualized therapy depending on the tumor’s molecular profile.
Click Here to Manage Email Alerts