A new paper, published in the journal Nature Communications, reports that researchers have mapped the “genomic landscape” of these rare childhood tumors. The discovery could lead to better identification of malignant pediatric adrenocortical tumors, and ultimately to better treatment.

The first genomic mapping of childhood adrenocortical tumors has revealed unprecedented details of the aberrant genetic and chromosomal changes that drive the cancer. Understanding these data that drives tumors is critical because of the difficulty in reliably classifying which childhood adrenocortical tumors would prove to be malignant. Currently, about half of children with these tumors remain cancer-free after treatment, and those with advanced cancers have very poor overall survival.

The new mapping would offer a clue for identifying good markers to establish a prognosis. Searching good markers is a key point to predict the risk of cancer, which broaden the normal concept where larger tumors have a worse outcome than smaller ones.

Key mutations pinpointed

A participant said, “Pediatric adrenocortical tumors had never been analyzed on a genomic scale before. After sequencing the genomes of the tumor and blood samples from the 37 patients with early-to-late stage disease, my team pinpointed key mutations involved in these tumors as well as their timing in cancer development.

One key genetic mutation was found in the gene called TP53, which stands on chromosome 17p. TP53 acts as a “brake” on cell division under stress conditions, so its inactivation by mutation would unleash the uncontrolled proliferation of cancer cells.

A key molecular event uncovered by the study occurs on chromosome 11. This chromosome harbors a gene called IGF2, which expresses a protein from the paternal allele that promotes cell growth. Analysis of genomic DNA revealed the selective loss of the maternal chromosome 11 and duplication of paternal chromosome 11 in the pediatric adrenocortical tumors, leading to the continuous high expression of the IGF2 protein and abnormal cell growth.

With the chromosome 11 abnormality plus the TP53 mutation, the patients would be lost the brakes and stepped on the accelerator at the same time. Additionally, the genomic analysis also yielded the timing of these molecular events, the chromosomal 17 and 11 abnormalities, for instance, occurred early in tumor development, indicating a fundamental role for these genetic alterations in triggering tumor development.

Determining the prognosis

The genetic and chromosomal data on the cancers’ genetic landscape offer a highly promising research pathway to understanding the biology and evolution of childhood adrenocortical tumors. This research focuses on determining whether the genomic abnormalities distinguished by researchers have clinical value in determining the prognosis for these tumors.

In particular, the research team wants to confirm in a larger group of patients that a specific combination of mutations in genes called ATRX and TP53 do lead to more aggressive tumors with poorer prognosis.

The researchers said their studies may also lead to insights into other childhood cancers that also show deregulation of chromosome 11 and over-activity of IGF2, such as rhabdomyosarcoma, Wilms tumor and hepatoblastoma.

The findings also offer considerable promise for improving the treatment of childhood adrenocortical tumors. The study reveals tumor cases with more chaotic molecular changes that will require a different treatment approach.  A key to improving treatment will be using the new genomic knowledge to develop mouse models that would enable more systematic testing, not only of existing therapies, but new ones.

Reference：

Genomic landscape of paediatric adrenocortical tumours. Nature Communications, 2015; 6: 6302