St Jude: In an advance that could lead to better identification of malignant
pediatric adrenocortical tumors, and ultimately to better treatment,
researchers have mapped the “genomic landscape” of these rare childhood
tumors. Their genomic mapping has revealed unprecedented details, not
only of the aberrant genetic and chromosomal changes that drive the
cancer, but the sequence of those changes that trigger it.
The study was led by Raul Ribeiro, M.D., Jinghui Zhang, Ph.D., and
Gerard Zambetti, Ph.D., all members respectively, of the Departments of
Oncology, Computational Biology and Pathology at St. Jude Children’s
Research Hospital. The researchers published their findings online today
in the journal Nature Communications. First authors of the paper were
Emilia Pinto, Ph.D., St. Jude Pathology, and Xiang Chen, Ph.D., St. Jude
Computational Biology.
Understanding the genetic machinery that drives these tumors is
critical because of the difficulty in reliably classifying which
childhood adrenocortical tumors would prove to be malignant. Currently,
only about half of children with these tumors remain cancer-free after
treatment, and those with advanced cancers have very poor overall
survival.
“We haven’t had any good markers to establish a prognosis,” Ribeiro
said. “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.”
Zambetti said scientists in the field had identified only a few
genetic markers that seemed to predispose children to these tumors.
“Pediatric adrenocortical tumors had never been analyzed on a genomic
scale before,” Zambetti said. When the researchers sequenced the
genomes of the tumor and blood samples from the 37 patients with
early-to late-stage disease, they pinpointed key mutations involved in
these tumors as well as their timing in cancer development.
One key genetic mutation was detected in the gene called TP53, which
resides 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 second 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 from the patients and their parents by Pinto
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, you’ve
lost the brakes and stepped on the accelerator at the same time,”
Zambetti said.
The genomic analysis also yielded the timing of these molecular
events. Bioinformaticists Chen and Zhang determined that the chromosomal
17 and 11 abnormalities occur early in tumor development, indicating a
fundamental role for these genetic alterations in triggering tumor
development.
According to Ribeiro, data on the cancers’ genetic landscape offer a
highly promising research pathway to understanding the biology and
evolution of childhood adrenocortical tumors. “Our focus now will be to
determine whether the genomic abnormalities we have distinguished have
clinical value in determining the prognosis for these tumors,” he said.
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,”
Zambetti said.
The other authors are John Easton, David Finkelstein, Zhifa Liu,
Stanley Pounds, Kristy Boggs, Donald Yergeau, Jinjun Cheng, Heather
Mulder, Jayanthi Manne, Jesse Jenkins, Michael Dyer, Alberto Pappo and
James Downing, all of St. Jude; Carlos Rodriguez-Galindo, of Harvard
Medical School, Boston; Troy Lund, of University of Minnesota Medical
School, Minneapolis; Elaine Mardis and Richard Wilson, both of
Washington University School of Medicine, St. Louis; Maria Mastellaro,
of Boldrini Children’s Research Hospital, Campinas, Brazil; and Bonald
Figueiredo, of Instituto de Pesquisa Pele Pequeno Prıncipe, Curitiba,
Brazil.
This work was supported in part by the St. Jude Children’s Research
Hospital—Washington University Pediatric Cancer Genome Project,
including Kay Jewelers, a lead sponsor; a grant (CA21765) from the
National Cancer Institute at the National Institutes of Health (NIH);
grants (EY014867, EY018599 and CA168875) from NIH; and ALSAC.
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