Healio
Healio
February 14, 2011
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Novel p53 mutations identified in children with adrenocortical carcinoma

Canadian Pediatric Endocrine Group

TORONTO — The severity of a mutation of p53 may affect the presentation of disease in children with adrenocortical carcinoma, according to preclinical research presented here at the Canadian Pediatric Endocrine Group 2011 Scientific Meeting.

Adrenocortical carcinoma is a rare condition that affects 0.4 per million children worldwide, said Jonathan Wasserman, MD, PhD, a clinical fellow at the Hospital for Sick Children in Toronto. Mortality rates are high; however, limited treatment options exist.

About 50% to 80% of children with adrenocortical carcinoma have germline mutations in the p53 tumor suppressor gene, according to previous research. Wasserman and colleagues conducted a study to evaluate the prevalence and spectrum of p53 mutations in a large cohort of children who had adrenocortical carcinoma.

The researchers found that 50% of children with adrenocortical carcinoma carried a heterozygous mutation in p53. Only two mutations were detected more than once in the cohort. According to the researchers, this finding contrasts with the observation that six hotspot mutations in families with Li-Fraumeni syndrome account for about 20% of patients with p53 mutations. Li-Fraumeni syndrome is a familial cancer predisposition syndrome strongly associated with germline p53 mutation.

Overall, the researchers identified several novel mutations in the children with adrenocortical carcinoma, showing either full p53 function or partial loss of function.

"We are beginning to get a better picture regarding the function or loss of function of this particularly crucial gene," Wasserman said during the oral abstract session. "When the mutation is much more severe, children appear to be affected with multiple primary tumors."

Mutations that are milder seem to have effects restricted to the adrenal gland, Wasserman said.

"It is important to try to understand if the adrenal gland is particularly vulnerable to this loss of function and requires less of a 'hit' in p53 compared to some of the other tissues that require a significant amount of function to be lost before they develop tumors," he said. "This may allow us to give patients better expectations of how likely they are to develop other tumors or recurrence of tumors. We cannot yet say that based on the data we have."

Genome-wide analysis is under way to identify disease-modifying loci and pathogenic loci in children with normal p53 genes. The Hospital for Sick Children offers testing and counseling for first-degree relatives of those who test positive for p53 mutations. – by Louise Gagnon

For more information:

Disclosure: Dr. Wasserman reports no relevant financial disclosures.

PERSPECTIVE

The discovery of novel variants is fascinating, and the variants need to be tracked down. The issue of screening for the p53 mutation in first-degree family relatives is a sensitive one and should be restricted to experimental protocols. Typically, screening is conducted when clinicians can influence morbidity and mortality. There is no good evidence-based medicine that the benefits outweigh the risks [of screening for p53 mutations], particularly when there is not 100% penetrance.

– Cheri Deal, MD, PhD
Professor of Medicine, University of Montreal
President, Canadian Society for Endocrinology and Metabolism

Disclosure: Dr. Deal has been a speaker for Pfizer, Eli Lilly, EMD Serono and Novo Nordisk.

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