GENETICS OF PEDIATRIC ADRENOCORTICAL CARCINOMA

In a Children’s Oncology Group study reported in the Journal of Clinical Oncology, Wasserman et al found that germline TP53 mutations are common in children with adrenocortical carcinoma, with mutations encoding proteins with greater loss of function being at increased risk of multiple primary malignancies or a family history of cancer. Adrenocortical carcinoma occurs with excess frequency in Li-Fraumeni syndrome, which results primarily from germline TP53 mutations.

Study Details

Germline TP53 sequencing was performed in 88 consecutive unrelated children unselected for family history. The International Agency for Research on Cancer (IARC) p53 database was used to further analyze mutational distribution, association with family history, and risk for multiple primary malignancies.

Frequency 

After exclusion of carriers of the TP53-R337H allele, TP53 mutations were found in 34 of 68 children (50%). Only 2 of the 34 variants corresponded to conventional TP53 hotspot mutations. Diagnosis of adrenocortical carcinoma before age 12 years was more likely to be associated with germline TP53 mutation than diagnosis in adolescence.

The mutations were associated with a wide range of mutant protein function, with patients with greater protein loss of function being more likely to have multiple primary malignancies or a strong family history of cancer and those with higher protein functionality being less likely to have a strong family cancer history. No patients with wild-type disease had a strong family history of cancer. Among 33 patients with multiple primary malignancies in the study and IARC cohorts, adrenocortical carcinoma was the most frequent initial malignancy, occurring as the first cancer alone or simultaneously with other tumors in 26 patients (79%).

The investigators concluded: “TP53 mutations are prevalent in children with [adrenocortical carcinoma] but decline with age. Mutations result in a broad spectrum of functional loss. Effect of individual mutations may predict carrier and familial disease penetrance, with potentially broad implications for clinical surveillance and counseling.”

Jonathan D. Wasserman, MD, PhD, of The Hospital for Sick Children, Toronto, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by the Canadian Institutes of Health Research, U.S. National Cancer Institute, and American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. The study authors reported no potential conflicts of interest.