An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma

doi:10.1073/pnas.161479898

An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma

Departments of ^aHematology-Oncology and ^gBiochemistry and the ^bInternational Outreach Program, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105; Departments of ^cPediatrics and ^hBiochemistry, University of Tennessee College of Medicine, Memphis, TN 38101; ^jDNA Profiling Laboratory, Gene Logic, Inc., Gaithersburg, MD 20878; ⁱUnit on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892; and Departments of ^ePediatrics and ^lPathology and the ^fDivision of Endocrinology, Clinics Hospital, Federal University of Paraná, Curitiba 80060-90 Brazil

Edited by Alfred G. Knudson, Jr., Institute for Cancer Research, Philadelphia, PA, and approved June 8, 2001 (received for review October 10, 2000)

Abstract

The incidence of pediatric adrenal cortical carcinoma (ACC) in southern Brazil is 10–15 times higher than that of pediatric ACC worldwide. Because childhood ACC is associated with Li-Fraumeni syndrome, we examined the cancer history and p53 status of 36 Brazilian patients and their families. Remarkably, 35 of 36 patients had an identical germ-line point mutation of p53 encoding an R337H amino acid substitution. Differences within intragenic polymorphic markers demonstrated that at least some mutant alleles arose independently, thus eliminating a founder effect. In tumor cells, the wild-type allele was deleted, and mutant p53 protein accumulated within the nuclei. Although these features are consistent with Li-Fraumeni syndrome-associated adrenal tumors, there was no history of increased cancer incidence among family members. Therefore, this inherited R337H p53 mutation represents a low-penetrance p53 allele that contributes in a tissue-specific manner to the development of pediatric ACC.

Footnotes

↵ d To whom reprint requests should be addressed. E-mail: raul.ribeiro{at}stjude.org.
↵ k Present address: Genaissance Pharmaceuticals, Inc., 5 Science Park, New Haven, CT 06511.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

ACC,

adrenal cortical carcinoma;

CMV,

cytomegalovirus