Impact of Neonatal Screening and Surveillance for the TP53 R337H Mutation on Early Detection of Childhood Adrenocortical Tumors

Abstract

A B S T R A C T PurposeThe incidence of pediatric adrenocortical tumors (ACTs) is remarkably high in southern Brazil, where more than 90% of patients carry the germline TP53 mutation R337H. We assessed the impact of early detection of this mutation and of surveillance of carriers. Patients and MethodsFree newborn screening was offered at all hospitals in the state of Paraná . Parents of positive newborns were tested, and relatives in the carrier line were offered screening. Positive newborns and their relatives age Ͻ 15 years were offered surveillance (periodic clinical, laboratory, and ultrasound evaluations). ACTs detected by imaging were surgically resected. ResultsOf 180,000 newborns offered screening, 171,649 were screened, and 461 (0.27%) were carriers. As of April 2012, ACTs had been diagnosed in 11 of these carriers but in only two neonatally screened noncarriers (P Ͻ .001); six patient cases were identified among 228 carrier relatives age Ͻ 15 years (total, 19 ACTs). Surveillance participants included 347 (49.6%) of 699 carriers. Tumors were smaller in surveillance participants (P Ͻ .001) and more advanced in nonparticipants (four with stage III disease; two deaths). Neonatally screened carriers also had neuroblastoma (n ϭ 1), glioblastoma multiforme (n ϭ 1), choroid plexus carcinoma (n ϭ 2), and Burkitt lymphoma (n ϭ 1). Cancer histories and pedigrees were obtained for 353 families that included 1,704 identified carriers. ACTs were the most frequent cancer among carrier children (n ϭ 48). ConclusionThese findings establish the prevalence of the TP53 R337H mutation in Paraná state and the penetrance of ACTs among carriers. Importantly, screening and surveillance of heterozygous carriers are effective in detecting ACTs when readily curable.

IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis

“…Interestingly, in response to cellular stress such as oncogene activation, the p53 can shutdown the IGF pathway, reducing IGF2 and IGF1R expression and the receptor tyrosine phosphorylation (Sampaoli et al 2012). Similar to other Brazilian childhood ACT series (Sandrini et al 2005, Custódio et al 2013, we observed high frequency of TP53 p.R337H mutation in tumor samples, but no significant differences in IGF2 or IGF1R expression profiles between samples with or without the mutation.…”

Mutations in BRCA1, BRCA2 and other breast and ovarian cancer susceptibility genes in Central and South American populations

“…We found three articles that studied variations in TP53, all in Brazilian populations [31,84,85]. These articles studied the c.1010G>A (p.R337H) mutation, which occurs at a high frequency in southern and southeastern Brazil [86][87][88][89][90]. Silva et al [31] reported a frequency of 2.5% for this variant and suggested that all BRCA-negative female BC patients with clinical criteria for hereditary breast-ovarian cancer should be tested for the c.1010G>A variant.…”

Population-based strategy for breast cancer screening in Brazil

“…Most of the current evidence comes from studies in Europe and North America (15). Studies in Brazil have shown that a particular mutant, p.R337H, has incomplete penetrance and may be quite common due to a founder effect (estimated frequency in the general population: 1:300 in certain regions) (16)(17)(18)(19). Several studies have assessed p.R337H mutation prevalence in Brazilian BC patients.…”