TP53 p.Arg337His geographic distribution correlates with adrenocortical tumor occurrence

Abstract

Background The p.Arg337His mutation of the TP53 is the most frequent germline missense variant associated with cancer described so far in this gene. It is mainly found in the South and Southeastern regions of Brazil, where it has been associated with a high incidence of pediatric adrenocortical (ACT) and choroid plexus tumors. The frequency and geographic distribution of this mutation is largely unknown, except for the Parana State, where a mean prevalence of 0.27% was reported. In the present study, we developed a high‐throughput method for p.Arg337His genotyping, what allowed us to determine the frequency and geographic distribution of this mutation in a cohort from the most populous state in Brazil. Methods Consecutive samples from 31,612 newborns from São Paulo State were screened for p.Arg337His. The allelic discrimination was done by real‐time polymerase chain reaction (PCR) and the presence of haplotype A3 in carriers was examined by using allele‐specific oligonucleotide PCR, followed by nested‐PCR to detect the SNP rs9894946. Results We found 67 (0.21%) samples positive for this mutation. The highest p.Arg337His frequencies were found in the cities close to the boundary between São Paulo and Minas Gerais State. No association could be found between p.Arg337His and gender, ethnicity, premature birth or twinning. Remarkably, a trend was found between the geographic distribution of p.Arg337His carriers and occurrence of ACT. Conclusion We presented for the first time the p.Arg337His frequency among individuals unselected for any disease from a subset of the São Paulo State, the most populous in Brazil. The allele discrimination assay we presented here has proven to be a reliable and efficient method for high‐throughput genotyping. ACT was found to be a good sentinel cancer to suppose p.Arg337His presence in our region.

Adrenocortical Carcinoma in Childhood: A Systematic Review

“…A total of 29 cases of secondary malignancies/neoplasia were described [ 7 , 40 , 48 , 60 , 61 , 66 , 74 , 79 , 84 , 92 ], including the following entities: astrocytoma ( n = 4), osteosarcoma ( n = 3), liposarcoma ( n = 2), hepatoblastoma, chondrosarcoma, amelanotic melanoma, non-Hodgkin lymphoma, optic nerve glioma, kidney cell carcinoma, contralateral ACC, and choroid plexus papilloma ( n = 1 each), as well as lipoma ( n = 3) and hemangioma ( n = 2) as benign neoplasias. Even if there are only sporadic reports, nationwide analyses and genomic profiles [ 11 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 ] hypothesize that the number of CPSs may be much higher than thought, and genetic counseling should be recommended to all parents and legal guardians of pediatric patients with ACC.…”

What 20 years of research has taught us about the TP53 p.R337H mutation

“…21 Another study assessed the frequency of the TP53 p.R337H variant by screening 32,130 newborns from São Paulo State, and it found that 68 (0.21%) were carriers. 22 These studies 21,22 have established that the germline TP53 p.R337H variant is widespread in South and Southeast Brazil and occurs at a population frequency of 0.3%. Although these original studies have not addressed the constitutive haplotype, screening haplotype-defining variants in newborns (n = 42,538) with an unknown history of cancer from South Brazil showed that 69% of p.R337H carriers also have the XAF1 p.E134* variant in the same haplotype.…”

“…In the largest population‐based screening study, 171,649 newborns from Paraná State were genotyped, and the p.R337H variant was identified in 461 patients (0.27%) 21 . Another study assessed the frequency of the TP53 p.R337H variant by screening 32,130 newborns from São Paulo State, and it found that 68 (0.21%) were carriers 22 . These studies 21,22 have established that the germline TP53 p.R337H variant is widespread in South and Southeast Brazil and occurs at a population frequency of 0.3%.…”

Clinical and molecular characterization of patients fulfilling Chompret criteria for Li-Fraumeni syndrome in Southern Brazil

“…In more recent studies, prevalence of TP53 PV heterozygotes was proposed to reach 0.2% in Europeans [ 5 , 6 ]. In addition, a germline TP53 founder PV, c.1010G>A (p.Arg337His), widely referred as R337H, has been reported in Southern Brazil at a frequency of 1 in approximately 300 newborns [ 7 – 9 ], but tumor penetrance appears to be lower than that observed in carriers of DNA-binding domain (DBD) PV [ 10 – 13 ]. The arginine residue at codon 337 is involved in the protein oligomerization and functional data have shown that its replacement with histidine disrupts the tetramer form, making the domain unable to fully oligomerize in conditions of slightly elevated pH [ 14 ].…”