Penetrance of the TP53 R337H Mutation and Pediatric Adrenocortical Carcinoma Incidence Associated with Environmental Influences in a 12-Year Observational Cohort in Southern Brazil

Abstract

The TP53 R337H mutation is associated with increased incidence of pediatric adrenocortical tumor (ACT). The different environmental conditions where R337H carriers live have not been systematically analyzed. Here, the R337H frequencies, ACT incidences, and R337H penetrance for ACT were calculated using the 2006 cohort with 4165 R337H carriers living in Paraná state (PR) subregions. The effectiveness of a second surveillance for R337H probands selected from 42,438 tested newborns in PR (2016 cohort) was tested to detect early stage I tumor among educated families without periodical exams. Estimation of R337H frequencies and ACT incidence in Santa Catarina state (SC) used data from 50,115 tested newborns without surveillance, ACT cases from a SC hospital, and a public cancer registry. R337H carrier frequencies in the population were 0.245% (SC) and 0.306% (PR), and 87% and 95% in ACTs, respectively. The ACT incidence was calculated as ~6.4/million children younger than 10 years per year in PR (95% CI: 5.28; 7.65) and 4.15/million in SC (CI 95%: 2.95; 5.67). The ACT penetrance in PR for probands followed from birth to 12 years was 3.9%. R337H carriers living in an agricultural subregion (C1) had a lower risk of developing pediatric ACT than those living in industrial and large urban subregion (relative risk = 2.4). One small ACT (21g) without recurrence (1/112) was detected by the parents in the 2016 cohort. ACT incidence follows R337H frequency in each population, but remarkably environmental factors modify these rates.

Frequency of the TP53 R337H variant in sporadic breast cancer and its impact on genomic instability

“…We also conducted a comprehensive computational analysis to determine the impact of the TP53 R337H variant on genomic instability, evaluating both the breast tumor tissue of the patients and homozygous (R337H+/ R337H+) and heterozygous (Wt/R337H+) fibroblast cell cultures established from a patient with adrenocortical cancer and a variant carrier, respectively. The frequency of the TP53 R337H variant was observed in 2.36% of the sporadic breast cancer cases we evaluated, with an increase of 7.71 in genotypic frequency (2.36% versus 0.306%) when considering all 214,087 newborns tested by Custódio et al 5 and Costa et al 4 . This is the first report on the R337H genotypic frequency in breast cancer tissue without family history of cancer in Paraná state.…”

“…The R337H was first reported in the southern region of Brazil as a germline variant in pediatric patients with adrenocortical tumors (ACTs), where it was identified in 95% of the cases 2 . It was later characterized as a low penetrance TP53 variant 3 , 4 . Large population studies evaluating the presence of TP53 R337H in the state of Paraná in southern Brazil revealed its presence in 0.27% 5 and 0.306% 4 of 214,087 tested newborns.…”

A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence

“…3,4 Newborn screening for the R337H in Southern and South-eastern Brazil showed that this mutation has a frequency of 0.21-0.30%. [5][6][7] This mutation is responsible for the increased incidence of paediatric ACC in Paraná state (3.4 per million before the age 15 years per year compared to 0.3 per million in the USA, or 6.4/million children younger than 10 years per year). 2,5 A hospital-based cohort estimated that the penetrance of this mutation for paediatric ACC is 10%.…”

“…8 However in a large population-based cohort, the penetrance for paediatric ACC is less than 5%, whilst the overall cancer risk among females and males is less than 50% before the seventh decade. 5,7 The frequency of R337H prevalence among paediatric ACC varies from 75-96%, and is nearly 15% among adult ACC in Southern and South-eastern Brazil. 7,9,10 The phenotypic heterogeneity among R337H carriers in terms of cancer risk and the variability in age-of-onset may indicate the involvement of environmental and/or genetic variants that are able to modulate cancer development.…”

“…5,7 The frequency of R337H prevalence among paediatric ACC varies from 75-96%, and is nearly 15% among adult ACC in Southern and South-eastern Brazil. 7,9,10 The phenotypic heterogeneity among R337H carriers in terms of cancer risk and the variability in age-of-onset may indicate the involvement of environmental and/or genetic variants that are able to modulate cancer development. 5,7 The enormous heterogeneity in cancer development noted in families carrying the germline R337H mutation 5 has prompted us to gain further insight into potential genetic factors cooperating to modify the agedependent incidence of cancer onset in the adrenal cortex.…”