TP53p.R337H is a conditional cancer-predisposing mutation: further evidence from a homozygous patient

Abstract

BackgroundAdrenocortical carcinomas (ACCs) are among the most common childhood cancers occurring in infants affected with the Li-Fraumeni and Li- Fraumeni-like (LFS/LFL) syndromes, which are caused by dominant germline mutations in the TP53 gene. In Brazil, a particular mutation, occurring in the tetramerisation domain of the gene, p.R337H, is exceedingly common due to a founder effect and is strongly associated with ACC. In this report, we describe the phenotype and long-term clinical follow-up of a female child diagnosed with ACC and homozygous for the TP53 p.R337H founder mutation.Case presentationAt age 11 months, the patient was diagnosed with a virilising anaplastic adrenal cortical tumour, which was completely excised without disturbing the adrenal capsule. Family history was consistent with an LFL tumour pattern, and genotyping identified the TP53 p.R337H mutation in both alleles in genomic DNA from lymphocytes and fibroblasts. Haplotype analysis confirmed the occurrence of the mutation in the same founder haplotype previously described in other Brazilian patients. No other germline or somatic TP53 mutations or rearrangements were identified. At age 9 years, the child was asymptomatic and had no evidence of endocrine derangements. Full body and brain magnetic resonance imaging (MRI) failed to detect any suspicious proliferative lesions, and cardiopulmonary exercise testing results were within the normal reference for the child’s age, ruling out a major exercise capacity deficiency.ConclusionThis is the first clinical and aerobic functional capacity documentation of a patient who carries two mutant TP53 alleles and no wild-type allele. Our results support the hypothesis that TP53 p.R337H, the most common TP53 mutation ever described in any population, is a conditional mutant. Furthermore, our observations over a long period of clinical follow-up suggest that TP53 p.R337H homozygotes do not have a more severe disease phenotype than do heterozygote carriers of the same mutation. Patients with the homozygous TP53 p.R337H genotype will require careful surveillance for lifetime cancer risk and for effects on metabolic capacity later in life.

Prevalence of the TP53 p.R337H Mutation in Breast Cancer Patients in Brazil

“…Therefore, once tuned to mutant phenotype in a pH-dependent manner, this protein may interfere with p53 oligomerization in a way that may prevent the assembly of wild-type p53 complexes, thus making it unnecessary to eliminate the wild-type allele through LOH. This hypothesis may also account for the observation that tumor patterns in subjects who have inherited two mutant alleles are not more severe than in heterozygote carriers [31]. While the exact disease-causing mechanism of the p.R337H mutation remains elusive, alternative hypotheses should be considered, such as the influence of environmental changes onto pH and occurrence of constant, more subtle changes to oligomerisation in vivo without the requirement for drastic pH changes.…”

Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies

“…[13][14][15][16][17][18][19][20][21][22] TP53 mutations have been reported in ACC at frequencies ranging from 10% to 70% and have been associated with decreased disease-free survival and poor outcomes. [23][24][25][26] Germline TP53 mutations have also been linked with the development of ACC, particularly in paediatric patients with a family history of LFS and Li-Fraumeni-like Syndrome. 26 In this study, the mean age of the patients with ACC with and without TP53 mutation was 59.4 years versus 50.2 years, respectively, and no TP53-mutated ACC was identified in a patient younger than 46 years.…”

“…[23][24][25][26] Germline TP53 mutations have also been linked with the development of ACC, particularly in paediatric patients with a family history of LFS and Li-Fraumeni-like Syndrome. 26 In this study, the mean age of the patients with ACC with and without TP53 mutation was 59.4 years versus 50.2 years, respectively, and no TP53-mutated ACC was identified in a patient younger than 46 years. Patient-matched normal specimens required to definitively determine the germline status of TP53 mutation were not available for this study.…”

Szlaki molekularne w raku kory nadnercza — od wiedzy o sygnalizacji komórkowej do metod diagnostyki i leczenia

“…Pomimo wcześniejszych alternatywnych teorii, ostatnie badania potwierdzają, że wysoki współczyn-nik występowania tej mutacji u około 0,3% populacji tego regionu wynika z wystąpienia efektu założyciela w populacji Brazylii. W południowej Brazylii częstość występowania ACC u dzieci jest 10-15-krotnie wyższa niż w innych częściach świata i jest silnie związana z mutacją p.R337H [115][116][117].…”

“…Despite the previous alternative theories, a recent study has confirmed that the high prevalence of this mutation, around 0.3% in the population of this region, results from the occurrence of a founder effect in the Brazilian population. In Southern Brazil the incidence of childhood ACC is 10-15 higher compared with other parts of the world, being strongly associated with the p.R337H mutation [115][116][117].…”