TP53 p.R337H is a conditional cancer-predisposing mutation: further evidence from a homozygous patient
1 Genomic Medicine Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
2 Post-Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
3 Pediatric Oncology Service, HCPA, Porto Alegre, Brazil
4 Radiology Service, HCPA, Porto Alegre, Brazil
5 Exercise Pathophysiology Research Laboratory and Cardiology Division, HCPA, Porto Alegre, Brazil
6 Post-Graduate Program in Genetics and Molecular Biology, UFRGS, Porto Alegre, Brazil
7 School of Medicine, UFRGS, Porto Alegre, Brazil
8 Department of Internal Medicine, Faculty of Medicine, UFRGS, Porto Alegre, Brazil
9 Service of Endocrinology, HCPA, Porto Alegre, Brazil
10 Service of Medical Genetics, HCPA, Porto Alegre, Brazil
11 International Prevention Research Institute, Lyon, France
12 Departamento de Genética, UFRGS e Serviço de Genética Médica e Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, 90035-903 Porto Alegre, RS, Brazil
BMC Cancer 2013, 13:187 doi:10.1186/1471-2407-13-187Published: 9 April 2013
Adrenocortical 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.
At 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.
This 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.