BMC Cancer. 2013 Apr 9;13:187. doi: 10.1186/1471-2407-13-187.
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.
肾上腺皮质癌（ACC）是婴儿中最常见的儿童癌症之一，这些婴儿患有李-佛美尼（Li-Fraumeni）和李-佛美尼样（Li-Fraumeni-like，LFS/LFL）综合征，这是由 TP53 基因的显性种系突变引起的。在巴西，由于一个奠基者效应，基因的四聚化结构域中发生的特定突变，p.R337H，非常常见，并且与 ACC 强烈相关。在本报告中，我们描述了一名被诊断为 ACC 且 TP53 p.R337H 奠基者突变纯合子的女性儿童的表型和长期临床随访结果。
患儿在 11 个月时被诊断为具有男性化的间变性肾上腺皮质肿瘤，肿瘤完全切除，未破坏肾上腺包膜。家族史符合 LFL 肿瘤模式，基因分型在淋巴细胞和成纤维细胞的基因组 DNA 中发现 TP53 p.R337H 突变存在于两个等位基因中。单体型分析证实了该突变发生在以前在其他巴西患者中描述的相同奠基者单体型中。未发现其他种系或体细胞 TP53 突变或重排。9 岁时，患儿无症状，无内分泌紊乱证据。全身和脑磁共振成像（MRI）未发现任何可疑的增殖性病变，心肺运动试验结果在患儿年龄的正常参考范围内，排除了主要运动能力缺陷。
这是首例携带两个突变 TP53 等位基因和没有野生型等位基因的患者的临床和有氧功能能力的记录。我们的结果支持以下假说，即 p.R337H 是最常见的 TP53 突变，是一种条件性突变。此外，我们在长期临床随访中的观察结果表明，TP53 p.R337H 纯合子的疾病表型并不比具有相同突变的杂合子携带者更严重。携带纯合 TP53 p.R337H 基因型的患者需要终生密切监测癌症风险，并监测其在以后的生活中对代谢能力的影响。
