Molecular Biology Laboratory, Boldrini Children's Center, Campinas, Sao Paulo, Brazil.
Cancer. 2011 May 15;117(10):2228-35. doi: 10.1002/cncr.25826. Epub 2010 Dec 29.
The inherited, low-penetrance arginine-to-histidine substitution at codon 337 (R337H) of the tumor protein 53 gene (TP53) is clustered in southeast Brazil (estimated frequency, 0.3%). Although its tumorigenic effect initially appeared to be tissue-specific, recent evidence suggests its association with a broader range of tumors. Therefore, the authors of this report investigated the spectrum of pediatric malignancies associated with the TP53 R337H mutation at a single referral institution in southeast Brazil.
Genomic DNA samples from 493 children with malignancies were screened for the R337H mutation. Available tumor samples from carriers were investigated for loss of heterozygosity (LOH) and nuclear p53 accumulation. Clinical data were obtained from medical records.
Sixty-five of 70 patients (93%) with adrenocortical tumors (ACTs), 9 of 13 patients (69%) with choroid plexus carcinoma (CPC), and 3 of 41 patients (7.3%) with osteosarcoma carried the mutation. The proportion of CPC to choroid plexus papilloma (CPP) was much higher than that reported elsewhere. Osteosarcoma in carriers had a significantly poorer outcome (P = .02). The mutation was not identified in patients who had acute lymphoblastic leukemia (ALL) (n = 187), recurrent ALL (n = 49), acute myeloid leukemia (n = 44), lymphoma (n = 30), non-CPC central nervous system tumors (n = 26), Ewing sarcoma (n = 25), or rhabdomyosarcoma (n = 8). Among the tumors that were available for analysis, LOH with retention of the mutant allele was confirmed in 21 of 21 ACTs, in 2 of 2 CPCs, and in 2 of 3 osteosarcomas that were positive for R337H. CPCs and osteosarcomas that were positive for R337H had marked nuclear accumulation of p53.
The current findings demonstrated compellingly that the TP53 R337H mutation is associated not only with ACT but also with CPC and, to a lesser extent, with osteosarcoma, both of which are core-component tumors of the Li-Fraumeni syndrome.
肿瘤抑制基因 53 蛋白（TP53）第 337 密码子由精氨酸突变为组氨酸的遗传低外显率（R337H）在巴西东南部聚集（估计频率为 0.3%）。尽管其最初的致瘤作用似乎具有组织特异性，但最近的证据表明其与更广泛的肿瘤有关。因此，本报告的作者在巴西东南部的一家转诊机构中研究了与 TP53 R337H 突变相关的儿科恶性肿瘤谱。
对 493 名患有恶性肿瘤的儿童的基因组 DNA 样本进行 R337H 突变筛查。对突变携带者的可用肿瘤样本进行杂合性丢失（LOH）和核 p53 积聚的检测。从病历中获取临床数据。
65 例（93%）肾上腺皮质肿瘤（ACTs）、13 例（69%）脉络丛癌（CPC）和 41 例（7.3%）骨肉瘤患者携带该突变。CPC 与脉络丛乳头瘤（CPP）的比例远高于其他地方报道的比例。携带突变的骨肉瘤患者的预后明显较差（P=0.02）。未在急性淋巴细胞白血病（ALL）患者（n=187）、复发性 ALL（n=49）、急性髓细胞白血病（n=44）、淋巴瘤（n=30）、非 CPC 中枢神经系统肿瘤（n=26）、尤因肉瘤（n=25）或横纹肌肉瘤（n=8）中发现该突变。在可进行分析的肿瘤中，21 例 ACTs、2 例 CPCs 和 3 例阳性的骨肉瘤中证实了保留突变等位基因的 LOH，这 3 例骨肉瘤均为 R337H 阳性。CPCs 和 R337H 阳性的骨肉瘤中 p53 核积聚明显。
目前的研究结果有力地表明，TP53 R337H 突变不仅与 ACT 有关，而且与 CPC 有关，在较小程度上与骨肉瘤有关，这两者都是 Li-Fraumeni 综合征的核心肿瘤。
