Grayson G H, Moore S, Schneider B G, Saldivar V, Hensel C H
Department of Pediatrics, University of Texas Health Science Center, San Antonio 78284-7810.
Am J Pediatr Hematol Oncol. 1994 Nov;16(4):341-7.
We report a case of adrenal cortical carcinoma in an infant, which was incidentally discovered by renal sonography after a urinary tract infection. The previous death of a sibling after rhabdomyosarcoma in infancy prompted a search for a heritable p53 tumor suppressor gene mutation in this family.
Starting with frozen adrenal carcinoma tissue, polymerase chain reaction (PCR) amplification followed by direct sequencing of exons 4-8 of p53 was used to search for a mutation. When a mutation was identified in exon 6 of the tumor p53 sequence, PCR amplification and direct sequencing of exon 6 alone was then performed on DNA from peripheral blood lymphocytes (PBLs) of all immediate family members to determine whether a germline mutation was present. A different set of primers was used by a second laboratory at our institution to independently confirm the presence of the mutation in the adrenal carcinoma and in paraffin-embedded rhabdomyosarcoma tissue of the deceased sibling.
A C-to-T transition was identified at a CpG site in codon 196 resulting in a change from arginine to a stop codon (CGA to TGA). The identical mutation, present as the sole p53 allele in the tumor DNA samples and in the heterozygous state with wild type p53 allele in DNA from PBLs (germline), was found in the adrenal carcinoma, the rhabdomyosarcoma, and the PBLs of the tumor-bearing child and her healthy father and 5-year-old brother. This nonsense mutation of p53 has never before been reported in the germline. The extended pedigree showed only one known additional cancer.
A novel germline p53 mutation was identified by investigation of a sibling pair with cancers associated with the Li-Fraumeni syndrome in a family with an otherwise negative history for cancer. The implications of this case for identification of carriers of p53 germline mutations and their clinical management are discussed.
我们报告一例婴儿肾上腺皮质癌，该病例是在尿路感染后通过肾脏超声偶然发现的。该婴儿的一名同胞在婴儿期患横纹肌肉瘤后死亡，促使对该家族进行遗传性p53肿瘤抑制基因突变的筛查。
从冷冻的肾上腺癌组织开始，采用聚合酶链反应（PCR）扩增，随后对p53基因的第4至8外显子进行直接测序以寻找突变。当在肿瘤p53序列的第6外显子中鉴定出突变时，随后对所有直系家庭成员外周血淋巴细胞（PBL）的DNA单独进行第6外显子的PCR扩增和直接测序，以确定是否存在种系突变。我们机构的另一个实验室使用不同的引物组独立确认肾上腺癌和已故同胞石蜡包埋的横纹肌肉瘤组织中突变的存在。
在密码子196的一个CpG位点发现了一个从C到T的转换，导致从精氨酸变为终止密码子（CGA变为TGA）。在肾上腺癌、横纹肌肉瘤以及患肿瘤儿童及其健康父亲和5岁弟弟的PBL中发现了相同的突变，该突变在肿瘤DNA样本中作为唯一的p53等位基因存在，在PBL的DNA中与野生型p53等位基因呈杂合状态（种系）。这种p53的无义突变以前从未在种系中报道过。扩展的家系仅显示一例已知的其他癌症。
通过对一个癌症家族史阴性的家庭中一对患与李-弗劳梅尼综合征相关癌症的同胞进行调查，鉴定出一种新的种系p53突变。讨论了该病例对鉴定p53种系突变携带者及其临床管理的意义。
