GERMLINE MUTATIONS OF THE P53 TUMOR-SUPPRESSOR GENE IN CHILDREN AND YOUNG-ADULTS WITH 2ND MALIGNANT NEOPLASMS
GERMLINE MUTATIONS OF THE P53 TUMOR-SUPPRESSOR GENE IN CHILDREN AND YOUNG-ADULTS WITH 2ND MALIGNANT NEOPLASMS
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DOI：
10.1056/nejm199205143262002
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发表时间：
1992-05-14
影响因子：
158.5
通讯作者：
STRONG, LC
中科院分区：
文献类型：
--
作者：
MALKIN, D;JOLLY, KW;STRONG, LC
背景资料。已在包括结肠癌、乳腺癌和肺癌在内的几种人类癌症中检测到p53肿瘤抑制基因的获得性突变。该基因的遗传突变(通过胚系传播)可能是Li-Fraumeni综合征的基础，Li-Fraumeni综合征是年轻女性乳腺癌、儿童肉瘤和其他恶性肿瘤的一种罕见的家族性关联。我们调查了胚系中P53突变与第二原发癌相关的可能性，这些第二原发癌发生在儿童和年轻人中，他们不被认为属于Li-Fraumeni家族。从59名患有第二原发癌的儿童和年轻人的血白细胞中提取基因组DNA。采用聚合酶链式反应结合变性凝胶电泳法和测序法对p53基因突变进行检测。在59例患者中，有4例(6.8%)的白细胞DNA中发现了改变预测氨基酸序列的P53突变。在三个案例中，突变与之前在p53基因中发现的突变相同。第四个突变是在密码子325的外显子9上发现的第一个生殖系突变。对其中三名患者近亲的白细胞DNA分析表明，突变是遗传的，但在研究开始时，父母中只有一人患上了癌症。这些发现确定了一个重要的年轻癌症患者亚群，他们携带着p53肿瘤抑制基因的胚系突变，但他们的家族史并不表明有Li-Fraumeni综合征的迹象。及早检测到这种突变不仅有助于治疗这些患者，还有助于识别可能有高风险患肿瘤的家庭成员。
Background. Acquired mutations in the p53 tumor-suppressor gene have been detected in several human cancers, including colon, breast, and lung cancer. Inherited mutations (transmitted through the germline) of this gene can underlie the Li-Fraumeni syndrome, a rare familial association of breast cancer in young women, childhood sarcomas, and other malignant neoplasms. We investigated the possibility that p53 mutations in the germline are associated with second primary cancers that arise in children and young adults who would not be considered as belonging to Li-Fraumeni families.Methods. Genomic DNA was extracted from the blood leukocytes of 59 children and young adults with a second primary cancer. The polymerase chain reaction, in combination with denaturant-gel electrophoresis and sequencing, was used to identify p53 gene mutations.Results. Mutations of p53 that changed the predicted amino acid sequence were identified in leukocyte DNA from 4 of the 59 patients (6.8 percent). In three cases, the mutations were identical to ones previously found in the p53 gene. The fourth mutation was the first germline mutation to be identified in exon 9, at codon 325. Analysis of leukocyte DNA from close relatives of three of the patients indicated that the mutations were inherited, but cancer had developed in only one parent at the start of the study.Conclusions. These findings identify an important subgroup of young patients with cancer who carry germline mutations in the p53 tumor-suppressor gene but whose family histories are not indicative of the Li-Fraumeni syndrome. The early detection of such mutations would be useful not only in treating these patients, but also in identifying family members who may be at high risk for the development of tumors.