Sun X F, Johannsson O, Håkansson S, Sellberg G, Nordenskjöld B, Olsson H, Borg A
Department of Oncology, University Hospital, Linköping, Sweden.
Oncogene. 1996 Jul 18;13(2):407-11.
Germline mutations in the p53 tumor suppressor gene are associated with the Li-Fraumeni syndrome, characterized by childhood sarcoma, leukemia and early onset breast cancer and has occasionally been found also in familial breast-ovarian cancer. Most mutations found are of missense type and located in the central region of the gene (exons 5 to 8). In the present study, a germline p53 alteration was identified in a late onset breast cancer family (kindred Lund 5; mean age 58 years) using single stranded conformation polymorphism and sequence analysis. The mutation (a CCG to CTG transition) at codon 82 in exon 4, resulting in a proline to leucine substitution, has not previously been reported and was not present in a control set of 60 healthy individuals. Three of five woman with breast cancer (45, 57 and 65 years) were carriers of the alteration. Loss of heterozygosity at the p53 locus was not seen in the primary tumors of these women, but appeared as a partial loss of the wildtype allele in subsequent recurrent lesions of two gene carriers. The family manifested no linkage to the p53 gene (a two-point LOD-score of -0.41), and has previously also been excluded for linkage to the BRCA1 and BRCA2 loci, as well as being carrier of a BRCA1 germline mutation. Although it seems unlikely that the p53 germline mutation is the major cause of disease predisposition in Lund 5, the data suggest that some p53 alteration may confer a subtle influence on breast cancer development and progression.
p53肿瘤抑制基因的种系突变与李-佛美尼综合征相关，其特征为儿童期肉瘤、白血病和早发性乳腺癌，偶尔也在家族性乳腺-卵巢癌中发现。发现的大多数突变是错义型，位于基因的中央区域（外显子5至8）。在本研究中，使用单链构象多态性和序列分析，在一个晚发性乳腺癌家族（伦德5家族；平均年龄58岁）中鉴定出一种种系p53改变。外显子4中第82密码子的突变（CCG到CTG的转换）导致脯氨酸被亮氨酸取代，此前未见报道，在60名健康个体的对照组中也不存在。五名乳腺癌女性（45岁、57岁和65岁）中有三名是这种改变的携带者。在这些女性的原发性肿瘤中未观察到p53基因座的杂合性缺失，但在两名基因携带者随后的复发病变中表现为野生型等位基因的部分缺失。该家族与p53基因无连锁关系（两点LOD分数为-0.41），此前也已排除与BRCA1和BRCA2基因座的连锁关系，并且不是BRCA1种系突变的携带者。尽管p53种系突变似乎不太可能是伦德5家族疾病易感性的主要原因，但数据表明，某些p53改变可能对乳腺癌的发生和发展产生微妙影响。
