A novel TP53 germline inframe deletion identified in a Spanish series of Li-fraumeni syndrome suspected families

AbstractLi-Fraumeni syndrome (LFS) is an autosomal dominant, inherited tumor predisposition syndrome associated with heterozygous germline mutations in theTP53 gene. The molecular diagnosis of LFS is important to develop strategies for early detection and access to the genetic counseling. Our study evaluated germlineTP53 mutations in Spanish families with a history suggestive of LFS. GermlineTP53 alterations in 22 families with a history suggestive of LFS were evaluated by Sanger sequencing and multiplex ligation-dependent probe amplification. Loss of heterozygosity analysis and immunohistochemistry of the protein in the tumor were performed in order to evaluate the pathogenicity of a novel alteration detected. A total of sevenTP53 mutations were detected, six point mutations (4 missense and 2 nonsense) and a novel inframe deletion. 93% of mutation carriers developed at least one malignancy (mainly breast cancer and sarcomas), with a mean age at diagnosis of the first tumor of 30.2 years. Two missense mutations acted as dominant-negative. The novel inframe mutation c.437_445del was located in the DNA-binding domain. This mutation segregated with cancer in the family, and both high expression of the protein and loss of the wild-typeTP53 allele were detected in the tumor of the carrier. We have found a novel inframe deletion inTP53 that likely results in the loss of p53 function and acts in a non-dominant negative way, although further studies are necessary to clarify this issu...
Source: Familial Cancer - Category: Cancer & Oncology Source Type: research