Abstract P2-07-04: HER2 overexpressing breast cancers are more frequent in carriers of TP53 DNA-binding domain mutations than in carriers of oligomerization-site mutations

Abstract

Abstract Germline TP53 mutations are associated with Li-Fraumeni Syndrome (LFS), an autosomal dominant disorder characterized by predisposition to multiple early-onset cancers including breast cancer (BC), the most prevalent tumor among women. The majority of germline TP53 mutations are missense substitutions clustered within the DNA-binding domain of the gene that disrupt the structure and function of the protein. Recently, the germline mutation p.R337H (c.1010G>A), lying in the oligomerization domain of p53, was reported at a high frequency in Southern and Southeastern Brazil. This mutation appears to result in a more subtle defect in the protein, which becomes functionally deficient only under particular conditions and specific tissues. Recent reports suggest that BC are HER2-postive in a high proportion (63-83%) of TP53 mutation carriers. Histopathologic features of breast cancers among carriers of oligomerization domain mutations have not been reported. Our objective was to analize HER2 status in breast cancers from carriers of germline TP53 mutations, both in the DNA-binding and oligomerization domains. We retrospectively reviewed the immunohistochemistry data of breast cancers from 64 carriers of TP53 p.R337H and 6 carriers of nonfunctional germline TP53 mutations (p.G245S, p.R273H, p.G244D or c.672+1G>T). All patients were recruited from the cancer genetics clinic at Hospital de Clínicas de Porto Alegre, Brazil. Germline TP53 mutations were identified by Sanger sequencing of the entire coding sequence and flanking intronic regions. Immunohistochemistry (IHC) was performed using standard procedures. HER2 expression was assessed using a 0 to 3+ scale according the ASCO-CAP Guidelines. All of the six patients with nonfunctional TP53 mutations showed strong (3+) HER2 staining by IHC in their breast tumors. In the group of p.R337H carriers, 23.4% showed significant HER2 overexpression (3+), 21.9% presented ambiguous HER2 results (2+), and 54.7% showed weak or no HER2 expression (1+ or 0). Thus, HER2 overexpressing breast cancers were more frequent in carriers of TP53 nonfunctional (DNA binding domain) mutations (p≤0.001) than in those carrying the oligomerization domain mutation. Preliminary results from this study suggest that germline mutations in different domains of the TP53 gene may predispose to breast cancer through different mechanisms. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-07-04.