Germline TP53 mutations are associated with Li–Fraumeni syndrome, an autosomal dominant disorder characterized by a predisposition to multiple early-onset cancers including breast cancer (BC), the most prevalent tumor among women. The majority of germline TP53 mutations are clustered within the DNA-binding domain of the gene, disrupting the structure and function of the protein. A specific germline mutation in the tetramerization domain of p53, p.R337H, 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. Recent studies show that the BC phenotype in TP53 mutation carriers is often HER2 positive (63–83 %). Considering that the immunophenotype of BC among p.R337H carriers has not been reported, we reviewed immunohistochemistry data of 66 p.R337H carriers in comparison with 12 patients with other non-functional TP53 germline mutation. Although 75 % of carriers of these mutations showed significant HER2 overexpression (3+), corroborating previous studies, only 22.7 % of p.R337H patients had BC overexpressing HER2. These results reinforce the notion that different germline mutations in TP53 may predispose to BC via different mechanisms.
Breast cancer HER2 Li–Fraumeni syndrome TP53p.R337H
This is a preview of subscription content, log in to check access.
Conflict of interest
The authors declare that they have no conflict of interest.
In all cases, patients underwent pre- and post-test genetic counseling and signed an informed consent for genetic testing. Information on mutation status and clinical data necessary for this study were obtained only after approval by the institutional ethics committees.
Malkin D, Li FP, Strong LC et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250(80):1233–1238CrossRefPubMedGoogle Scholar
Li FP, Fraumeni JF, Mulvihill JJ et al (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48:5358–5362PubMedGoogle Scholar
Kleihues P, Schauble B, zur Hausen A et al (1997) Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol 150:1–13PubMedCentralPubMedGoogle Scholar
Olivier M, Goldgar DE, Sodha N et al (2003) Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 63:6643–6650PubMedGoogle Scholar
Petitjean A, Mathe E, Kato S et al (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 28:622–629. doi:10.1002/humu.20495CrossRefPubMedGoogle Scholar
Palmero EI, Schüler-Faccini L, Caleffi M et al (2008) Detection of R337H, a germline TP53 mutation predisposing to multiple cancers, in asymptomatic women participating in a breast cancer screening program in Southern Brazil. Cancer Lett 261:21–25. doi:10.1016/j.canlet.2007.10.044CrossRefPubMedGoogle Scholar
Seidinger AL, Mastellaro MJ, Paschoal Fortes F et al (2011) Association of the highly prevalent TP53 R337H mutation with pediatric choroid plexus carcinoma and osteosarcoma in Southeast Brazil. Cancer 117:2228–2235. doi:10.1002/cncr.25826CrossRefPubMedGoogle Scholar
DiGiammarino EL, Lee AS, Cadwell C et al (2002) A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol 9:12–16. doi:10.1038/nsb730CrossRefPubMedGoogle Scholar
Hammond MEH, Hayes DF, Wolff AC et al (2010) American society of clinical oncology/college of american pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Oncol Pract 6:195–197. doi:10.1200/JOP.777003CrossRefPubMedCentralPubMedGoogle Scholar
Wolff AC, Hammond MEH, Hicks DG et al (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31:3997–4013. doi:10.1200/JCO.2013.50.9984CrossRefPubMedGoogle Scholar
Slamon DJ, Godolphin W, Jones LA et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244(80):707–712CrossRefPubMedGoogle Scholar