title: TP53 germline mutation may affect response to anticancer treatments: analysis of an intensively treated Li-Fraumeni family.
abstract: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant inherited disorder associated with the occurrence of a wide spectrum of early-onset malignancies, the most prevalent being breast cancer and sarcoma. The presence of TP53 germline mutations in the majority of LFS patients suggests a genetic basis for the cancer predisposition. No special recommendations for the treatment of LFS patients have been made to date, except that of minimizing radiation. We hypothesized that TP53 germline mutations may be associated not only with cancer predisposition, but also with lack of response to chemo- and radiotherapy. Here, we present an Austrian LFS family whose members were intensively treated with chemo- and radiotherapy due to cancers that occurred at a predominantly young age, including eight breast cancers in six patients. Material from seven family members was screened for p53 mutation by Sanger sequencing and immunohistochemistry. A rare missense mutation in the tetramerization domain of exon 10 of the TP53 gene was found to segregate with malignant disease in this family. Lack of response to various chemotherapies and radiotherapy could be ascertained by histopathology of surgical specimens after neoadjuvant treatment, by cancer relapse occurring while receiving adjuvant systemic treatment and by the occurrence of second primaries in areas of adjuvant radiation. Our observations suggest that current standards of cancer treatment may not be valid for patients with LFS. In patients with TP53 germline mutation, cytotoxic treatment may bear not only the risk of tumor induction but also the risk of treatment failure.
authors.affiliation: Department of Surgery, Surgical Research, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria, sonja.kappel@meduniwien.ac.at.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kappel
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Janschek
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wolf
authors.forename: Margaretha
authors.initials: M
authors.lastname: Rudas
authors.forename: Bela
authors.initials: B
authors.lastname: Teleky
authors.forename: Raimund
authors.initials: R
authors.lastname: Jakesz
authors.forename: Daniela
authors.initials: D
authors.lastname: Kandioler
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001317:Austria / Q000453:epidemiology; D001943:Breast Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology* / Q000628:therapy*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000150:complications* / Q000453:epidemiology / Q000235:genetics*; D008875:Middle Aged; D010375:Pedigree; D017211:Treatment Failure; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult
chemical_list: D016159:Tumor Suppressor Protein p53