TP53 germline mutation may affect response to anticancer treatments: analysis of an intensively treated Li–Fraumeni family
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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.
KeywordsLi–Fraumeni syndrome p53 Cytotoxic treatment Radiation
Cyclophosphamide, methotrexate and 5-fluorouracil
Formalin-fixed paraffin-embedded tissue
Peripheral blood mononuclear cells
Polymerase chain reaction
The authors are grateful to the LFS family members for support in data collection and for assistance in completing the pedigree.
Conflict of interest
Sonja Kappel is a part-time employee of MARK53 LTD Vienna. Daniela Kandioler is an uncompensated consultant and holds a leadership position at MARK53 LTD Vienna. Other authors have no conflicts of interest to declare.
The Medical University of Vienna commits to the principles of the Declaration of Helsinki, and thus ethical guidelines were observed in all procedures concerning the LFS family. The p53 Research Group (Medical University of Vienna) received approval for TP53 germline testing from the Austrian Federal Ministry of Health and Women.
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