Screening for predisposing mutations in Polish families with Li-Fraumeni/Li-Fraumeni- like syndrome or with breast and ovarian cancer.

L Fiszer-Maliszewska, PhD,a M Bebenek, MD,b B Gorski, MD,c B Kazanowska, MD,d G Kurzawski, PhD,c A Sikorska, MD,e D Sorokin, MD,b, B Wojciechowska, MSc,a

aInstitute of Immunology & Experimental Therapy, Wroclaw, Poland, bOncology Center, Wroclaw, Poland, cPomeranian Academy of Medicine, Szczecin, Poland, d Wroclaw Medical University, Wroclaw, Poland, eInstitute of Hematology & Blood Transfusion, Warszawa, Poland.

Aim. Patients with Li-Fraumeni syndrome (LFS) or Li-Fraumeni-like syndrome (LFL) have strong familial histories of diverse tumor types. Due to a marked overlap between LFS/LFL and other cancer syndromes, it is of importance to gain further information on cancer phenotype and predisposing gene defects. Methods. From Low Silesia, 90 cancer families with LFS/LFL or with breast/ovarian cancer (HBOC) were selected and screened for mutations of BRCA1 and p53. In some families, in which no such mutation was detected, a search for defects in other genes was performed. Genomic DNA was isolated from blood samples, and appropriate sequences were PCR amplified. The PCR products were prescreened (SSCP, DHPLC) or directly sequenced. Results. In this series of cancer families, several displayed very complex phenotypes. In 60 breast/ovarian families already tested for specific BRCA1 mutations, namely, 5382insC, C61G and 4153delA, 13 mutations were found. The most prevalent one, 5382insC, was found in eight families. Thus far, no germline p53 mutation has been detected. In one of the LFL families of complex cancer phenotype, a germline mutation of the huMLH1 gene was discovered. Conclusions. Of the three common BRCA1 mutations, the 5382insC is the most frequent one in Low Silesia, as it is in other parts of Poland. In contrast to germline p53 mutations, which are very rare, BRCA1 mutations may significantly contribute to familial cancer aggregations in Poland. The complex cancer phenotype of the studied families might reflect an interaction between genotype and environment.

KEY WORDS: Germline mutation, hereditary breast/ovary cancer, Li-Fraumeni syndrome, Li-Fraumeni-like syndrome, p53.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Familial and Hereditary Cancer.