Germline TP53mutations in Finnish breast cancer patients

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Breast cancer is the most frequent malignancy among women, positive family history being one of the strongest risk factors. Mutations in BRCA1 and BRCA2 account for a portion of inherited predisposition to breast cancer, but recently it was discovered that mutations in these two genes were less common in the studied Finnish cancer families than expected. Therefore, mutations in other susceptibility genes have actively been searched for. TP53 is a tumor suppressor gene that is often found mutated in the Li-Fraumeni syndrome (LFS). Germline alterations of TP53 are also thought to cause predisposition to breast cancer. In a previous study by Huusko et al [1], we screened Finnish LFS families for TP53 exon 5-8 mutations and detected two, Tyr220Cys (exon 6) and Asn235Ser (exon 7), both of which appeared to be associated with accumulation of female breast cancer cases in particular.

We have now screened 130 BRCA1 and BRCA2 negative breast cancer patients from 104 families for germline TP53 mutations covering the whole protein-encoding region of the gene. Our criteria for inclusion were: three or more cases of breast cancer in first- or second-degree relatives, early onset of the disease (<35 years), bilateral breast cancer, or multiple tumors including breast cancer in the same individual. The screen for mutations was performed using conformation sensitive gel electrophoresis (CSGE) or fluorescence-CSGE (F-CSGE). One missense mutation (Arg248Gln in exon 7) was identified in a family with multiple cases of breast cancer, one of which was bilateral, at very young age of onset. All three Finnish TP53 germline mutations have previously been observed in LFS and breast cancer patients with bilateral tumors or young age of onset. To characterize further the nature of the identified mutations, control DNAs from 500 unselected consecutive breast cancer cases were studied. No additional mutations were found, supporting the notion that these TP53 germline alterations are disease-related. These mutations were also searched for in additional breast cancer families originating from the same geographical regions as those with mutations, but there was no evidence of founder effects that otherwise are common in hereditary diseases in Finland. Our results indicate that the breast cancer-related germline TP53 mutations mainly occur at specific mutation-prone regions of conserved regions of the gene (exons 6-7), and explain a small additional fraction of the BRCA1 and BRCA2-negative breast cancer cases.

K Rapakko and M Allinen made an equal contribution to this work.