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BMC Cancer  2008 

Association of the germline TP53 R337H mutation with breast cancer in southern Brazil

DOI: 10.1186/1471-2407-8-357

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We conducted a case-control study to determine the prevalence of the R337H mutation by sequencing TP53 exon 10 in 123 women with breast cancer and 223 age- and sex-matched control subjects from southern Brazil. Fisher's test was used to compare the prevalence of the R337H.The R337H mutation was found in three patients but in none of the controls (p = 0.0442). Among the carriers, two had familial history of cancer meeting the Li-Fraumeni-like criteria. Remarkably, tumors in each of these three cases underwent loss of heterozygosity by eliminating the mutant TP53 allele rather than the wild-type allele. Polymorphisms were identified within the TP53 (R72P and Ins16) and MDM2 (SNP309) genes that may further diminish TP53 tumor suppressor activity.These results demonstrate that the R337H mutation can significantly increase the risk of breast cancer in carriers, which likely depends on additional cooperating genetic factors. These findings are also important for understanding how low-penetrant mutant TP53 alleles can differentially influence tumor susceptibility.Mutations in the TP53 tumor supressor gene usually occur within the highly conserved DNA-binding domain (aa 100–298) and, when inherited, are typically associated with Li-Fraumeni syndrome (LFS), in which carriers develop a broad spectrum of cancers (e.g., breast, brain, soft tissue, bone, blood, and adrenal cortex tumors) during childhood or young adulthood [1]. Families with incomplete features of LFS are referred to as having Li-Fraumeni-like (LFL) syndrome [2,3].In southern Brazil, a unique germline TP53 point mutation resulting in an Arg to His amino acid substitution (R337H) within the C-terminal oligomerization domain is strongly associated with childhood adrenocortical tumors (ACT) [4-6]. Unlike the protypical DNA binding mutants, p53-R337H retains significant activity, although its thermal stability is reduced and it is highly sensitive to slight changes in pH [7]. The R337H mutation has a low overall mal


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