Abstract
BackgroundThe germline TP53-R337H mutation is strongly associated with pediatric adrenocortical tumors (ACT) in southern Brazil; it has low penetrance and limited tissue specificity in most families and therefore is not associated with Li-Fraumeni syndrome. However, other tumor types, mainly breast cancer, have been observed in carriers of several unrelated kindreds, raising the possibility that the R337H mutation may also contribute to breast tumorigenesis in a genetic background-specific context.MethodsWe 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.ResultsThe 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.ConclusionThese 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.
Highlights
Mutations in the TP53 tumor supressor gene usually occur within the highly conserved DNA-binding domain and, when inherited, are typically associated with Li-Fraumeni syndrome (LFS), in which carriers develop a broad spectrum of cancers during childhood or young adulthood [1]
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) [4,5,6]
Identification of the germline R337H TP53 mutation in breast cancer patients The R337H mutation was detected in the germline DNA of three of 123 breast cancer patients in southern Brazil
Summary
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]. Achatz and coworkers [8] identified R337H carriers among Brazilian LFL families, including one case of breast carcinoma that underwent loss of the wild-type allele and retained the mutant allele. These observations suggested that the R337H mutation may play a role in breast tumorigenesis. The germline TP53-R337H mutation is strongly associated with pediatric adrenocortical tumors (ACT) in southern Brazil; it has low penetrance and limited tissue specificity in most families and is not associated with Li-Fraumeni syndrome. Other tumor types, mainly breast cancer, have been observed in carriers of several unrelated kindreds, raising the possibility that the R337H mutation may contribute to breast tumorigenesis in a genetic background-specific context
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