Research article

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

Juliana G Assumpção¹ , Ana Luíza Seidinger¹ , Maria José Mastellaro¹ , Raul C Ribeiro^2,3 , Gerard P Zambetti⁴ , Ramapriya Ganti⁵ , Kumar Srivastava⁶ , Sheila Shurtleff⁵ , Deqing Pei⁶ , Luiz Carlos Zeferino⁷ , Rozany M Dufloth⁸ , Silvia Regina Brandalise¹ and José Andres Yunes¹

¹Centro Infantil Boldrini, Campinas, Brazil

²Department of Oncology, St. Jude Children's Research Hospital, Memphis, USA

³International Outreach Program, St. Jude Children's Research Hospital, Memphis, USA

⁴Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, USA

⁵Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA

⁶Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, USA

⁷Universidade Estadual de Campinas, Campinas, Brazil

⁸Universidade Federal de Santa Catarina, Florianópolis, Brazil

author email corresponding author email

BMC Cancer 2008, 8:357doi:10.1186/1471-2407-8-357

Published:	1 December 2008

Abstract

Background

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 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.

Methods

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.

Results

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.

Conclusion

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.