title: Association of the germline TP53 R337H mutation with breast cancer in southern Brazil.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centro Infantil Boldrini, Campinas, Brazil. julianaassumpcao@yahoo.com.br
authors.forename: Juliana G
authors.initials: JG
authors.lastname: Assumpção
authors.forename: Ana Luíza
authors.initials: AL
authors.lastname: Seidinger
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Mastellaro
authors.forename: Raul C
authors.initials: RC
authors.lastname: Ribeiro
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Zambetti
authors.forename: Ramapriya
authors.initials: R
authors.lastname: Ganti
authors.forename: Kumar
authors.initials: K
authors.lastname: Srivastava
authors.forename: Sheila
authors.initials: S
authors.lastname: Shurtleff
authors.forename: Deqing
authors.initials: D
authors.lastname: Pei
authors.forename: Luiz Carlos
authors.initials: LC
authors.lastname: Zeferino
authors.forename: Rozany M
authors.initials: RM
authors.lastname: Dufloth
authors.forename: Silvia Regina
authors.initials: SR
authors.lastname: Brandalise
authors.forename: José Andres
authors.initials: JA
authors.lastname: Yunes
mesh_terms: D000328:Adult; D001938:Brazil; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D003627:Data Interpretation, Statistical; D005190:Family; D005260:Female; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D011110:Polymorphism, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2