title: Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients.
abstract: BACKGROUND
  Germline TP53 mutations cause an increased risk to early-onset breast cancer in Li-Fraumeni syndrome (LFS) families and the majority of carriers identified through breast cancer cohorts have LFS or Li-Fraumeni-like (LFL) features. However, in Asia and in many low resource settings, it is challenging to obtain accurate family history and we, therefore, sought to determine whether the presence of early-onset breast cancer is an appropriate selection criteria for germline TP53 testing.
  
  
  METHODS
  A total of 100 patients with early-onset breast cancer (≤ 35 years) treated at University Malaya Medical Centre between 2003 and 2009, were analyzed for germline mutations in BRCA1, BRCA2 and TP53 by full DNA sequencing. Of the mutations identified, we examined their likely pathogenicity on the basis of prevalence in a case-control cohort, co-segregation analyses and loss of heterozygosity (LOH) in tumor tissues.
  
  
  RESULTS
  We identified 11 BRCA1 (11%) and 6 BRCA2 (6%) germline carriers among early-onset breast cancer patients. Of the 83 BRCA-negative patients, we identified four exonic variants and three intronic variants in TP53. Of these, two exonic variants are clinically relevant (E346X and p. G334_R335dup6) and two novel missense mutations (A138V and E285K) are likely to be clinically relevant, on the basis of co-segregation and loss of heterozygosity (LOH). Notably, E285K was found in two unrelated individuals and haplotype analyses suggest a founder effect. Two of the three intronic variants are likely benign based on their prevalence in a control population. Clinically relevant TP53 germline mutations were identified in three of the four patients (75%) with a family history of at least two LFS-linked cancers (breast, bone or soft tissue sarcoma, brain tumors or adrenocortical cancer); 1 of the 17 patients (6%) with a family history of breast cancer only, and 1 of the 62 patients (< 2%) with no family history of breast or LFS-linked cancers.
  
  
  CONCLUSIONS
  Our study reports germline BRCA1, BRCA2 and TP53 mutations are found in early-onset breast cancer patients at 11%, 6% and 5% respectively, suggesting that TP53 mutation screening should be considered for these patients. However, we find that even in low resource Asian settings where family history is poorly reported, germline TP53 mutations are found predominantly among breast cancer patients with a family history of LFS-linked cancers.
authors.affiliation: Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, Subang Jaya, 47500 Selangor, Malaysia.
authors.forename: Daphne S C
authors.initials: DS
authors.lastname: Lee
authors.forename: Sook-Yee
authors.initials: SY
authors.lastname: Yoon
authors.forename: Lai Meng
authors.initials: LM
authors.lastname: Looi
authors.forename: Peter
authors.initials: P
authors.lastname: Kang
authors.forename: In Nee
authors.initials: IN
authors.lastname: Kang
authors.forename: Kavitta
authors.initials: K
authors.lastname: Sivanandan
authors.forename: Hany
authors.initials: H
authors.lastname: Ariffin
authors.forename: Meow Keong
authors.initials: MK
authors.lastname: Thong
authors.forename: Kin Fah
authors.initials: KF
authors.lastname: Chin
authors.forename: Nur Aishah
authors.initials: NA
authors.lastname: Mohd Taib
authors.forename: Cheng-Har
authors.initials: CH
authors.lastname: Yip
authors.forename: Soo-Hwang
authors.initials: SH
authors.lastname: Teo
mesh_terms: D000328:Adult; D017668:Age of Onset; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D019656:Loss of Heterozygosity; D008296:Malaysia / Q000453:epidemiology / Q000208:ethnology; D012509:Sarcoma / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D016159:Tumor Suppressor Protein p53