title: The PALB2 gene is a strong candidate for clinical testing in BRCA1- and BRCA2-negative hereditary breast cancer.
abstract: BACKGROUND
  Several reports indicate that inherited mutations in the PALB2 gene predispose to breast cancer. However, there is little agreement about the clinical relevance and usefulness of mutation screening in this gene. We analyzed the prevalence and spectrum of germline mutations in PALB2 to estimate their contribution to hereditary breast and/or ovarian cancer in the Czech Republic.
  
  
  METHODS
  The entire PALB2 coding region was sequenced in 409 breast/ovarian cancer patients negative for BRCA1 and BRCA2 mutations. Testing for large genomic rearrangements (LGR) was performed by multiplex ligation-dependent probe amplification (MLPA) analysis.
  
  
  RESULTS
  We have identified 13 different pathogenic alterations including 10 truncating mutations and three LGRs in 16 of 409 patients (3.9%), whereas one truncating mutation was found in a group of 1,226 controls (0.08%; P = 2.6 × 10(-9)). Three novel LGRs included deletions involving exons 7-8 and 9-10, respectively, and a duplication spanning exons 9-11. Five frameshift and two nonsense mutations were novel, whereas three truncating mutations were described previously. The only recurrent mutation was the c.172_175delTTGT detected in four unrelated breast cancer individuals.
  
  
  CONCLUSIONS
  Our analyses demonstrated the significant role of the PALB2 gene in breast cancer susceptibility. The highest frequency of PALB2 mutations (comparable with that previously reported for BRCA2) was found in a subgroup of patients with hereditary breast cancer (HBC) (13/235; 5.5%).
  
  
  CONCLUSIONS
  Our results show that mutation analysis of the PALB2 gene, including the analysis of LGRs, is primarily indicated in patients with HBC in case of their BRCA1 and BRCA2 negativity.
authors.affiliation: Authors' Affiliations: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague; Institutes of Biology and Medical Genetics and Pathology, and Department of Oncology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Marketa
authors.initials: M
authors.lastname: Janatova
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Kleibl
authors.forename: Jana
authors.initials: J
authors.lastname: Stribrna
authors.forename: Ales
authors.initials: A
authors.lastname: Panczak
authors.forename: Kamila
authors.initials: K
authors.lastname: Vesela
authors.forename: Martina
authors.initials: M
authors.lastname: Zimovjanova
authors.forename: Petra
authors.initials: P
authors.lastname: Kleiblova
authors.forename: Pavel
authors.initials: P
authors.lastname: Dundr
authors.forename: Jana
authors.initials: J
authors.lastname: Soukupova
authors.forename: Petr
authors.initials: P
authors.lastname: Pohlreich
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D004252:DNA Mutational Analysis / Q000379:methods; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D017353:Gene Deletion; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D010375:Pedigree; D015995:Prevalence; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins