title: BRCA1, BRCA2 and PALB2 mutations and CHEK2 c.1100delC in different South African ethnic groups diagnosed with premenopausal and/or triple negative breast cancer.
abstract: BACKGROUND
  Current knowledge of the aetiology of hereditary breast cancer in the four main South African population groups (black, coloured, Indian and white) is limited. Risk assessments in the black, coloured and Indian population groups are challenging because of restricted information regarding the underlying genetic contributions to inherited breast cancer in these populations. We focused this study on premenopausal patients (diagnosed with breast cancer before the age of 50; n = 78) and triple negative breast cancer (TNBC) patients (n = 30) from the four South African ethnic groups. The aim of this study was to determine the frequency and spectrum of germline mutations in BRCA1, BRCA2 and PALB2 and to evaluate the presence of the CHEK2 c.1100delC allele in these patients.
  
  
  METHODS
  In total, 108 South African breast cancer patients underwent mutation screening using a Next-Generation Sequencing (NGS) approach in combination with Multiplex Ligation-dependent Probe Amplification (MLPA) to detect large rearrangements in BRCA1 and BRCA2.
  
  
  RESULTS
  In 13 (12 %) patients a deleterious mutation in BRCA1/2 was detected, three of which were novel mutations in black patients. None of the study participants was found to have an unequivocal pathogenic mutation in PALB2. Two (white) patients tested positive for the CHEK2 c.1100delC mutation, however, one of these also carried a deleterious BRCA2 mutation. Additionally, six variants of unknown clinical significance were identified (4 in BRCA2, 2 in PALB2), all in black patients. Within the group of TNBC patients, a higher mutation frequency was obtained (23.3 %; 7/30) than in the group of patients diagnosed before the age of 50 (7.7 %; 6/78).
  
  
  CONCLUSIONS
  This study highlights the importance of evaluating germline mutations in major breast cancer genes in all of the South African population groups. This NGS study shows that mutation analysis is warranted in South African patients with triple negative and/or in premenopausal breast cancer.
authors.affiliation: iThemba LABS-National Research Foundation, Somerset West, South Africa. flavia.zita4@gmail.com.|Department of Radiation Sciences, University of the Witwatersrand, Johannesburg, South Africa. flavia.zita4@gmail.com.
authors.forename: F Z
authors.initials: FZ
authors.lastname: Francies
authors.affiliation: Division of Human Genetics, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa. Tasha.Wainstein@nhls.ac.za.
authors.forename: T
authors.initials: T
authors.lastname: Wainstein
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. Kim.Deleeneer@ugent.be.
authors.forename: K
authors.initials: K
authors.lastname: De Leeneer
authors.affiliation: Department of Surgery, Charlotte Maxeke Johannesburg Academic Hospital and Donald Gordon Medical Centre, Johannesburg, South Africa. acairns@tiscali.co.za.
authors.forename: A
authors.initials: A
authors.lastname: Cairns
authors.affiliation: Department of Surgery, Charlotte Maxeke Johannesburg Academic Hospital and Donald Gordon Medical Centre, Johannesburg, South Africa. marshall.murdoch@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Murdoch
authors.affiliation: Department of Surgery, Charlotte Maxeke Johannesburg Academic Hospital and Donald Gordon Medical Centre, Johannesburg, South Africa. sarah.nietz@gmx.de.
authors.forename: S
authors.initials: S
authors.lastname: Nietz
authors.affiliation: Batho Pele Breast Unit, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa. hcubasch@worldonline.co.za.
authors.forename: H
authors.initials: H
authors.lastname: Cubasch
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. Bruce.Poppe@ugent.be.
authors.forename: B
authors.initials: B
authors.lastname: Poppe
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. Tom.Vanmaerken@ugent.be.
authors.forename: T
authors.initials: T
authors.lastname: Van Maerken
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. Brecht.Crombez@ugent.be.
authors.forename: B
authors.initials: B
authors.lastname: Crombez
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. Ilse.Coene@ugent.be.
authors.forename: I
authors.initials: I
authors.lastname: Coene
authors.affiliation: Division of Human Genetics, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa. Robyn.Kerr@nhls.ac.za.
authors.forename: R
authors.initials: R
authors.lastname: Kerr
authors.affiliation: iThemba LABS-National Research Foundation, Somerset West, South Africa. jps@tlabs.ac.za.
authors.forename: J P
authors.initials: JP
authors.lastname: Slabbert
authors.affiliation: Department of Basic Medical Sciences, Ghent University, Ghent, Belgium. Anne.vral@ugent.be.
authors.forename: A
authors.initials: A
authors.lastname: Vral
authors.affiliation: Division of Human Genetics, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa. Amanda.Krause@nhls.ac.za.|Division of Human Genetics, National Health Laboratory Services, Johannesburg, South Africa. Amanda.Krause@nhls.ac.za.
authors.forename: A
authors.initials: A
authors.lastname: Krause
authors.affiliation: iThemba LABS-National Research Foundation, Somerset West, South Africa. Ans.Baeyens@wits.ac.za.|Department of Radiation Sciences, University of the Witwatersrand, Johannesburg, South Africa. Ans.Baeyens@wits.ac.za.|Department of Basic Medical Sciences, Ghent University, Ghent, Belgium. Ans.Baeyens@wits.ac.za.
authors.forename: A
authors.initials: A
authors.lastname: Baeyens
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. Kathleen.Claes@ugent.be.
authors.forename: K B M
authors.initials: KB
authors.lastname: Claes
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D064447:Checkpoint Kinase 2 / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D017697:Premenopause; D017384:Sequence Deletion / Q000235:genetics; D013019:South Africa; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human