title: Mutation analysis of PALB2 in BRCA1 and BRCA2-negative breast and/or ovarian cancer families from Eastern Ontario, Canada.
abstract: BACKGROUND
  PALB2 has emerged as a breast cancer susceptibility gene. Mutations in PALB2 have been identified in almost all breast cancer populations studied to date, but the rarity of these mutations and lack of information regarding their penetrance makes genetic counseling for these families challenging. We studied BRCA1/2 -negative breast and/or ovarian cancer families to a) assess the contribution of PALB2 mutations in this series and b) identify clinical, pathological and family history characteristics that might make PALB2 screening more efficient.
  
  
  METHODS
  The coding region of the PALB2 gene was analyzed in 175 probands with family histories of breast and/or ovarian cancer ascertained from a single Canadian institution in Eastern Ontario.
  
  
  RESULTS
  We identified 2 probands with PALB2 mutations that are known or strongly considered to be pathogenic and 3 probands with missense mutations that are possibly pathogenic. One of the identified truncating mutations [c.3113G > A (p.Gly1000_Trp1038del - major product)], has been previously described while the other four mutations [c.3507_3508delTC (p.H1170Ffs*19), c.1846G > C (p.D616H), c.3418 T > G (p.W1140G), c.3287A > G (p.N1096S)] have not been previously reported. Loss of heterozygosity was detected in two breast tumors from one c.3507_3508delTC mutation carrier but not in other available tumors from that family or in tumors from carriers of other mutations.
  
  
  CONCLUSIONS
  PALB2 mutation screening identifies a small, but significant number of mutations in BRCA1/2 -negative breast and/or ovarian cancer families. We show that mutations are more likely to be found in families with three or more breast cancers as well as other BRCA2-related cancers. In our cohort, both clearly pathogenic mutations were identified in premenopausal breast cancer cases (2/77, 2.6%). Testing should be preferentially offered to affected women from such families.
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Rd, K1H 8 L1 Ottawa, ON, Canada.
authors.forename: Taila
authors.initials: T
authors.lastname: Hartley
authors.affiliation: Program in Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, McGill University, Montreal, QC, Canada ; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada.
authors.forename: Luca
authors.initials: L
authors.lastname: Cavallone
authors.affiliation: Program in Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, McGill University, Montreal, QC, Canada ; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada.
authors.forename: Nelly
authors.initials: N
authors.lastname: Sabbaghian
authors.affiliation: Program in Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, McGill University, Montreal, QC, Canada ; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada.
authors.forename: Rachel
authors.initials: R
authors.lastname: Silva-Smith
authors.affiliation: Program in Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, McGill University, Montreal, QC, Canada ; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Hamel
authors.affiliation: Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada ; Department of Pathology, McGill University, Montreal, QC, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Aleynikova
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Rd, K1H 8 L1 Ottawa, ON, Canada.
authors.forename: Erika
authors.initials: E
authors.lastname: Smith
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Rd, K1H 8 L1 Ottawa, ON, Canada.
authors.forename: Valerie
authors.initials: V
authors.lastname: Hastings
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Pinto
authors.affiliation: Program in Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, McGill University, Montreal, QC, Canada ; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada ; Department of Medical Genetics, University of Cambridge, Cambridge, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Tischkowitz
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Rd, K1H 8 L1 Ottawa, ON, Canada ; Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Eva
authors.initials: E
authors.lastname: Tomiak
authors.affiliation: Program in Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, McGill University, Montreal, QC, Canada ; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada ; Department of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada.
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
keywords: BRCA1 and BRCA2 mutation-negative; Hereditary breast cancer; Melanoma; PALB2; Pancreatic cancer