title: Rare germline large rearrangements in the BRCA1/2 genes and eight candidate genes in 472 patients with breast cancer predisposition.
abstract: Hereditary breast cancers account for up to 5-10 % of breast cancers and a majority are related to the BRCA1 and BRCA2 genes. However, many families with breast cancer predisposition do not carry any known mutations for BRCA1 and BRCA2 genes. We explored the incidence of rare large rearrangements in the coding, noncoding and flanking regions of BRCA1/2 and in eight other candidate genes--CHEK2, BARD1, ATM, RAD50, RAD51, BRIP1, RAP80 and PALB2. A dedicated zoom-in CGH-array was applied to screen for rearrangements in 472 unrelated French individuals from breast-ovarian cancer families that were being followed in eight French oncogenetic laboratories. No new rearrangement was found neither in the genomic regions of BRCA1/2 nor in candidate genes, except for the CHEK2 and BARD1 genes. Three heterozygous deletions were detected in the 5' and 3' flanking regions of BRCA1. One large deletion introducing a frameshift was identified in the CHEK2 gene in two families and one heterozygous deletion was detected within an intron of BARD1. The study demonstrates the usefulness of CGH-array in routine genetic analysis and, aside from the CHEK2 rearrangements, indicates there is a very low incidence of large rearrangements in BRCA1/2 and in the other eight candidate genes in families already explored for BRCA1/2 mutations. Finally, next-generation sequencing should bring new information about point mutations in intronic and flanking regions and also medium size rearrangements.
authors.affiliation: Laboratoire d'Oncogénétique, Institut Curie-Hôpital René Huguenin, 35 rue Dailly, 92210 Saint-Cloud, France. etienne.rouleau@curie.net
authors.forename: E
authors.initials: E
authors.lastname: Rouleau
authors.forename: B
authors.initials: B
authors.lastname: Jesson
authors.forename: A
authors.initials: A
authors.lastname: Briaux
authors.forename: C
authors.initials: C
authors.lastname: Nogues
authors.forename: V
authors.initials: V
authors.lastname: Chabaud
authors.forename: L
authors.initials: L
authors.lastname: Demange
authors.forename: J
authors.initials: J
authors.lastname: Sokolowska
authors.forename: F
authors.initials: F
authors.lastname: Coulet
authors.forename: E
authors.initials: E
authors.lastname: Barouk-Simonet
authors.forename: Y J
authors.initials: YJ
authors.lastname: Bignon
authors.forename: F
authors.initials: F
authors.lastname: Bonnet
authors.forename: V
authors.initials: V
authors.lastname: Bourdon
authors.forename: M
authors.initials: M
authors.lastname: Bronner
authors.forename: S
authors.initials: S
authors.lastname: Caputo
authors.forename: L
authors.initials: L
authors.lastname: Castera
authors.forename: C
authors.initials: C
authors.lastname: Delnatte
authors.forename: C
authors.initials: C
authors.lastname: Delvincourt
authors.forename: J
authors.initials: J
authors.lastname: Fournier
authors.forename: A
authors.initials: A
authors.lastname: Hardouin
authors.forename: D
authors.initials: D
authors.lastname: Muller
authors.forename: J P
authors.initials: JP
authors.lastname: Peyrat
authors.forename: C
authors.initials: C
authors.lastname: Toulas
authors.forename: N
authors.initials: N
authors.lastname: Uhrhammer
authors.forename: V
authors.initials: V
authors.lastname: Vidal
authors.forename: D
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.forename: I
authors.initials: I
authors.lastname: Bieche
authors.forename: R
authors.initials: R
authors.lastname: Lidereau
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000235:genetics; D055028:Comparative Genomic Hybridization; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D055815:Young Adult