title: Germline CDH1 deletions in hereditary diffuse gastric cancer families.
abstract: Germline CDH1 point or small frameshift mutations can be identified in 30-50% of hereditary diffuse gastric cancer (HDGC) families. We hypothesized that CDH1 genomic rearrangements would be found in HDGC and identified 160 families with either two gastric cancers in first-degree relatives and with at least one diffuse gastric cancer (DGC) diagnosed before age 50, or three or more DGC in close relatives diagnosed at any age. Sixty-seven carried germline CDH1 point or small frameshift mutations. We screened germline DNA from the 93 mutation negative probands for large genomic rearrangements by Multiplex Ligation-Dependent Probe Amplification. Potential deletions were validated by RT-PCR and breakpoints cloned using a combination of oligo-CGH-arrays and long-range-PCR. In-silico analysis of the CDH1 locus was used to determine a potential mechanism for these rearrangements. Six of 93 (6.5%) previously described mutation negative HDGC probands, from low GC incidence populations (UK and North America), carried genomic deletions (UK and North America). Two families carried an identical deletion spanning 193 593 bp, encompassing the full CDH3 sequence and CDH1 exons 1 and 2. Other deletions affecting exons 1, 2, 15 and/or 16 were identified. The statistically significant over-representation of Alus around breakpoints indicates it as a likely mechanism for these deletions. When all mutations and deletions are considered, the overall frequency of CDH1 alterations in HDGC is approximately 46% (73/160). CDH1 large deletions occur in 4% of HDGC families by mechanisms involving mainly non-allelic homologous recombination in Alu repeat sequences. As the finding of pathogenic CDH1 mutations is useful for management of HDGC families, screening for deletions should be offered to at-risk families.
authors.affiliation: Institute of Molecular Pathology and Immunology, University of Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Oliveira
authors.forename: Janine
authors.initials: J
authors.lastname: Senz
authors.forename: Pardeep
authors.initials: P
authors.lastname: Kaurah
authors.forename: Hugo
authors.initials: H
authors.lastname: Pinheiro
authors.forename: Remo
authors.initials: R
authors.lastname: Sanges
authors.forename: Anne
authors.initials: A
authors.lastname: Haegert
authors.forename: Giovanni
authors.initials: G
authors.lastname: Corso
authors.forename: Jan
authors.initials: J
authors.lastname: Schouten
authors.forename: Rebecca
authors.initials: R
authors.lastname: Fitzgerald
authors.forename: Holger
authors.initials: H
authors.lastname: Vogelsang
authors.forename: Gisela
authors.initials: G
authors.lastname: Keller
authors.forename: Sarah
authors.initials: S
authors.lastname: Dwerryhouse
authors.forename: Donna
authors.initials: D
authors.lastname: Grimmer
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.forename: Han-Kwang
authors.initials: HK
authors.lastname: Yang
authors.forename: Charles E
authors.initials: CE
authors.lastname: Jackson
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Franco
authors.initials: F
authors.lastname: Roviello
authors.forename: Elia
authors.initials: E
authors.lastname: Stupka
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.forename: David
authors.initials: D
authors.lastname: Huntsman
mesh_terms: D000328:Adult; D015703:Antigens, CD; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D017384:Sequence Deletion; D013274:Stomach Neoplasms / Q000235:genetics*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins