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Germline CDH1 deletions in hereditary diffuse gastric cancer families

Cited 127 time in Web of Science Cited 144 time in Scopus
Authors
Oliveira, Carla; Senz, Janine; Kaurah, Pardeep; Pinheiro, Hugo; Haegert, Anne; Schouten, Jan; Vogelsang, Holger; Dwerryhouse, Sarah; Chin, Suet-Feung; Huntsman, David; Caldas, Carlos; Stupka, Elia; Roviello, Franco; Seruca, Raquel; Jackson, Charles E.; Yang, Han-Kwang; Grimmer, Donna; Keller, Gisela; Fitzgerald, Rebecca; Corso, Giovanni; Sanges, Remo
Issue Date
2009-05-01
Publisher
OXFORD UNIV PRESS
Citation
HUMAN MOLECULAR GENETICS; Vol.18; no.9; 1545-1555
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 similar to 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.
ISSN
0964-6906
Language
English
URI
https://hdl.handle.net/10371/77874
DOI
https://doi.org/10.1093/hmg/ddp046
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College of Medicine/School of Medicine (의과대학/대학원)Surgery (외과학전공)Journal Papers (저널논문_외과학전공)
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