Germline CDH1 deletions in hereditary diffuse gastric cancer families

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.Simoes-Correia J, 2008, HUM MOL GENET, V17, P3566, DOI 10.1093/hmg/ddn249Barber M, 2008, J PATHOL, V216, P295, DOI 10.1002/path.2426de Smith AJ, 2008, PLOS ONE, V3, DOI 10.1371/journal.pone.0003104Lynch HT, 2008, CANCER, V112, P2655, DOI 10.1002/cncr.23501Perry GH, 2008, AM J HUM GENET, V82, P685, DOI 10.1016/j.ajhg.2007.12.010ELSO C, 2008, J NATL CANC I MONOGR, V39, P91BONAGLIA MC, 2008, EUR J HUM GENETKorbel JO, 2007, SCIENCE, V318, P420, DOI 10.1126/science.1149504Lee K, 2007, GENETICS, V176, P2003, DOI 10.1534/genetics.107.076539Chan CY, 2007, NUCLEIC ACIDS RES, V35, P5051, DOI 10.1093/nar/gkm442Kaurah P, 2007, JAMA-J AM MED ASSOC, V297, P2360Roviello F, 2007, EJSO-EUR J SURG ONC, V33, P448, DOI 10.1016/j.ejso.2006.10.028Pistorius S, 2007, CANCER LETT, V248, P89, DOI 10.1016/j.canlet.2006.06.002Knappskog S, 2006, GENE CHROMOSOME CANC, V45, P1155, DOI 10.1002/gcc.20379Casilli F, 2006, J MED GENET, V43, DOI 10.1136/jmg.2005.040212Thomassen M, 2006, CANCER GENET CYTOGEN, V168, P168, DOI 10.1016/j.cancergencyto.2005.12.016Matejas V, 2006, NEUROGENETICS, V7, P119, DOI 10.1007/s10048-006-0030-8Frebourg T, 2006, J MED GENET, V43, P138, DOI 10.1136/jmg.2005.031385Oliveira C, 2006, INT J SURG PATHOL, V14, P21Biedermann K, 2005, J PATHOL, V207, P199, DOI 10.1002/path.1821Baudhuin LM, 2005, GASTROENTEROLOGY, V129, P846, DOI 10.1053/j.gastro.2005.06.026Suriano G, 2005, CLIN CANCER RES, V11, P5401Kjaer KW, 2005, J MED GENET, V42, P292, DOI 10.1136/jmg.2004.027821Michils G, 2005, HUM MUTAT, V25, P125, DOI 10.1002/humu.20122Oliveira C, 2004, EUR J CANCER, V40, P1897, DOI 10.1016/j.ejca.2004.04.027Brooks-Wilson AR, 2004, J MED GENET, V41, P508, DOI 10.1136/jmg.2004.018275Keller G, 2004, J MED GENET, V41, DOI 10.1136/jmg.2003.015594Venturin M, 2004, HUM GENET, V115, P69, DOI 10.1007/s00439-004-1101-2OLIVEIRA C, 2004, ONCOGENE, V23, P9192NAKAGAWA H, 2003, HUM MUTAT, V22, P258Schouten JP, 2002, NUCLEIC ACIDS RES, V30Charbonnier F, 2002, CANCER RES, V62, P848Oliveira C, 2002, HUM MUTAT, V19, P510, DOI 10.1002/humu.10068Pharoah PDP, 2001, GASTROENTEROLOGY, V121, P1348, DOI 10.1053/gast.2001.29611Sprecher E, 2001, NAT GENET, V29, P134Chun YS, 2001, CANCER, V92, P181Huntsman DG, 2001, NEW ENGL J MED, V344, P1904Avizienyte E, 2001, J MED GENET, V38, P49Caldas C, 1999, J MED GENET, V36, P873Keller G, 1999, AM J PATHOL, V155, P337Richards FM, 1999, HUM MOL GENET, V8, P607Wijnen J, 1998, NAT GENET, V20, P326Gayther SA, 1998, CANCER RES, V58, P4086Guilford P, 1998, NATURE, V392, P402Lewis SM, 1997, MOL CELL BIOL, V17, P3125Ramsden DA, 1996, EMBO J, V15, P3197KRAWCZAK M, 1991, HUM GENET, V86, P4252