Characterization of a Recurrent Germ Line Mutation of the E-Cadherin Gene: Implications for Genetic Testing and Clinical Management

• Published in: Clinical cancer research 2005-08, Vol.11 (15), p.5401-5409
• Main Authors: SURIANO, Gianpaolo, YEW, Sandie, OLIVEIRA, Maria J, MACGILLIVRAY, Barbara, RAO, Arundhati, SEARS, Dawn, JACKSON, Charles E, BOYD, Jeff, YEE, Cindy, DETERS, Carolyn, PAI, G. Shashidhar, HAMMOND, Lyn S, FERREIRA, Paulo, MCGIVERN, Bobbi J, MEDGYESY, Diane, SARTZ, Denise, ARUN, Banu, OELSCHLAGER, Brant K, UPTON, Mellisa P, NEUFELD-KAISER, Whitney, SILVA, Orlando E, DONENBERG, Talia R, KOOBY, David A, SENZ, Janine, SHARMA, Shobha, JONSSON, Bjorn-Anders, GRONBERG, Henrik, GALLINGER, Steve, SERUCA, Raquel, LYNCH, Henry, HUNTSMAN, David G, KAURAH, Pardeep, FORD, James M, LONGACRE, Teri A, NORTON, Jeffrey A, CHUN, Nicki, YOUNG, Sean
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Biological and medical sciences; Blotting, Western; Cadherins - genetics; Chromatography, High Pressure Liquid; Codon, Nonsense; Collagen - pharmacology; DNA Mutational Analysis; DNA Primers - metabolism; Drug Combinations; E-cadherin germ line mutation; Exons; Germ-Line Mutation; haplotype; Haplotypes; hereditary diffuse gastric cancer; Heterozygote; Humans; Laminin - pharmacology; lobular breast cancer; Medical sciences; Middle Aged; Mutation, Missense; Neoplasm Invasiveness; Pedigree; Pharmacology. Drug treatments; Plasmids - metabolism; Polymerase Chain Reaction; Proteoglycans - pharmacology; recurrent mutation; Risk; Sequence Analysis, DNA; Stomach Neoplasms - diagnosis; Stomach Neoplasms - genetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0247

Purpose: To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals. Experimental Design: We ascertained 31 HDGC previously unreported families, including 10 isolated early-onset diffuse gastric cancer (DGC) cases. Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing. Results: We identified eight inactivating and one missense CDH1 germ line mutation. The missense mutation conferred in vitro loss of protein function. Two families had the previously described 1003C>T nonsense mutation. Haplotype analysis revealed this to be a recurrent and not a founder mutation. Thirty-six percent (5 of 14) of the families with a documented DGC diagnosed before the age of 50 and other cases of gastric cancer carried CDH1 germ line mutations. Two of 10 isolated cases of DGC in individuals ages T mutation carriers. Conclusions: In addition to families with a strong history of early-onset DGC, CDH1 mutation screening should be offered to isolated cases of DGC in individuals ages