Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management.
OBJECTIVE
To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals.


METHODS
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 <35 years harbored CDH1 germ line mutations. One mutation positive family was ascertained through a family history of lobular breast cancer (LBC) and another through an individual with both DGC and LBC. Occult DGC was identified in five of six prophylactic gastrectomies done on asymptomatic, endoscopically negative 1003C>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 <35 years and for families with multiple cases of LBC, with any history of DGC or unspecified GI malignancies. Prophylactic gastrectomy is potentially a lifesaving procedure and clinical breast screening is recommended for asymptomatic mutation carriers.
Suriano
Gianpaolo
G
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Yew
Sandie
S
Ferreira
Paulo
P
Senz
Janine
J
Kaurah
Pardeep
P
Ford
James M
JM
Longacre
Teri A
TA
Norton
Jeffrey A
JA
Chun
Nicki
N
Young
Sean
S
Oliveira
Maria J
MJ
Macgillivray
Barbara
B
Rao
Arundhati
A
Sears
Dawn
D
Jackson
Charles E
CE
Boyd
Jeff
J
Yee
Cindy
C
Deters
Carolyn
C
Pai
G Shashidhar
GS
Hammond
Lyn S
LS
McGivern
Bobbi J
BJ
Medgyesy
Diane
D
Sartz
Denise
D
Arun
Banu
B
Oelschlager
Brant K
BK
Upton
Mellisa P
MP
Neufeld-Kaiser
Whitney
W
Silva
Orlando E
OE
Donenberg
Talia R
TR
Kooby
David A
DA
Sharma
Shobha
S
Jonsson
Björn-Anders
BA
Gronberg
Henrik
H
Gallinger
Steve
S
Seruca
Raquel
R
Lynch
Henry
H
Huntsman
David G
DG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D018389:Codon, Nonsense; D003094:Collagen / Q000494:pharmacology; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000378:metabolism; D004338:Drug Combinations; D005091:Exons; D018095:Germ-Line Mutation; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D008875:Middle Aged; D020125:Mutation, Missense; D009361:Neoplasm Invasiveness; D010375:Pedigree; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011509:Proteoglycans / Q000494:pharmacology; D012306:Risk; D017422:Sequence Analysis, DNA; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000235:genetics*
D015820:Cadherins; D018389:Codon, Nonsense; D017931:DNA Primers; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen