Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer.
BACKGROUND
Hereditary diffuse gastric cancer is caused by germline mutations in the epithelial cadherin (CDH1) gene and is characterized by an increased risk for diffuse gastric cancer and lobular breast cancer.


OBJECTIVE
To determine whether recurring germline CDH1 mutations occurred due to independent mutational events or common ancestry.


METHODS
Thirty-eight families diagnosed clinically with hereditary diffuse gastric cancer were accrued between November 2004 and January 2006 and were analyzed for CDH1 mutations as part of an ongoing study at the British Columbia Cancer Agency. Twenty-six families had at least 2 gastric cancer cases with 1 case of diffuse gastric cancer in a person younger than 50 years; 12 families had either a single case of diffuse gastric cancer diagnosed in a person younger than 35 years or multiple cases of diffuse gastric cancer diagnosed in persons older than 50 years.


METHODS
Classification of family members as carriers or noncarriers of CDH1 mutations. Haplotype analysis to assess recurring mutations for common ancestry was performed on 7 families from this study and 7 previously reported families with the same mutations.


RESULTS
Thirteen mutations (6 novel) were identified in 15 of the 38 families (40% detection rate). The 1137G>A splicing mutation and the 1901C>T (A634V) missense/splicing mutation occurred on common haplotypes in 2 families but on different haplotypes in a third family. The 2195G>A (R732Q) missense/splicing mutation occurred in 2 families on different haplotypes. The 2064-2065delTG mutation occurred on a common haplotype in 2 families. Two families from this study plus 2 additional families carrying the novel 2398delC mutation shared a common haplotype, suggesting a founder effect. All 4 families originate from the southeast coast of Newfoundland. Due to concentrations of lobular breast cancer cases, 2 branches of this family had been diagnosed as having hereditary breast cancer and were tested for BRCA mutations. Within these 4 families, the cumulative risk by age 75 years in mutation carriers for clinically detected gastric cancer was 40% (95% confidence interval [CI], 12%-91%) for males and 63% (95% CI, 19%-99%) for females and the risk for breast cancer in female mutation carriers was 52% (95% CI, 29%-94%).


CONCLUSIONS
Recurrent CDH1 mutations in families with hereditary diffuse gastric cancer are due to both independent mutational events and common ancestry. The presence of a founder mutation from Newfoundland is strongly supported.
Kaurah
Pardeep
P
Hereditary Cancer Program, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
MacMillan
Andrée
A
Boyd
Niki
N
Senz
Janine
J
De Luca
Alessandro
A
Chun
Nicki
N
Suriano
Gianpaolo
G
Zaor
Sonya
S
Van Manen
Lori
L
Gilpin
Cathy
C
Nikkel
Sarah
S
Connolly-Wilson
Mary
M
Weissman
Scott
S
Rubinstein
Wendy S
WS
Sebold
Courtney
C
Greenstein
Robert
R
Stroop
Jennifer
J
Yim
Dwight
D
Panzini
Benoit
B
McKinnon
Wendy
W
Greenblatt
Marc
M
Wirtzfeld
Debrah
D
Fontaine
Daniel
D
Coit
Daniel
D
Yoon
Sam
S
Chung
Daniel
D
Lauwers
Gregory
G
Pizzuti
Antonio
A
Vaccaro
Carlos
C
Redal
Maria Ana
MA
Oliveira
Carla
C
Tischkowitz
Marc
M
Olschwang
Sylviane
S
Gallinger
Steven
S
Lynch
Henry
H
Green
Jane
J
Ford
James
J
Pharoah
Paul
P
Fernandez
Bridget
B
Huntsman
David
D
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D006580:Genetic Carrier Screening; D005817:Genetic Counseling; D018095:Germ-Line Mutation; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009523:Newfoundland and Labrador / Q000453:epidemiology; D010375:Pedigree; D019683:Penetrance; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins