A genome wide linkage search for breast cancer susceptibility genes.
Mutations in known breast cancer susceptibility genes account for a minority of the familial aggregation of the disease. To search for further breast cancer susceptibility genes, we performed a combined analysis of four genome-wide linkage screens, which included a total of 149 multiple case breast cancer families. All families included at least three cases of breast cancer diagnosed below age 60 years, at least one of whom had been tested and found not to carry a BRCA1 or BRCA2 mutation. Evidence for linkage was assessed using parametric linkage analysis, assuming both a dominant and a recessive mode of inheritance, and using nonparametric methods. The highest LOD score obtained in any analysis of the combined data was 1.80 under the dominant model, in a region on chromosome 4 close to marker D4S392. Three further LOD scores over 1 were identified in the parametric analyses and two in the nonparametric analyses. A maximum LOD score of 2.40 was found on chromosome arm 2p in families with four or more cases of breast cancer diagnosed below age 50 years. The number of linkage peaks did not differ from the number expected by chance. These results suggest regions that may harbor novel breast cancer susceptibility genes. They also indicate that no single gene is likely to account for a large fraction of the familial aggregation of breast cancer that is not due to mutations in BRCA1 or BRCA2.
CR-UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Paula
P
Smith
Lesley
L
McGuffog
Douglas F
DF
Easton
Graham J
GJ
Mann
Gulietta M
GM
Pupo
Beth
B
Newman
Georgia
G
Chenevix-Trench
Csilla
C
Szabo
Melissa
M
Southey
Hélène
H
Renard
Fabrice
F
Odefrey
Henry
H
Lynch
Dominique
D
Stoppa-Lyonnet
Fergus
F
Couch
John L
JL
Hopper
Graham G
GG
Giles
Margaret R E
MR
McCredie
Saundra
S
Buys
Irene
I
Andrulis
Ruby
R
Senie
David E
DE
Goldgar
Rogier
R
Oldenburg
Karin
K
Kroeze-Jansema
Jaennelle
J
Kraan
Hanne
H
Meijers-Heijboer
Jan G M
JG
Klijn
Christi
C
van Asperen
Inge
I
van Leeuwen
Hans F A
HF
Vasen
Cees J
CJ
Cornelisse
Peter
P
Devilee
Linda
L
Baskcomb
Sheila
S
Seal
Rita
R
Barfoot
Jon
J
Mangion
Anita
A
Hall
Sarah
S
Edkins
Elizabeth
E
Rapley
Richard
R
Wooster
Jenny
J
Chang-Claude
Diana
D
Eccles
D Gareth
DG
Evans
P  Andrew
P
Futreal
Katherine L
KL
Nathanson
Barbara L
BL
Weber
Nazneen
N
Rahman
Michael R
MR
Stratton
D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D015894:Genome, Human; D006801:Humans; D008126:Lod Score; D008297:Male; D015233:Models, Statistical