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.
Smith
Paula
P
CR-UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
McGuffog
Lesley
L
Easton
Douglas F
DF
Mann
Graham J
GJ
Pupo
Gulietta M
GM
Newman
Beth
B
Chenevix-Trench
Georgia
G
Szabo
Csilla
C
Southey
Melissa
M
Renard
Hélène
H
Odefrey
Fabrice
F
Lynch
Henry
H
Stoppa-Lyonnet
Dominique
D
Couch
Fergus
F
Hopper
John L
JL
Giles
Graham G
GG
McCredie
Margaret R E
MR
Buys
Saundra
S
Andrulis
Irene
I
Senie
Ruby
R
Goldgar
David E
DE
Oldenburg
Rogier
R
Kroeze-Jansema
Karin
K
Kraan
Jaennelle
J
Meijers-Heijboer
Hanne
H
Klijn
Jan G M
JG
van Asperen
Christi
C
van Leeuwen
Inge
I
Vasen
Hans F A
HF
Cornelisse
Cees J
CJ
Devilee
Peter
P
Baskcomb
Linda
L
Seal
Sheila
S
Barfoot
Rita
R
Mangion
Jon
J
Hall
Anita
A
Edkins
Sarah
S
Rapley
Elizabeth
E
Wooster
Richard
R
Chang-Claude
Jenny
J
Eccles
Diana
D
Evans
D Gareth
DG
Futreal
P  Andrew
P
Nathanson
Katherine L
KL
Weber
Barbara L
BL
Rahman
Nazneen
N
Stratton
Michael R
MR
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