Genetic analysis of a breast-ovarian cancer family, with 7 cases of colorectal cancer linked to BRCA1, fails to support a role for BRCA1 in colorectal tumorigenesis.
Mutations in the BRCA1 gene cause strongly elevated risks of breast and ovarian cancers but may also confer a 3-fold increased risk for colorectal cancer. To address the relationship between BRCA1 carriership and colorectal tumorigenesis, we studied the genetics of a breast-ovarian cancer family with 7 cases of colorectal cancer. A germline 3938insG mutation in BRCA1 was found in 5 breast-cancer patients, 1 with ductal carcinoma in situ, ovarian cancer and an adenoma of the colon, and in 4/5 colorectal-cancer patients investigated. However, the youngest patient, diagnosed at age 23, was a non-carrier. Loss of the wild-type BRCA1 allele was observed in 3/3 breast tissues (2 breast carcinomas and 1 ductal carcinoma in situ) but in 0/6 colorectal tissues (5 carcinomas and 1 adenoma), suggesting that BRCA1 loss is not critical for colorectal tumorigenesis. To examine the possibility that an as yet unknown gene linked to BRCA1 was involved in the colorectal cancers, chromosome 17 segregation was studied with 7 polymorphic markers encompassing a 20 cM region including BRCA1. None of these markers showed complete allele sharing among all 5 colorectal-cancer patients studied. Clinical history, mutation analysis and microsatellite instability analysis excluded a role for any of the known colorectal-cancer susceptibility genes. In 4 other Dutch families carrying the same BRCA1 mutation, only 1 colorectal-cancer case was reported, of which the carrier status is unknown.
Peelen
T
T
Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
de Leeuw
W
W
van Lent
K
K
Morreau
H
H
van Eijk
R
R
van Vliet
M
M
Wijnen
J
J
Ligtenberg
M
M
Ginjaar
H B
HB
Zweemer
R
R
Menko
F
F
Fodde
R
R
van Ommen
G J
GJ
Vasen
H F
HF
Cornelisse
C J
CJ
Devilee
P
P
D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics* / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
D019313:BRCA1 Protein