The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers.
Klotho (KL) is a putative tumor suppressor gene in breast and pancreatic cancers located at chromosome 13q12. A functional sequence variant of Klotho (KL-VS) was previously reported to modify breast cancer risk in Jewish BRCA1 mutation carriers. The effect of this variant on breast and ovarian cancer risks in non-Jewish BRCA1/BRCA2 mutation carriers has not been reported. The KL-VS variant was genotyped in women of European ancestry carrying a BRCA mutation: 5,741 BRCA1 mutation carriers (2,997 with breast cancer, 705 with ovarian cancer, and 2,039 cancer free women) and 3,339 BRCA2 mutation carriers (1,846 with breast cancer, 207 with ovarian cancer, and 1,286 cancer free women) from 16 centers. Genotyping was accomplished using TaqMan(®) allelic discrimination or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data were analyzed within a retrospective cohort approach, stratified by country of origin and Ashkenazi Jewish origin. The per-allele hazard ratio (HR) for breast cancer was 1.02 (95% CI 0.93-1.12, P = 0.66) for BRCA1 mutation carriers and 0.92 (95% CI 0.82-1.04, P = 0.17) for BRCA2 mutation carriers. Results remained unaltered when analysis excluded prevalent breast cancer cases. Similarly, the per-allele HR for ovarian cancer was 1.01 (95% CI 0.84-1.20, P = 0.95) for BRCA1 mutation carriers and 0.9 (95% CI 0.66-1.22, P = 0.45) for BRCA2 mutation carriers. The risk did not change when carriers of the 6174delT mutation were excluded. There was a lack of association of the KL-VS Klotho variant with either breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
The Susanne Levy Gertner Oncogenetics Unit 1, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel.
Yael
Y
Laitman
Karoline B
KB
Kuchenbaecker
Johanna
J
Rantala
Frans
F
Hogervorst
Susan
S
Peock
Andrew K
AK
Godwin
Adalgeir
A
Arason
Tomas
T
Kirchhoff
Kenneth
K
Offit
Claudine
C
Isaacs
Rita K
RK
Schmutzler
Barbara
B
Wappenschmidt
Heli
H
Nevanlinna
Xiaoqing
X
Chen
Georgia
G
Chenevix-Trench
Sue
S
Healey
Fergus
F
Couch
Paolo
P
Peterlongo
Paolo
P
Radice
Katherine L
KL
Nathanson
Maria Adelaide
MA
Caligo
Susan L
SL
Neuhausen
Patricia
P
Ganz
Olga M
OM
Sinilnikova
Lesley
L
McGuffog
Douglas F
DF
Easton
Antonis C
AC
Antoniou
Ido
I
Wolf
Eitan
E
Friedman
D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005966:Glucuronidase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D000090265:Klotho Proteins; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D005966:Glucuronidase; D000090265:Klotho Proteins