Functional variant of the tumor suppressor klotho: a novel risk modifier for breast cancer among BRCA1/2 carriers.

Abstract

Abstract Abstract #1041 Background: The aging suppressor klotho is a transmembrane protein which is expressed in the kidneys, brain and hormone-responsive tissues and can be shed and act as a circulating hormone. The klotho gene is located on chromosome 13q12, about 700,000 base-pairs upstream to the BRCA2 gene. Klotho is a potent inhibitor of the insulin-like growth factor (IGF)-1 signaling pathway. We have recently found high klotho expression in normal breast tissue and low expression in breast cancer. Over-expression of klotho suppressed growth and inhibited the IGF-1 pathway in breast cancer cells. These data suggest klotho as a tumor suppressor gene in breast cancer. A single nucleotide polymorphism (SNP) in the klotho gene results in an amino acid substitution, F325V, which is associated with altered activity of klotho and reduced lifespan in human. As BRCA mutations may be associated with increased expression of IGF-1 and its receptor in breast cancer, we hypothesized that klotho functional variant may be associated with increased cancer risk among BRCA mutations carriers.
 Material and Methods: The presence of F325V variant was evaluated using exon-specific polymerase chain reaction followed by restriction enzyme analysis, in a cohort of 784 Israeli women consisting of 236 non-BRCA mutations carriers (healthy: 109, breast cancer: 94, ovarian cancer: 33), 340 BRCA1 185delAG and 5382insC mutation carriers (healthy: 138, breast cancer: 142, ovarian cancer: 60) and 208 BRCA2 6174delT carriers (healthy: 75, breast cancer: 106, ovarian cancer: 27).
 Results: Similar distribution of the F325V variant was noted in non-carriers and BRCA1 carriers (FF, wild-type 78%; FV, heterozygous 19%; VV, recessive 3%). However, F352V was over-represented among BRCA2 carriers: FF 25%, FV 50% and VV 25%. Analysis of additional SNPs indicated linkage disequilibrium between FV and BRCA2 6174delT mutation. Yet, among BRCA2 carriers, FF was significantly more frequent among healthy individuals compared to cancer patients (18% vs. 6% respectively, p=0.02). Surprisingly, among BRCA1 carriers FV status was associated with significantly younger age at breast cancer presentation compared to FF status (38±1.8 vs. 46±1.6 years respectively, p<0.001). Association between FV status and age at ovarian cancer presentation among BRCA1 carriers could not be assessed due to small sample size. No association was noted between the klotho functional variant and age at presentation among non-carriers of BRCA mutations.
 Discussion: Taken together, these data suggest klotho F352V functional variant as a novel risk modifier among BRCA mutation carriers but not among non-carriers. As BRCA1/2 mutations can enhance and wild type klotho inhibits the activity of the IGF-1 signaling in cancer, it is possible that the presence of the less active variant of klotho attenuates this balance, thus leading to enhanced activation of the pathway. If validated by additional studies, the presence of the F352V klotho variant may serve as a predictor of cancer risk among BRCA mutation carriers and may also be a novel target for cancer therapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1041.