The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers

Abstract

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.

Inorganic phosphate and the risk of cancer in the Swedish AMORIS study

“…vitamin D, FGF-23 and PTH, are related to cancer incidence [42-44], and thus their abnormal levels may be responsible for the association between Pi and cancer risks. Finally, the klotho gene encoding the obligate co-receptor for FGF-23 is also a putative tumour suppressor gene [45], further implying the link between Pi regulation and carcinogenesis.…”

Biochemical and Functional Characterization of the Klotho-VS Polymorphism Implicated in Aging and Disease Risk

“…There are also age-dependent increases in bone mineral density in both male and female heterozygotes, but whether there is a homozygote disadvantage could not be determined due to the low frequency of that genotype (26,27). Contrary to the other effects, heterozygosity for KLVS increases the risk of BRCA1 associated breast and ovarian cancer and decreases the risk in homozygous patients from an Ashkenazi Jewish population, but not in a larger cohort of European ancestry (28,29).…”

Klotho and the Treatment of Human Malignancies

“…Klotho expression has been shown to be significantly down-regulated in malignant tissue compared to adjacent non-malignant tissue using immunohistochemical (IHC) techniques, including colorectal [44,45], pancreatic [46], gastric [47], oesophageal [48], breast [49], hepatocellular [50], ovarian [51], and renal cancers [52] (Table 1). Furthermore, more than ten single nucleotide polymorphisms (SNPs) have been identified in the human KLOTHO gene, and a number of studies have been performed to evaluate the associations between allelic variations in the KLOTHO gene and the aetiology of ageing-related diseases [53][54][55][56][57][58][59][60][61], including the effect of Klotho's functional variants on cancer predisposition [62][63][64]. A meta-analysis of 29 case-control studies has been undertaken to derive a pooled estimate of effect and to quantify the variability observed between individual studies [65].…”