Functional variant of KLOTHO: A breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin

I. Wolf, Y. Laitman, T. Rubinek, L. Abramovitz, I. Novikov, R. Beeri, M. Kuro-O, H. P. Koeffler, R. Catane, L. S. Freedman, E. Levy-Lahad, B. Y. Karlan, E. Friedman, B. Kaufman

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Klotho is a transmembrane protein that can be shed and act as a circulating hormone and is a putative tumor suppressor in breast cancer. A functional variant of KLOTHO (KL-VS) contains two amino acid substitutions F352V and C370S and shows reduced activity. Germ-line mutations in BRCA1 and BRCA2 substantially increase lifetime risk of breast and ovarian cancers. Yet, penetrance of deleterious BRCA1 and BRCA2 mutations is incomplete even among carriers of identical mutations. We examined the association between KL-VS and cancer risk among 1115 Ashkenazi Jewish women: 236 non-carriers, 631 BRCA1 (185delAG, 5382insC) carriers and 248 BRCA2 (6174delT) carriers. Among BRCA1 carriers, heterozygosity for the KL-VS allele was associated with increased breast and ovarian cancer risk (hazard ratio 1.40, 95% confidence intervals 1.08-1.83, P0.01) and younger age at breast cancer diagnosis (median age 48 vs 43 P0.04). KLOTHO and BRCA2 are located on 13q12, and we identified linkage disequilibrium between KL-VS and BRCA2 6174delT mutation. Studies in breast cancer cells showed reduced growth inhibitory activity and reduced secretion of klotho F352V compared with wild-type klotho. These data suggest KL-VS as a breast and ovarian cancer risk modifier among BRCA1 mutation carriers. If validated in additional cohorts, the presence of KL-VS may serve as a predictor of cancer risk among BRCA1 mutation carriers.

Original languageEnglish
Pages (from-to)26-33
Number of pages8
JournalOncogene
Volume29
Issue number1
DOIs
StatePublished - 7 Jan 2010
Externally publishedYes

Bibliographical note

Funding Information:
This research was supported by the United States-Israel Binational Science Foundation (BSF) (grant no. 2005150 to IW and HPK); the Chief Scientist Office of the Ministry of Health, Israel (grant no. 4055_3 to IW); the Koschitzky Family Foundation for Breast Cancer Research; the Israel Cancer Association Research Grant; the ‘Talpiut’ Sheba Career Development Award; the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and the Breast Cancer Research Foundation (to ELL). HPK is a member of the Molecular Biology Institute and Jonsson Comprehensive Cancer Center at UCLA, and holds the endowed Mark Goodson Chair of Oncology Research at Cedars-Sinai Medical Center/UCLA School of Medicine.

Keywords

  • BRCA
  • Breast cancer
  • Insulin growth factor-1
  • Klotho
  • Ovarian cancer
  • Tumor suppressor

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