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

被引：45

作者：

Wolf, I. ^{[1
,2
]}

Laitman, Y. ^{[3
]}

Rubinek, T. ^{[1
]}

Abramovitz, L. ^{[1
]}

Novikov, I. ^{[4
]}

Beeri, R. ^{[5
]}

Kuro-O, M. ^{[6
]}

Koeffler, H. P. ^{[7
]}

Catane, R. ^{[1
,2
]}

Freedman, L. S. ^{[4
]}

Levy-Lahad, E. ^{[5
]}

Karlan, B. Y. ^{[8
]}

Friedman, E. ^{[2
,3
]}

Kaufman, B. ^{[1
]}

机构：

[1] Chaim Sheba Med Ctr, Inst Oncol, IL-52621 Tel Hashomer, Ramat Gan, Israel

[2] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel

[3] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, Inst Human Genet, IL-52621 Tel Hashomer, Ramat Gan, Israel

[4] Chaim Sheba Med Ctr, Gertner Inst Epidemiol & Hlth Policy Res, IL-52621 Tel Hashomer, Ramat Gan, Israel

[5] Shaare Zedek Med Ctr, Med Genet Unit, Jerusalem, Israel

[6] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

[7] Cedars Sinai Med Ctr, Div Hematol Oncol, Los Angeles, CA 90048 USA

[8] Cedars Sinai Med Ctr, Womens Canc Res Inst, Los Angeles, CA 90048 USA

来源：

ONCOGENE | 2010年 / 29卷 / 01期

关键词：

breast cancer; klotho; BRCA; ovarian cancer; insulin growth factor-1; tumor suppressor; TRANSCRIPTS ENCODING MEMBRANE; MOLECULAR-CLONING; HORMONE KLOTHO; PROTEIN; GENE; SUSCEPTIBILITY; EXPRESSION; ASSOCIATION; PATHWAYS; CLEAVAGE;

D O I：

10.1038/onc.2009.301

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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, P=0.01) and younger age at breast cancer diagnosis (median age 48 vs 43 P=0.04). 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 wildtype 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.

引用

页码：26 / 33

页数：8

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