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

Yael Laitman, Karoline B. Kuchenbaecker, Johanna Rantala, Frans Hogervorst, Susan Peock, Andrew K. Godwin, Adalgeir Arason, Tomas Kirchhoff, Kenneth Offit, Claudine Isaacs, Rita K. Schmutzler, Barbara Wappenschmidt, Heli Nevanlinna, Xiaoqing Chen, Georgia Chenevix-Trench, Sue Healey, Fergus J Couch, Paolo Peterlongo, Paolo Radice, Katherine L. NathansonMaria Adelaide Caligo, Susan L. Neuhausen, Patricia Ganz, Olga M. Sinilnikova, Lesley McGuffog, Douglas F. Easton, Antonis C. Antoniou, Ido Wolf, Eitan Friedman

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1119-1126
Number of pages8
JournalBreast Cancer Research and Treatment
Volume132
Issue number3
DOIs
StatePublished - Apr 2012

Fingerprint

Mutation
Breast Neoplasms
Ovarian Neoplasms
Neoplasms
Alleles
Tumor Suppressor Genes
Pancreatic Neoplasms
Mass Spectrometry
Lasers
Chromosomes

Keywords

  • BRCA
  • Breast cancer
  • Modifier gene
  • Ovarian cancer-klotho

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Laitman, Y., Kuchenbaecker, K. B., Rantala, J., Hogervorst, F., Peock, S., Godwin, A. K., ... Friedman, E. (2012). The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers. Breast Cancer Research and Treatment, 132(3), 1119-1126. https://doi.org/10.1007/s10549-011-1938-8

The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers. / Laitman, Yael; Kuchenbaecker, Karoline B.; Rantala, Johanna; Hogervorst, Frans; Peock, Susan; Godwin, Andrew K.; Arason, Adalgeir; Kirchhoff, Tomas; Offit, Kenneth; Isaacs, Claudine; Schmutzler, Rita K.; Wappenschmidt, Barbara; Nevanlinna, Heli; Chen, Xiaoqing; Chenevix-Trench, Georgia; Healey, Sue; Couch, Fergus J; Peterlongo, Paolo; Radice, Paolo; Nathanson, Katherine L.; Caligo, Maria Adelaide; Neuhausen, Susan L.; Ganz, Patricia; Sinilnikova, Olga M.; McGuffog, Lesley; Easton, Douglas F.; Antoniou, Antonis C.; Wolf, Ido; Friedman, Eitan.

In: Breast Cancer Research and Treatment, Vol. 132, No. 3, 04.2012, p. 1119-1126.

Research output: Contribution to journalArticle

Laitman, Y, Kuchenbaecker, KB, Rantala, J, Hogervorst, F, Peock, S, Godwin, AK, Arason, A, Kirchhoff, T, Offit, K, Isaacs, C, Schmutzler, RK, Wappenschmidt, B, Nevanlinna, H, Chen, X, Chenevix-Trench, G, Healey, S, Couch, FJ, Peterlongo, P, Radice, P, Nathanson, KL, Caligo, MA, Neuhausen, SL, Ganz, P, Sinilnikova, OM, McGuffog, L, Easton, DF, Antoniou, AC, Wolf, I & Friedman, E 2012, 'The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers', Breast Cancer Research and Treatment, vol. 132, no. 3, pp. 1119-1126. https://doi.org/10.1007/s10549-011-1938-8
Laitman Y, Kuchenbaecker KB, Rantala J, Hogervorst F, Peock S, Godwin AK et al. The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers. Breast Cancer Research and Treatment. 2012 Apr;132(3):1119-1126. https://doi.org/10.1007/s10549-011-1938-8
Laitman, Yael ; Kuchenbaecker, Karoline B. ; Rantala, Johanna ; Hogervorst, Frans ; Peock, Susan ; Godwin, Andrew K. ; Arason, Adalgeir ; Kirchhoff, Tomas ; Offit, Kenneth ; Isaacs, Claudine ; Schmutzler, Rita K. ; Wappenschmidt, Barbara ; Nevanlinna, Heli ; Chen, Xiaoqing ; Chenevix-Trench, Georgia ; Healey, Sue ; Couch, Fergus J ; Peterlongo, Paolo ; Radice, Paolo ; Nathanson, Katherine L. ; Caligo, Maria Adelaide ; Neuhausen, Susan L. ; Ganz, Patricia ; Sinilnikova, Olga M. ; McGuffog, Lesley ; Easton, Douglas F. ; Antoniou, Antonis C. ; Wolf, Ido ; Friedman, Eitan. / The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers. In: Breast Cancer Research and Treatment. 2012 ; Vol. 132, No. 3. pp. 1119-1126.
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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 {\circledR} 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.",
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author = "Yael Laitman and Kuchenbaecker, {Karoline B.} and Johanna Rantala and Frans Hogervorst and Susan Peock and Godwin, {Andrew K.} and Adalgeir Arason and Tomas Kirchhoff and Kenneth Offit and Claudine Isaacs and Schmutzler, {Rita K.} and Barbara Wappenschmidt and Heli Nevanlinna and Xiaoqing Chen and Georgia Chenevix-Trench and Sue Healey and Couch, {Fergus J} and Paolo Peterlongo and Paolo Radice and Nathanson, {Katherine L.} and Caligo, {Maria Adelaide} and Neuhausen, {Susan L.} and Patricia Ganz and Sinilnikova, {Olga M.} and Lesley McGuffog and Easton, {Douglas F.} and Antoniou, {Antonis C.} and Ido Wolf and Eitan Friedman",
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T1 - The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers

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AU - Hogervorst, Frans

AU - Peock, Susan

AU - Godwin, Andrew K.

AU - Arason, Adalgeir

AU - Kirchhoff, Tomas

AU - Offit, Kenneth

AU - Isaacs, Claudine

AU - Schmutzler, Rita K.

AU - Wappenschmidt, Barbara

AU - Nevanlinna, Heli

AU - Chen, Xiaoqing

AU - Chenevix-Trench, Georgia

AU - Healey, Sue

AU - Couch, Fergus J

AU - Peterlongo, Paolo

AU - Radice, Paolo

AU - Nathanson, Katherine L.

AU - Caligo, Maria Adelaide

AU - Neuhausen, Susan L.

AU - Ganz, Patricia

AU - Sinilnikova, Olga M.

AU - McGuffog, Lesley

AU - Easton, Douglas F.

AU - Antoniou, Antonis C.

AU - Wolf, Ido

AU - Friedman, Eitan

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N2 - 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.

AB - 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.

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KW - Breast cancer

KW - Modifier gene

KW - Ovarian cancer-klotho

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