Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

A. Jakubowska; D. Rozkrut; A. Antoniou; U. Hamann; R. J. Scott; L. McGuffog; S. Healy; O. M. Sinilnikova; G. Rennert; F. Lejbkowicz; A. Flugelman; I. L. Andrulis; G. Glendon; H. Ozcelik; M. Thomassen; M. Paligo; P. Aretini; J. Kantala; B. Aroer; A. Von Wachenfeldt; A. Liljegren; N. Loman; K. Herbst; U. Kristoffersson; R. Rosenquist; P. Karlsson; M. Stenmark-Askmalm; B. Melin; K. L. Nathanson; S. M. Domchek; T. Byrski; T. Huzarski; J. Gronwald; J. Menkiszak; C. Cybulski; P. Serrano; A. Osorio; T. R. Cajal; M. Tsitlaidou; J. Benitez; M. Gilbert; M. Rookus; C. M. Aalfs; I. Kluijt; J. L. Boessenkool-Pape; H. E. J. Meijers-Heijboer; J. C. Oosterwijk; C. J. van Asperen; M. J. Blok; M. R. Nelen; OCGN; SWE-BRCA; HEBON; EMBRACE; GEMO Study Collaborators; kConFab; CIMBA

doi:10.1038/bjc.2012.160

Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

A. Jakubowska^*
, D. Rozkrut
, A. Antoniou
, U. Hamann
, R. J. Scott
, L. McGuffog
, S. Healy
, O. M. Sinilnikova
, G. Rennert
, F. Lejbkowicz
, A. Flugelman
, I. L. Andrulis
, G. Glendon
, H. Ozcelik
, M. Thomassen
, M. Paligo
, P. Aretini
, J. Kantala
, B. Aroer
, A. Von Wachenfeldt

A. Liljegren, N. Loman, K. Herbst, U. Kristoffersson, R. Rosenquist, P. Karlsson, M. Stenmark-Askmalm, B. Melin, K. L. Nathanson, S. M. Domchek, T. Byrski, T. Huzarski, J. Gronwald, J. Menkiszak, C. Cybulski, P. Serrano, A. Osorio, T. R. Cajal, M. Tsitlaidou, J. Benitez, M. Gilbert, M. Rookus, C. M. Aalfs, I. Kluijt, J. L. Boessenkool-Pape, H. E. J. Meijers-Heijboer, J. C. Oosterwijk, C. J. van Asperen, M. J. Blok, M. R. Nelen, OCGN, SWE-BRCA, HEBON, EMBRACE, GEMO Study Collaborators, kConFab, CIMBA

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity.

METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively.

RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele.

CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. British Journal of Cancer (2012) 106, 2016-2024. doi:10.1038/bjc.2012.160 www.bjcancer.com Published online 15 May 2012 (C) 2012 Cancer Research UK

Original language	English
Pages (from-to)	2016-2024
Number of pages	9
Journal	British Jounal of Cancer
Volume	106
Issue number	12
DOIs	https://doi.org/10.1038/bjc.2012.160
Publication status	Published - 5-Jun-2012

Keywords

BRCA1/2 mutation carriers
PHB 1630 C > T polymorphism
MTHFR 677 C > T polymorphism
breast/ovarian cancer risk
METHYLENETETRAHYDROFOLATE REDUCTASE MTHFR
PROHIBITIN 3'-UNTRANSLATED REGION
COMMON MUTATION
FOLATE STATUS
GENE
EXPRESSION
RNA
CARCINOGENESIS
SUSCEPTIBILITY
CHROMOSOME-17

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Jakubowska, A., Rozkrut, D., Antoniou, A., Hamann, U., Scott, R. J., McGuffog, L., Healy, S., Sinilnikova, O. M., Rennert, G., Lejbkowicz, F., Flugelman, A., Andrulis, I. L., Glendon, G., Ozcelik, H., Thomassen, M., Paligo, M., Aretini, P., Kantala, J., Aroer, B., ... CIMBA (2012). Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study. British Jounal of Cancer, 106(12), 2016-2024. https://doi.org/10.1038/bjc.2012.160

@article{95b5d0409d8640bf8c878731292eb10a,

title = "Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study",

abstract = "BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity.METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively.RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95\% CI 1.10-2.04 and HR 2.16, 95\% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele.CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. British Journal of Cancer (2012) 106, 2016-2024. doi:10.1038/bjc.2012.160 www.bjcancer.com Published online 15 May 2012 (C) 2012 Cancer Research UK",

keywords = "BRCA1/2 mutation carriers, PHB 1630 C > T polymorphism, MTHFR 677 C > T polymorphism, breast/ovarian cancer risk, METHYLENETETRAHYDROFOLATE REDUCTASE MTHFR, PROHIBITIN 3'-UNTRANSLATED REGION, COMMON MUTATION, FOLATE STATUS, GENE, EXPRESSION, RNA, CARCINOGENESIS, SUSCEPTIBILITY, CHROMOSOME-17",

author = "A. Jakubowska and D. Rozkrut and A. Antoniou and U. Hamann and Scott, \{R. J.\} and L. McGuffog and S. Healy and Sinilnikova, \{O. M.\} and G. Rennert and F. Lejbkowicz and A. Flugelman and Andrulis, \{I. L.\} and G. Glendon and H. Ozcelik and M. Thomassen and M. Paligo and P. Aretini and J. Kantala and B. Aroer and \{Von Wachenfeldt\}, A. and A. Liljegren and N. Loman and K. Herbst and U. Kristoffersson and R. Rosenquist and P. Karlsson and M. Stenmark-Askmalm and B. Melin and Nathanson, \{K. L.\} and Domchek, \{S. M.\} and T. Byrski and T. Huzarski and J. Gronwald and J. Menkiszak and C. Cybulski and P. Serrano and A. Osorio and Cajal, \{T. R.\} and M. Tsitlaidou and J. Benitez and M. Gilbert and M. Rookus and Aalfs, \{C. M.\} and I. Kluijt and Boessenkool-Pape, \{J. L.\} and Meijers-Heijboer, \{H. E. J.\} and Oosterwijk, \{J. C.\} and \{van Asperen\}, \{C. J.\} and Blok, \{M. J.\} and Nelen, \{M. R.\} and OCGN and SWE-BRCA and HEBON and EMBRACE and \{GEMO Study Collaborators\} and kConFab and CIMBA",

year = "2012",

month = jun,

day = "5",

doi = "10.1038/bjc.2012.160",

language = "English",

volume = "106",

pages = "2016--2024",

journal = "British Jounal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "12",

}

Jakubowska, A, Rozkrut, D, Antoniou, A, Hamann, U, Scott, RJ, McGuffog, L, Healy, S, Sinilnikova, OM, Rennert, G, Lejbkowicz, F, Flugelman, A, Andrulis, IL, Glendon, G, Ozcelik, H, Thomassen, M, Paligo, M, Aretini, P, Kantala, J, Aroer, B, Von Wachenfeldt, A, Liljegren, A, Loman, N, Herbst, K, Kristoffersson, U, Rosenquist, R, Karlsson, P, Stenmark-Askmalm, M, Melin, B, Nathanson, KL, Domchek, SM, Byrski, T, Huzarski, T, Gronwald, J, Menkiszak, J, Cybulski, C, Serrano, P, Osorio, A, Cajal, TR, Tsitlaidou, M, Benitez, J, Gilbert, M, Rookus, M, Aalfs, CM, Kluijt, I, Boessenkool-Pape, JL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Asperen, CJ, Blok, MJ, Nelen, MR, OCGN, SWE-BRCA, HEBON, EMBRACE, GEMO Study Collaborators, kConFab & CIMBA 2012, 'Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study', British Jounal of Cancer, vol. 106, no. 12, pp. 2016-2024. https://doi.org/10.1038/bjc.2012.160

TY - JOUR

T1 - Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers

T2 - results from a multicenter study

AU - Jakubowska, A.

AU - Rozkrut, D.

AU - Antoniou, A.

AU - Hamann, U.

AU - Scott, R. J.

AU - McGuffog, L.

AU - Healy, S.

AU - Sinilnikova, O. M.

AU - Rennert, G.

AU - Lejbkowicz, F.

AU - Flugelman, A.

AU - Andrulis, I. L.

AU - Glendon, G.

AU - Ozcelik, H.

AU - Thomassen, M.

AU - Paligo, M.

AU - Aretini, P.

AU - Kantala, J.

AU - Aroer, B.

AU - Von Wachenfeldt, A.

AU - Liljegren, A.

AU - Loman, N.

AU - Herbst, K.

AU - Kristoffersson, U.

AU - Rosenquist, R.

AU - Karlsson, P.

AU - Stenmark-Askmalm, M.

AU - Melin, B.

AU - Nathanson, K. L.

AU - Domchek, S. M.

AU - Byrski, T.

AU - Huzarski, T.

AU - Gronwald, J.

AU - Menkiszak, J.

AU - Cybulski, C.

AU - Serrano, P.

AU - Osorio, A.

AU - Cajal, T. R.

AU - Tsitlaidou, M.

AU - Benitez, J.

AU - Gilbert, M.

AU - Rookus, M.

AU - Aalfs, C. M.

AU - Kluijt, I.

AU - Boessenkool-Pape, J. L.

AU - Meijers-Heijboer, H. E. J.

AU - Oosterwijk, J. C.

AU - van Asperen, C. J.

AU - Blok, M. J.

AU - Nelen, M. R.

AU - OCGN

AU - SWE-BRCA

AU - HEBON

AU - EMBRACE

AU - GEMO Study Collaborators

AU - kConFab

AU - CIMBA

PY - 2012/6/5

Y1 - 2012/6/5

N2 - BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity.METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively.RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele.CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. British Journal of Cancer (2012) 106, 2016-2024. doi:10.1038/bjc.2012.160 www.bjcancer.com Published online 15 May 2012 (C) 2012 Cancer Research UK

AB - BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity.METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively.RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele.CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. British Journal of Cancer (2012) 106, 2016-2024. doi:10.1038/bjc.2012.160 www.bjcancer.com Published online 15 May 2012 (C) 2012 Cancer Research UK

KW - BRCA1/2 mutation carriers

KW - PHB 1630 C > T polymorphism

KW - MTHFR 677 C > T polymorphism

KW - breast/ovarian cancer risk

KW - METHYLENETETRAHYDROFOLATE REDUCTASE MTHFR

KW - PROHIBITIN 3'-UNTRANSLATED REGION

KW - COMMON MUTATION

KW - FOLATE STATUS

KW - GENE

KW - EXPRESSION

KW - RNA

KW - CARCINOGENESIS

KW - SUSCEPTIBILITY

KW - CHROMOSOME-17

U2 - 10.1038/bjc.2012.160

DO - 10.1038/bjc.2012.160

M3 - Article

C2 - 22669161

SN - 0007-0920

VL - 106

SP - 2016

EP - 2024

JO - British Jounal of Cancer

JF - British Jounal of Cancer

IS - 12

ER -

Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

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