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 Benítez; 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; A M W van den Ouweland; C Seynaeve; R B van der Luijt; P Devilee; D F Easton; S Peock; D Frost; R Platte; S D Ellis; E Fineberg; D G Evans; F Lalloo; R Eeles; C Jacobs; J Adlard; R Davidson; D Eccles; T Cole; J Cook; A Godwin; B Bove; D Stoppa-Lyonnet; V Caux-Moncoutier; M Belotti; C Tirapo; S Mazoyer; L Barjhoux; N Boutry-Kryza; P Pujol; I Coupier; J-P Peyrat; P Vennin; D Muller; J-P Fricker; L Venat-Bouvet; Óskar Þór Jóhannsson; C Isaacs; R Schmutzler; B Wappenschmidt; A Meindl; N Arnold; R Varon-Mateeva; D Niederacher; C Sutter; H Deissler; S Preisler-Adams; J Simard; P Soucy; F Durocher; G Chenevix-Trench; J Beesley; X Chen; T Rebbeck; F Couch; X Wang; N Lindor; Z Fredericksen; V S Pankratz; P Peterlongo; B Bonanni; S Fortuzzi; B Peissel; C Szabo; P L Mai; J T Loud; J Lubinski

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 WachenfeldtA 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 Benítez, 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, A M W van den Ouweland, C Seynaeve, R B van der Luijt, P Devilee, D F Easton, S Peock, D Frost, R Platte, S D Ellis, E Fineberg, D G Evans, F Lalloo, R Eeles, C Jacobs, J Adlard, R Davidson, D Eccles, T Cole, J Cook, A Godwin, B Bove, D Stoppa-Lyonnet, V Caux-Moncoutier, M Belotti, C Tirapo, S Mazoyer, L Barjhoux, N Boutry-Kryza, P Pujol, I Coupier, J-P Peyrat, P Vennin, D Muller, J-P Fricker, L Venat-Bouvet, Óskar Þór Jóhannsson, C Isaacs, R Schmutzler, B Wappenschmidt, A Meindl, N Arnold, R Varon-Mateeva, D Niederacher, C Sutter, H Deissler, S Preisler-Adams, J Simard, P Soucy, F Durocher, G Chenevix-Trench, J Beesley, X Chen, T Rebbeck, F Couch, X Wang, N Lindor, Z Fredericksen, V S Pankratz, P Peterlongo, B Bonanni, S Fortuzzi, B Peissel, C Szabo, P L Mai, J T Loud, J Lubinski

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Abstract

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. 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. 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. 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.

Original language	English
Journal	British Journal of Cancer
DOIs	https://doi.org/10.1038/bjc.2012.160
Publication status	Published - 5 Jun 2012

Other keywords

Breast Neoplasms
Female
Genes, BRCA1
Genes, BRCA2
Genetic Predisposition to Disease
Heterozygote
Humans
Methylenetetrahydrofolate Reductase (NADPH2)
Mutation
Ovarian Neoplasms
Polymorphism, Genetic
Repressor Proteins
Risk

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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., ... Lubinski, J. (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 Journal of Cancer. https://doi.org/10.1038/bjc.2012.160

@article{f87c7a18fc1f4a2f8c71ac28bc39253e,

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 = "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. 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. 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. 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.",

keywords = "Breast Neoplasms, Female, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Heterozygote, Humans, Methylenetetrahydrofolate Reductase (NADPH2), Mutation, Ovarian Neoplasms, Polymorphism, Genetic, Repressor Proteins, Risk, Breast Neoplasms, Female, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Heterozygote, Humans, Methylenetetrahydrofolate Reductase (NADPH2), Mutation, Ovarian Neoplasms, Polymorphism, Genetic, Repressor Proteins, Risk",

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 Ben{\'i}tez 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 {van den Ouweland}, {A M W} and C Seynaeve and {van der Luijt}, {R B} and P Devilee and Easton, {D F} and S Peock and D Frost and R Platte and Ellis, {S D} and E Fineberg and Evans, {D G} and F Lalloo and R Eeles and C Jacobs and J Adlard and R Davidson and D Eccles and T Cole and J Cook and A Godwin and B Bove and D Stoppa-Lyonnet and V Caux-Moncoutier and M Belotti and C Tirapo and S Mazoyer and L Barjhoux and N Boutry-Kryza and P Pujol and I Coupier and J-P Peyrat and P Vennin and D Muller and J-P Fricker and L Venat-Bouvet and J{\'o}hannsson, {{\'O}skar {\TH}{\'o}r} and C Isaacs and R Schmutzler and B Wappenschmidt and A Meindl and N Arnold and R Varon-Mateeva and D Niederacher and C Sutter and H Deissler and S Preisler-Adams and J Simard and P Soucy and F Durocher and G Chenevix-Trench and J Beesley and X Chen and T Rebbeck and F Couch and X Wang and N Lindor and Z Fredericksen and Pankratz, {V S} and P Peterlongo and B Bonanni and S Fortuzzi and B Peissel and C Szabo and Mai, {P L} and Loud, {J T} and J Lubinski",

year = "2012",

month = jun,

day = "5",

doi = "10.1038/bjc.2012.160",

language = "English",

journal = "British Journal of Cancer",

issn = "1532-1827",

publisher = "Nature Publishing Group",

}

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, Benítez, J, Gilbert, M, Rookus, M, Aalfs, CM, Kluijt, I, Boessenkool-Pape, JL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Asperen, CJ, Blok, MJ, Nelen, MR, van den Ouweland, AMW, Seynaeve, C, van der Luijt, RB, Devilee, P, Easton, DF, Peock, S, Frost, D, Platte, R, Ellis, SD, Fineberg, E, Evans, DG, Lalloo, F, Eeles, R, Jacobs, C, Adlard, J, Davidson, R, Eccles, D, Cole, T, Cook, J, Godwin, A, Bove, B, Stoppa-Lyonnet, D, Caux-Moncoutier, V, Belotti, M, Tirapo, C, Mazoyer, S, Barjhoux, L, Boutry-Kryza, N, Pujol, P, Coupier, I, Peyrat, J-P, Vennin, P, Muller, D, Fricker, J-P, Venat-Bouvet, L, Jóhannsson, ÓÞ, Isaacs, C, Schmutzler, R, Wappenschmidt, B, Meindl, A, Arnold, N, Varon-Mateeva, R, Niederacher, D, Sutter, C, Deissler, H, Preisler-Adams, S, Simard, J, Soucy, P, Durocher, F, Chenevix-Trench, G, Beesley, J, Chen, X, Rebbeck, T, Couch, F, Wang, X, Lindor, N, Fredericksen, Z, Pankratz, VS, Peterlongo, P, Bonanni, B, Fortuzzi, S, Peissel, B, Szabo, C, Mai, PL, Loud, JT & Lubinski, J 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 Journal of Cancer. 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: 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 - Benítez, 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 - van den Ouweland, A M W

AU - Seynaeve, C

AU - van der Luijt, R B

AU - Devilee, P

AU - Easton, D F

AU - Peock, S

AU - Frost, D

AU - Platte, R

AU - Ellis, S D

AU - Fineberg, E

AU - Evans, D G

AU - Lalloo, F

AU - Eeles, R

AU - Jacobs, C

AU - Adlard, J

AU - Davidson, R

AU - Eccles, D

AU - Cole, T

AU - Cook, J

AU - Godwin, A

AU - Bove, B

AU - Stoppa-Lyonnet, D

AU - Caux-Moncoutier, V

AU - Belotti, M

AU - Tirapo, C

AU - Mazoyer, S

AU - Barjhoux, L

AU - Boutry-Kryza, N

AU - Pujol, P

AU - Coupier, I

AU - Peyrat, J-P

AU - Vennin, P

AU - Muller, D

AU - Fricker, J-P

AU - Venat-Bouvet, L

AU - Jóhannsson, Óskar Þór

AU - Isaacs, C

AU - Schmutzler, R

AU - Wappenschmidt, B

AU - Meindl, A

AU - Arnold, N

AU - Varon-Mateeva, R

AU - Niederacher, D

AU - Sutter, C

AU - Deissler, H

AU - Preisler-Adams, S

AU - Simard, J

AU - Soucy, P

AU - Durocher, F

AU - Chenevix-Trench, G

AU - Beesley, J

AU - Chen, X

AU - Rebbeck, T

AU - Couch, F

AU - Wang, X

AU - Lindor, N

AU - Fredericksen, Z

AU - Pankratz, V S

AU - Peterlongo, P

AU - Bonanni, B

AU - Fortuzzi, S

AU - Peissel, B

AU - Szabo, C

AU - Mai, P L

AU - Loud, J T

AU - Lubinski, J

PY - 2012/6/5

Y1 - 2012/6/5

N2 - 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. 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. 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. 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.

AB - 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. 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. 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. 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.

KW - Breast Neoplasms

KW - Female

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Genetic Predisposition to Disease

KW - Heterozygote

KW - Humans

KW - Methylenetetrahydrofolate Reductase (NADPH2)

KW - Mutation

KW - Ovarian Neoplasms

KW - Polymorphism, Genetic

KW - Repressor Proteins

KW - Risk

KW - Breast Neoplasms

KW - Female

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Genetic Predisposition to Disease

KW - Heterozygote

KW - Humans

KW - Methylenetetrahydrofolate Reductase (NADPH2)

KW - Mutation

KW - Ovarian Neoplasms

KW - Polymorphism, Genetic

KW - Repressor Proteins

KW - Risk

U2 - 10.1038/bjc.2012.160

DO - 10.1038/bjc.2012.160

M3 - Article

C2 - 22669161

SN - 1532-1827

JO - British Journal of Cancer

JF - British Journal of Cancer

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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