Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

I Blanco; K Kuchenbaecker; D Cuadras; XS Wang; D Barrowdale; GR Garibay; P Librado; A Sanchez-Gracia; J Rozas; N Bonifaci; L McGuffog; VS Pankratz; A Islam; F Mateo; A Berenguer; A Petit; I Catala; J Brunet; L Feliubadalo; E Tornero; J Benitez; A Osorio; TRY Cajal; H Nevanlinna; K Aittomaki; BK Arun; AE Toland; BY Karlan; C Walsh; J Lester; MH Greene; PL Mai; RL Nussbaum; IL Andrulis; SM Domchek; KL Nathanson; TR Rebbeck; RB Barkardottir; A Jakubowska; J Lubinski; K Durda; K Jaworska-Bieniek; K Claes; T Van Maerken; O Diez; TV Hansen; L Jonson; AM Gerdes; B Ejlertsen; M de la Hoya; T Caldees; AM Dunning; C Oliver; E Fineberg; M Cook; S Peock; E McCann; A Murray; C Jacobs; G Pichert; F Lalloo; C Chu; H Dorkins; J Paterson; KR Ong; MR Teixeira; null Teixeira; FBL Hogervorst; AH van der Hout; Caroline Seynaeve; RB van der Luijt; MJL Ligtenberg; P Devilee; JT Wijnen; MA Rookus; HEJ Meijers-Heijboer; MJ Blok; Ans van den Ouweland; CM Aalfs; GC Rodriguez; KAA Phillips; M Piedmonte; SR Nerenstone; VL Bae-Jump; DM O'Malley; ES Ratner; RK Schmutzler; B Wappenschmidt; K Rhiem; C Engel; A Meindl; N Ditsch; N Arnold; HJ Plendl; D Niederacher; C Sutter; S Wang-Gohrke; D Steinemann; S Preisler-Adams; K Kast; R Varon-Mateeva; A Gehrig; A Bojesen; IS Pedersen; L Sunde; UB Jensen; Marga Thomassen; TA Kruse; L Foretova; P Peterlongo; L Bernard; B Peissel; G Scuvera; S Manoukian; P Radice; L Ottini; M Montagna; S Agata; C Maugard; J Simard; P Soucy; A Berger; A Fink-Retter; CF Singer; C Rappaport; D Geschwantler-Kaulich; MK Tea; G Pfeiler; EM John; A Miron; SL Neuhausen; MB Terry; WK Chung; MB Daly; DE Goldgar; R Janavicius; CM Dorfling; EJ van Rensburg; F Fostira; I Konstantopoulou; J Garber; AK Godwin; E Olah; SA Narod; G Rennert; SS Paluch; Y Laitman; E Friedman; A Liljegren; J Rantala; M Stenmark-Askmalm; N Loman; EN Imyanitov; U Hamann; AB Spurdle; S Healey; JN Weitzel; J Herzog; D Margileth; C Gorrini; M Esteller; A Gomez; S Sayols; E Vidal; H Heyn; null Stoppa-Lyonnet; M Leone; L Barjhoux; M Fassy-Colcombet; A de Pauw; C Lasset; SF Ferrer; L Castera; P Berthet; F Cornelis; YJ Bignon; F Damiola; S Mazoyer; OM Sinilnikova; CA Maxwell; J Vijai; M Robson; N Kauff; MJ Corines; D Villano; J Cunningham; A van der Lee; N Lindor; C (Conxi) Lazaro; DF Easton; K Offit; G Chenevix-Trench; FJ Couch; AC Antoniou; MA Pujana

doi:10.1371/journal.pone.0120020

Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

I Blanco, K Kuchenbaecker, D Cuadras, XS Wang, D Barrowdale, GR Garibay, P Librado, A Sanchez-Gracia, J Rozas, N Bonifaci, L McGuffog, VS Pankratz, A Islam, F Mateo, A Berenguer, A Petit, I Catala, J Brunet, L Feliubadalo, E TorneroJ Benitez, A Osorio, TRY Cajal, H Nevanlinna, K Aittomaki, BK Arun, AE Toland, BY Karlan, C Walsh, J Lester, MH Greene, PL Mai, RL Nussbaum, IL Andrulis, SM Domchek, KL Nathanson, TR Rebbeck, RB Barkardottir, A Jakubowska, J Lubinski, K Durda, K Jaworska-Bieniek, K Claes, T Van Maerken, O Diez, TV Hansen, L Jonson, AM Gerdes, B Ejlertsen, M de la Hoya, T Caldees, AM Dunning, C Oliver, E Fineberg, M Cook, S Peock, E McCann, A Murray, C Jacobs, G Pichert, F Lalloo, C Chu, H Dorkins, J Paterson, KR Ong, MR Teixeira, Teixeira, FBL Hogervorst, AH van der Hout, Caroline Seynaeve, RB van der Luijt, MJL Ligtenberg, P Devilee, JT Wijnen, MA Rookus, HEJ Meijers-Heijboer, MJ Blok, Ans van den Ouweland, CM Aalfs, GC Rodriguez, KAA Phillips, M Piedmonte, SR Nerenstone, VL Bae-Jump, DM O'Malley, ES Ratner, RK Schmutzler, B Wappenschmidt, K Rhiem, C Engel, A Meindl, N Ditsch, N Arnold, HJ Plendl, D Niederacher, C Sutter, S Wang-Gohrke, D Steinemann, S Preisler-Adams, K Kast, R Varon-Mateeva, A Gehrig, A Bojesen, IS Pedersen, L Sunde, UB Jensen, Marga Thomassen, TA Kruse, L Foretova, P Peterlongo, L Bernard, B Peissel, G Scuvera, S Manoukian, P Radice, L Ottini, M Montagna, S Agata, C Maugard, J Simard, P Soucy, A Berger, A Fink-Retter, CF Singer, C Rappaport, D Geschwantler-Kaulich, MK Tea, G Pfeiler, EM John, A Miron, SL Neuhausen, MB Terry, WK Chung, MB Daly, DE Goldgar, R Janavicius, CM Dorfling, EJ van Rensburg, F Fostira, I Konstantopoulou, J Garber, AK Godwin, E Olah, SA Narod, G Rennert, SS Paluch, Y Laitman, E Friedman, A Liljegren, J Rantala, M Stenmark-Askmalm, N Loman, EN Imyanitov, U Hamann, AB Spurdle, S Healey, JN Weitzel, J Herzog, D Margileth, C Gorrini, M Esteller, A Gomez, S Sayols, E Vidal, H Heyn, Stoppa-Lyonnet, M Leone, L Barjhoux, M Fassy-Colcombet, A de Pauw, C Lasset, SF Ferrer, L Castera, P Berthet, F Cornelis, YJ Bignon, F Damiola, S Mazoyer, OM Sinilnikova, CA Maxwell, J Vijai, M Robson, N Kauff, MJ Corines, D Villano, J Cunningham, A van der Lee, N Lindor, C (Conxi) Lazaro, DF Easton, K Offit, G Chenevix-Trench, FJ Couch, AC Antoniou, MA Pujana

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

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Abstract

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p(interaction) values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

Original language	Undefined/Unknown
Journal	PLoS One (print)
Volume	10
Issue number	4
DOIs	https://doi.org/10.1371/journal.pone.0120020
Publication status	Published - 2015

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Cite this

Blanco, I., Kuchenbaecker, K., Cuadras, D., Wang, XS., Barrowdale, D., Garibay, GR., Librado, P., Sanchez-Gracia, A., Rozas, J., Bonifaci, N., McGuffog, L., Pankratz, VS., Islam, A., Mateo, F., Berenguer, A., Petit, A., Catala, I., Brunet, J., Feliubadalo, L., ... Pujana, MA. (2015). Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers. PLoS One (print), 10(4). https://doi.org/10.1371/journal.pone.0120020

@article{f4c83c6eb68147b8acceaa2cf4b9dec9,

title = "Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers",

abstract = "While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p(interaction) values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.",

author = "I Blanco and K Kuchenbaecker and D Cuadras and XS Wang and D Barrowdale and GR Garibay and P Librado and A Sanchez-Gracia and J Rozas and N Bonifaci and L McGuffog and VS Pankratz and A Islam and F Mateo and A Berenguer and A Petit and I Catala and J Brunet and L Feliubadalo and E Tornero and J Benitez and A Osorio and TRY Cajal and H Nevanlinna and K Aittomaki and BK Arun and AE Toland and BY Karlan and C Walsh and J Lester and MH Greene and PL Mai and RL Nussbaum and IL Andrulis and SM Domchek and KL Nathanson and TR Rebbeck and RB Barkardottir and A Jakubowska and J Lubinski and K Durda and K Jaworska-Bieniek and K Claes and {Van Maerken}, T and O Diez and TV Hansen and L Jonson and AM Gerdes and B Ejlertsen and {de la Hoya}, M and T Caldees and AM Dunning and C Oliver and E Fineberg and M Cook and S Peock and E McCann and A Murray and C Jacobs and G Pichert and F Lalloo and C Chu and H Dorkins and J Paterson and KR Ong and MR Teixeira and Teixeira and FBL Hogervorst and {van der Hout}, AH and Caroline Seynaeve and {van der Luijt}, RB and MJL Ligtenberg and P Devilee and JT Wijnen and MA Rookus and HEJ Meijers-Heijboer and MJ Blok and {van den Ouweland}, Ans and CM Aalfs and GC Rodriguez and KAA Phillips and M Piedmonte and SR Nerenstone and VL Bae-Jump and DM O'Malley and ES Ratner and RK Schmutzler and B Wappenschmidt and K Rhiem and C Engel and A Meindl and N Ditsch and N Arnold and HJ Plendl and D Niederacher and C Sutter and S Wang-Gohrke and D Steinemann and S Preisler-Adams and K Kast and R Varon-Mateeva and A Gehrig and A Bojesen and IS Pedersen and L Sunde and UB Jensen and Marga Thomassen and TA Kruse and L Foretova and P Peterlongo and L Bernard and B Peissel and G Scuvera and S Manoukian and P Radice and L Ottini and M Montagna and S Agata and C Maugard and J Simard and P Soucy and A Berger and A Fink-Retter and CF Singer and C Rappaport and D Geschwantler-Kaulich and MK Tea and G Pfeiler and EM John and A Miron and SL Neuhausen and MB Terry and WK Chung and MB Daly and DE Goldgar and R Janavicius and CM Dorfling and {van Rensburg}, EJ and F Fostira and I Konstantopoulou and J Garber and AK Godwin and E Olah and SA Narod and G Rennert and SS Paluch and Y Laitman and E Friedman and A Liljegren and J Rantala and M Stenmark-Askmalm and N Loman and EN Imyanitov and U Hamann and AB Spurdle and S Healey and JN Weitzel and J Herzog and D Margileth and C Gorrini and M Esteller and A Gomez and S Sayols and E Vidal and H Heyn and Stoppa-Lyonnet and M Leone and L Barjhoux and M Fassy-Colcombet and {de Pauw}, A and C Lasset and SF Ferrer and L Castera and P Berthet and F Cornelis and YJ Bignon and F Damiola and S Mazoyer and OM Sinilnikova and CA Maxwell and J Vijai and M Robson and N Kauff and MJ Corines and D Villano and J Cunningham and {van der Lee}, A and N Lindor and Lazaro, {C (Conxi)} and DF Easton and K Offit and G Chenevix-Trench and FJ Couch and AC Antoniou and MA Pujana",

year = "2015",

doi = "10.1371/journal.pone.0120020",

language = "Undefined/Unknown",

volume = "10",

journal = "PLoS One (print)",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "4",

}

Blanco, I, Kuchenbaecker, K, Cuadras, D, Wang, XS, Barrowdale, D, Garibay, GR, Librado, P, Sanchez-Gracia, A, Rozas, J, Bonifaci, N, McGuffog, L, Pankratz, VS, Islam, A, Mateo, F, Berenguer, A, Petit, A, Catala, I, Brunet, J, Feliubadalo, L, Tornero, E, Benitez, J, Osorio, A, Cajal, TRY, Nevanlinna, H, Aittomaki, K, Arun, BK, Toland, AE, Karlan, BY, Walsh, C, Lester, J, Greene, MH, Mai, PL, Nussbaum, RL, Andrulis, IL, Domchek, SM, Nathanson, KL, Rebbeck, TR, Barkardottir, RB, Jakubowska, A, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Claes, K, Van Maerken, T, Diez, O, Hansen, TV, Jonson, L, Gerdes, AM, Ejlertsen, B, de la Hoya, M, Caldees, T, Dunning, AM, Oliver, C, Fineberg, E, Cook, M, Peock, S, McCann, E, Murray, A, Jacobs, C, Pichert, G, Lalloo, F, Chu, C, Dorkins, H, Paterson, J, Ong, KR, Teixeira, MR, Teixeira, Hogervorst, FBL, van der Hout, AH, Seynaeve, C, van der Luijt, RB, Ligtenberg, MJL, Devilee, P, Wijnen, JT, Rookus, MA, Meijers-Heijboer, HEJ, Blok, MJ, van den Ouweland, A, Aalfs, CM, Rodriguez, GC, Phillips, KAA, Piedmonte, M, Nerenstone, SR, Bae-Jump, VL, O'Malley, DM, Ratner, ES, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Plendl, HJ, Niederacher, D, Sutter, C, Wang-Gohrke, S, Steinemann, D, Preisler-Adams, S, Kast, K, Varon-Mateeva, R, Gehrig, A, Bojesen, A, Pedersen, IS, Sunde, L, Jensen, UB, Thomassen, M, Kruse, TA, Foretova, L, Peterlongo, P, Bernard, L, Peissel, B, Scuvera, G, Manoukian, S, Radice, P, Ottini, L, Montagna, M, Agata, S, Maugard, C, Simard, J, Soucy, P, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Geschwantler-Kaulich, D, Tea, MK, Pfeiler, G, John, EM, Miron, A, Neuhausen, SL, Terry, MB, Chung, WK, Daly, MB, Goldgar, DE, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Fostira, F, Konstantopoulou, I, Garber, J, Godwin, AK, Olah, E, Narod, SA, Rennert, G, Paluch, SS, Laitman, Y, Friedman, E, Liljegren, A, Rantala, J, Stenmark-Askmalm, M, Loman, N, Imyanitov, EN, Hamann, U, Spurdle, AB, Healey, S, Weitzel, JN, Herzog, J, Margileth, D, Gorrini, C, Esteller, M, Gomez, A, Sayols, S, Vidal, E, Heyn, H, Stoppa-Lyonnet, Leone, M, Barjhoux, L, Fassy-Colcombet, M, de Pauw, A, Lasset, C, Ferrer, SF, Castera, L, Berthet, P, Cornelis, F, Bignon, YJ, Damiola, F, Mazoyer, S, Sinilnikova, OM, Maxwell, CA, Vijai, J, Robson, M, Kauff, N, Corines, MJ, Villano, D, Cunningham, J, van der Lee, A, Lindor, N, Lazaro, C, Easton, DF, Offit, K, Chenevix-Trench, G, Couch, FJ, Antoniou, AC & Pujana, MA 2015, 'Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers', PLoS One (print), vol. 10, no. 4. https://doi.org/10.1371/journal.pone.0120020

TY - JOUR

T1 - Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

AU - Blanco, I

AU - Kuchenbaecker, K

AU - Cuadras, D

AU - Wang, XS

AU - Barrowdale, D

AU - Garibay, GR

AU - Librado, P

AU - Sanchez-Gracia, A

AU - Rozas, J

AU - Bonifaci, N

AU - McGuffog, L

AU - Pankratz, VS

AU - Islam, A

AU - Mateo, F

AU - Berenguer, A

AU - Petit, A

AU - Catala, I

AU - Brunet, J

AU - Feliubadalo, L

AU - Tornero, E

AU - Benitez, J

AU - Osorio, A

AU - Cajal, TRY

AU - Nevanlinna, H

AU - Aittomaki, K

AU - Arun, BK

AU - Toland, AE

AU - Karlan, BY

AU - Walsh, C

AU - Lester, J

AU - Greene, MH

AU - Mai, PL

AU - Nussbaum, RL

AU - Andrulis, IL

AU - Domchek, SM

AU - Nathanson, KL

AU - Rebbeck, TR

AU - Barkardottir, RB

AU - Jakubowska, A

AU - Lubinski, J

AU - Durda, K

AU - Jaworska-Bieniek, K

AU - Claes, K

AU - Van Maerken, T

AU - Diez, O

AU - Hansen, TV

AU - Jonson, L

AU - Gerdes, AM

AU - Ejlertsen, B

AU - de la Hoya, M

AU - Caldees, T

AU - Dunning, AM

AU - Oliver, C

AU - Fineberg, E

AU - Cook, M

AU - Peock, S

AU - McCann, E

AU - Murray, A

AU - Jacobs, C

AU - Pichert, G

AU - Lalloo, F

AU - Chu, C

AU - Dorkins, H

AU - Paterson, J

AU - Ong, KR

AU - Teixeira, MR

AU - Teixeira, null

AU - Hogervorst, FBL

AU - van der Hout, AH

AU - Seynaeve, Caroline

AU - van der Luijt, RB

AU - Ligtenberg, MJL

AU - Devilee, P

AU - Wijnen, JT

AU - Rookus, MA

AU - Meijers-Heijboer, HEJ

AU - Blok, MJ

AU - van den Ouweland, Ans

AU - Aalfs, CM

AU - Rodriguez, GC

AU - Phillips, KAA

AU - Piedmonte, M

AU - Nerenstone, SR

AU - Bae-Jump, VL

AU - O'Malley, DM

AU - Ratner, ES

AU - Schmutzler, RK

AU - Wappenschmidt, B

AU - Rhiem, K

AU - Engel, C

AU - Meindl, A

AU - Ditsch, N

AU - Arnold, N

AU - Plendl, HJ

AU - Niederacher, D

AU - Sutter, C

AU - Wang-Gohrke, S

AU - Steinemann, D

AU - Preisler-Adams, S

AU - Kast, K

AU - Varon-Mateeva, R

AU - Gehrig, A

AU - Bojesen, A

AU - Pedersen, IS

AU - Sunde, L

AU - Jensen, UB

AU - Thomassen, Marga

AU - Kruse, TA

AU - Foretova, L

AU - Peterlongo, P

AU - Bernard, L

AU - Peissel, B

AU - Scuvera, G

AU - Manoukian, S

AU - Radice, P

AU - Ottini, L

AU - Montagna, M

AU - Agata, S

AU - Maugard, C

AU - Simard, J

AU - Soucy, P

AU - Berger, A

AU - Fink-Retter, A

AU - Singer, CF

AU - Rappaport, C

AU - Geschwantler-Kaulich, D

AU - Tea, MK

AU - Pfeiler, G

AU - John, EM

AU - Miron, A

AU - Neuhausen, SL

AU - Terry, MB

AU - Chung, WK

AU - Daly, MB

AU - Goldgar, DE

AU - Janavicius, R

AU - Dorfling, CM

AU - van Rensburg, EJ

AU - Fostira, F

AU - Konstantopoulou, I

AU - Garber, J

AU - Godwin, AK

AU - Olah, E

AU - Narod, SA

AU - Rennert, G

AU - Paluch, SS

AU - Laitman, Y

AU - Friedman, E

AU - Liljegren, A

AU - Rantala, J

AU - Stenmark-Askmalm, M

AU - Loman, N

AU - Imyanitov, EN

AU - Hamann, U

AU - Spurdle, AB

AU - Healey, S

AU - Weitzel, JN

AU - Herzog, J

AU - Margileth, D

AU - Gorrini, C

AU - Esteller, M

AU - Gomez, A

AU - Sayols, S

AU - Vidal, E

AU - Heyn, H

AU - Stoppa-Lyonnet, null

AU - Leone, M

AU - Barjhoux, L

AU - Fassy-Colcombet, M

AU - de Pauw, A

AU - Lasset, C

AU - Ferrer, SF

AU - Castera, L

AU - Berthet, P

AU - Cornelis, F

AU - Bignon, YJ

AU - Damiola, F

AU - Mazoyer, S

AU - Sinilnikova, OM

AU - Maxwell, CA

AU - Vijai, J

AU - Robson, M

AU - Kauff, N

AU - Corines, MJ

AU - Villano, D

AU - Cunningham, J

AU - van der Lee, A

AU - Lindor, N

AU - Lazaro, C (Conxi)

AU - Easton, DF

AU - Offit, K

AU - Chenevix-Trench, G

AU - Couch, FJ

AU - Antoniou, AC

AU - Pujana, MA

PY - 2015

Y1 - 2015

N2 - While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p(interaction) values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

AB - While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p(interaction) values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

U2 - 10.1371/journal.pone.0120020

DO - 10.1371/journal.pone.0120020

M3 - Article

C2 - 25830658

SN - 1932-6203

VL - 10

JO - PLoS One (print)

JF - PLoS One (print)

IS - 4

ER -