An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

S Blein; C Bardel; V Danjean; L McGuffog; S Healey; D Barrowdale; A van der Lee; J Dennis; KB Kuchenbaecker; P Soucy; MB Terry; WK Chung; DE Goldgar; SS Buys; R Janavicius; L Tihomirova; N Tung; CM Dorfling; EJ van Rensburg; SL Neuhausen; YC Ding; AM Gerdes; B Ejlertsen; FC Nielsen; TVO Hansen; A Osorio; J Benitez; RA Conejero; E Segota; JN Weitzel; M Thelander; P Peterlongo; P Radice; V Pensotti; R Dolcetti; B Bonanni; B Peissel; D Zaffaroni; G Scuvera; S Manoukian; L Varesco; GL Capone; L Papi; L Ottini; D Yannoukakos; I Konstantopoulou; J Garber; U Hamann; A Donaldson; A Brady; C Brewer; C Foo; DG Evans; D Frost; D Eccles; F Douglas; J Cook; J Adlard; J Barwell; L Walker; L Izatt; LE Side; MJ Kennedy; M Tischkowitz; MT Rogers; ME Porteous; PJ Morrison; R Platte; R Eeles; R Davidson; S Hodgson; T Cole; AK Godwin; C Isaacs; K Claes; K De Leeneer; A Meindl; A Gehrig; B Wappenschmidt; C Sutter; C Engel; D Niederacher; D Steinemann; H Plendl; K Kast; K Rhiem; N Ditsch; N Arnold; R Varon-Mateeva; RK Schmutzler; S Preisler-Adams; NB Markov; S Wang-Gohrke; A de Pauw; C Lefol; C Lasset; D Leroux; E Rouleau; F Damiola; H Dreyfus; L Barjhoux; L Golmard; N Uhrhammer; V Bonadona; V Sornin; YJ Bignon; J Carter; L Van Le; M Piedmonte; PA DiSilvestro; M de la Hoya; T Caldes; H Nevanlinna; K Aittomaki; Agnes Jager; Ans van den Ouweland; CM Kets; CM Aalfs; FE van Leeuwen; FBL Hogervorst; HEJ Meijers-Heijboer; JC Oosterwijk; KEP van Roozendaal; MA Rookus; P Devilee; RB van der Luijt; E Olah; O Diez; A Teule; C (Conxi) Lazaro; I Blanco; J Del Valle; A Jakubowska; G Sukiennicki; J Gronwald; J Lubinski; K Durda; K Jaworska-Bieniek; BA Agnarsson; C Maugard; A Amadori; M Montagna; MR Teixeira; AB Spurdle; W Foulkes; C Olswold; NM Lindor; VS Pankratz; CI Szabo; A Lincoln; L Jacobs; M Corines; M Robson; J Vijai; A Berger; A Fink-Retter; CF Singer; C Rappaport; DG Kaulich; G Pfeiler; MK Tea; MH Greene; PL Mai; G Rennert; EN Imyanitov; AM Mulligan; G Glendon; IL Andrulis; S Tchatchou; AE Toland; IS Pedersen; Marga Thomassen; TA Kruse; UB Jensen; MA Caligo; E Friedman; J Zidan; Y Laitman; A Lindblom; B Melin; B Arver; N Loman; R Rosenquist; OI Olopade; RL Nussbaum; SJ Ramus; KL Nathanson; SM Domchek; TR Rebbeck; BK Arun; G Mitchell; BY Karlan; J Lester; S Orsulic; D Stoppa-Lyonnet; Giju Thomas; J Simard; FJ Couch; K Offit; DF Easton; G Chenevix-Trench; AC Antoniou; S Mazoyer; CM Phelan; OM Sinilnikova; DG Cox

doi:10.1186/s13058-015-0567-2

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

S Blein, C Bardel, V Danjean, L McGuffog, S Healey, D Barrowdale, A van der Lee, J Dennis, KB Kuchenbaecker, P Soucy, MB Terry, WK Chung, DE Goldgar, SS Buys, R Janavicius, L Tihomirova, N Tung, CM Dorfling, EJ van Rensburg, SL NeuhausenYC Ding, AM Gerdes, B Ejlertsen, FC Nielsen, TVO Hansen, A Osorio, J Benitez, RA Conejero, E Segota, JN Weitzel, M Thelander, P Peterlongo, P Radice, V Pensotti, R Dolcetti, B Bonanni, B Peissel, D Zaffaroni, G Scuvera, S Manoukian, L Varesco, GL Capone, L Papi, L Ottini, D Yannoukakos, I Konstantopoulou, J Garber, U Hamann, A Donaldson, A Brady, C Brewer, C Foo, DG Evans, D Frost, D Eccles, F Douglas, J Cook, J Adlard, J Barwell, L Walker, L Izatt, LE Side, MJ Kennedy, M Tischkowitz, MT Rogers, ME Porteous, PJ Morrison, R Platte, R Eeles, R Davidson, S Hodgson, T Cole, AK Godwin, C Isaacs, K Claes, K De Leeneer, A Meindl, A Gehrig, B Wappenschmidt, C Sutter, C Engel, D Niederacher, D Steinemann, H Plendl, K Kast, K Rhiem, N Ditsch, N Arnold, R Varon-Mateeva, RK Schmutzler, S Preisler-Adams, NB Markov, S Wang-Gohrke, A de Pauw, C Lefol, C Lasset, D Leroux, E Rouleau, F Damiola, H Dreyfus, L Barjhoux, L Golmard, N Uhrhammer, V Bonadona, V Sornin, YJ Bignon, J Carter, L Van Le, M Piedmonte, PA DiSilvestro, M de la Hoya, T Caldes, H Nevanlinna, K Aittomaki, Agnes Jager, Ans van den Ouweland, CM Kets, CM Aalfs, FE van Leeuwen, FBL Hogervorst, HEJ Meijers-Heijboer, JC Oosterwijk, KEP van Roozendaal, MA Rookus, P Devilee, RB van der Luijt, E Olah, O Diez, A Teule, C (Conxi) Lazaro, I Blanco, J Del Valle, A Jakubowska, G Sukiennicki, J Gronwald, J Lubinski, K Durda, K Jaworska-Bieniek, BA Agnarsson, C Maugard, A Amadori, M Montagna, MR Teixeira, AB Spurdle, W Foulkes, C Olswold, NM Lindor, VS Pankratz, CI Szabo, A Lincoln, L Jacobs, M Corines, M Robson, J Vijai, A Berger, A Fink-Retter, CF Singer, C Rappaport, DG Kaulich, G Pfeiler, MK Tea, MH Greene, PL Mai, G Rennert, EN Imyanitov, AM Mulligan, G Glendon, IL Andrulis, S Tchatchou, AE Toland, IS Pedersen, Marga Thomassen, TA Kruse, UB Jensen, MA Caligo, E Friedman, J Zidan, Y Laitman, A Lindblom, B Melin, B Arver, N Loman, R Rosenquist, OI Olopade, RL Nussbaum, SJ Ramus, KL Nathanson, SM Domchek, TR Rebbeck, BK Arun, G Mitchell, BY Karlan, J Lester, S Orsulic, D Stoppa-Lyonnet, Giju Thomas, J Simard, FJ Couch, K Offit, DF Easton, G Chenevix-Trench, AC Antoniou, S Mazoyer, CM Phelan, OM Sinilnikova, DG Cox

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

30 Citations (Scopus)

Abstract

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

Original language	Undefined/Unknown
Journal	Breast Cancer Research
Volume	17
DOIs	https://doi.org/10.1186/s13058-015-0567-2
Publication status	Published - 2015

Research programs

EMC MGC-02-96-01
EMC MM-03-24-01
EMC MM-03-86-01

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1186/s13058-015-0567-2

Cite this

Blein, S., Bardel, C., Danjean, V., McGuffog, L., Healey, S., Barrowdale, D., van der Lee, A., Dennis, J., Kuchenbaecker, KB., Soucy, P., Terry, MB., Chung, WK., Goldgar, DE., Buys, SS., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, CM., van Rensburg, EJ., ... Cox, DG. (2015). An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers. Breast Cancer Research, 17. https://doi.org/10.1186/s13058-015-0567-2

@article{53e6b0f9a7454bff813d90347f09f6c9,

title = "An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers",

abstract = "Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.",

author = "S Blein and C Bardel and V Danjean and L McGuffog and S Healey and D Barrowdale and {van der Lee}, A and J Dennis and KB Kuchenbaecker and P Soucy and MB Terry and WK Chung and DE Goldgar and SS Buys and R Janavicius and L Tihomirova and N Tung and CM Dorfling and {van Rensburg}, EJ and SL Neuhausen and YC Ding and AM Gerdes and B Ejlertsen and FC Nielsen and TVO Hansen and A Osorio and J Benitez and RA Conejero and E Segota and JN Weitzel and M Thelander and P Peterlongo and P Radice and V Pensotti and R Dolcetti and B Bonanni and B Peissel and D Zaffaroni and G Scuvera and S Manoukian and L Varesco and GL Capone and L Papi and L Ottini and D Yannoukakos and I Konstantopoulou and J Garber and U Hamann and A Donaldson and A Brady and C Brewer and C Foo and DG Evans and D Frost and D Eccles and F Douglas and J Cook and J Adlard and J Barwell and L Walker and L Izatt and LE Side and MJ Kennedy and M Tischkowitz and MT Rogers and ME Porteous and PJ Morrison and R Platte and R Eeles and R Davidson and S Hodgson and T Cole and AK Godwin and C Isaacs and K Claes and {De Leeneer}, K and A Meindl and A Gehrig and B Wappenschmidt and C Sutter and C Engel and D Niederacher and D Steinemann and H Plendl and K Kast and K Rhiem and N Ditsch and N Arnold and R Varon-Mateeva and RK Schmutzler and S Preisler-Adams and NB Markov and S Wang-Gohrke and {de Pauw}, A and C Lefol and C Lasset and D Leroux and E Rouleau and F Damiola and H Dreyfus and L Barjhoux and L Golmard and N Uhrhammer and V Bonadona and V Sornin and YJ Bignon and J Carter and {Van Le}, L and M Piedmonte and PA DiSilvestro and {de la Hoya}, M and T Caldes and H Nevanlinna and K Aittomaki and Agnes Jager and {van den Ouweland}, Ans and CM Kets and CM Aalfs and {van Leeuwen}, FE and FBL Hogervorst and HEJ Meijers-Heijboer and JC Oosterwijk and {van Roozendaal}, KEP and MA Rookus and P Devilee and {van der Luijt}, RB and E Olah and O Diez and A Teule and Lazaro, {C (Conxi)} and I Blanco and {Del Valle}, J and A Jakubowska and G Sukiennicki and J Gronwald and J Lubinski and K Durda and K Jaworska-Bieniek and BA Agnarsson and C Maugard and A Amadori and M Montagna and MR Teixeira and AB Spurdle and W Foulkes and C Olswold and NM Lindor and VS Pankratz and CI Szabo and A Lincoln and L Jacobs and M Corines and M Robson and J Vijai and A Berger and A Fink-Retter and CF Singer and C Rappaport and DG Kaulich and G Pfeiler and MK Tea and MH Greene and PL Mai and G Rennert and EN Imyanitov and AM Mulligan and G Glendon and IL Andrulis and S Tchatchou and AE Toland and IS Pedersen and Marga Thomassen and TA Kruse and UB Jensen and MA Caligo and E Friedman and J Zidan and Y Laitman and A Lindblom and B Melin and B Arver and N Loman and R Rosenquist and OI Olopade and RL Nussbaum and SJ Ramus and KL Nathanson and SM Domchek and TR Rebbeck and BK Arun and G Mitchell and BY Karlan and J Lester and S Orsulic and D Stoppa-Lyonnet and Giju Thomas and J Simard and FJ Couch and K Offit and DF Easton and G Chenevix-Trench and AC Antoniou and S Mazoyer and CM Phelan and OM Sinilnikova and DG Cox",

year = "2015",

doi = "10.1186/s13058-015-0567-2",

language = "Undefined/Unknown",

volume = "17",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "BioMed Central Ltd.",

}

Blein, S, Bardel, C, Danjean, V, McGuffog, L, Healey, S, Barrowdale, D, van der Lee, A, Dennis, J, Kuchenbaecker, KB, Soucy, P, Terry, MB, Chung, WK, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Gerdes, AM, Ejlertsen, B, Nielsen, FC, Hansen, TVO, Osorio, A, Benitez, J, Conejero, RA, Segota, E, Weitzel, JN, Thelander, M, Peterlongo, P, Radice, P, Pensotti, V, Dolcetti, R, Bonanni, B, Peissel, B, Zaffaroni, D, Scuvera, G, Manoukian, S, Varesco, L, Capone, GL, Papi, L, Ottini, L, Yannoukakos, D, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brady, A, Brewer, C, Foo, C, Evans, DG, Frost, D, Eccles, D, Douglas, F, Cook, J, Adlard, J, Barwell, J, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Tischkowitz, M, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Cole, T, Godwin, AK, Isaacs, C, Claes, K, De Leeneer, K, Meindl, A, Gehrig, A, Wappenschmidt, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Plendl, H, Kast, K, Rhiem, K, Ditsch, N, Arnold, N, Varon-Mateeva, R, Schmutzler, RK, Preisler-Adams, S, Markov, NB, Wang-Gohrke, S, de Pauw, A, Lefol, C, Lasset, C, Leroux, D, Rouleau, E, Damiola, F, Dreyfus, H, Barjhoux, L, Golmard, L, Uhrhammer, N, Bonadona, V, Sornin, V, Bignon, YJ, Carter, J, Van Le, L, Piedmonte, M, DiSilvestro, PA, de la Hoya, M, Caldes, T, Nevanlinna, H, Aittomaki, K, Jager, A, van den Ouweland, A, Kets, CM, Aalfs, CM, van Leeuwen, FE, Hogervorst, FBL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Roozendaal, KEP, Rookus, MA, Devilee, P, van der Luijt, RB, Olah, E, Diez, O, Teule, A, Lazaro, C, Blanco, I, Del Valle, J, Jakubowska, A, Sukiennicki, G, Gronwald, J, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Agnarsson, BA, Maugard, C, Amadori, A, Montagna, M, Teixeira, MR, Spurdle, AB, Foulkes, W, Olswold, C, Lindor, NM, Pankratz, VS, Szabo, CI, Lincoln, A, Jacobs, L, Corines, M, Robson, M, Vijai, J, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Kaulich, DG, Pfeiler, G, Tea, MK, Greene, MH, Mai, PL, Rennert, G, Imyanitov, EN, Mulligan, AM, Glendon, G, Andrulis, IL, Tchatchou, S, Toland, AE, Pedersen, IS, Thomassen, M, Kruse, TA, Jensen, UB, Caligo, MA, Friedman, E, Zidan, J, Laitman, Y, Lindblom, A, Melin, B, Arver, B, Loman, N, Rosenquist, R, Olopade, OI, Nussbaum, RL, Ramus, SJ, Nathanson, KL, Domchek, SM, Rebbeck, TR, Arun, BK, Mitchell, G, Karlan, BY, Lester, J, Orsulic, S, Stoppa-Lyonnet, D, Thomas, G, Simard, J, Couch, FJ, Offit, K, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Mazoyer, S, Phelan, CM, Sinilnikova, OM & Cox, DG 2015, 'An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers', Breast Cancer Research, vol. 17. https://doi.org/10.1186/s13058-015-0567-2

TY - JOUR

T1 - An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

AU - Blein, S

AU - Bardel, C

AU - Danjean, V

AU - McGuffog, L

AU - Healey, S

AU - Barrowdale, D

AU - van der Lee, A

AU - Dennis, J

AU - Kuchenbaecker, KB

AU - Soucy, P

AU - Terry, MB

AU - Chung, WK

AU - Goldgar, DE

AU - Buys, SS

AU - Janavicius, R

AU - Tihomirova, L

AU - Tung, N

AU - Dorfling, CM

AU - van Rensburg, EJ

AU - Neuhausen, SL

AU - Ding, YC

AU - Gerdes, AM

AU - Ejlertsen, B

AU - Nielsen, FC

AU - Hansen, TVO

AU - Osorio, A

AU - Benitez, J

AU - Conejero, RA

AU - Segota, E

AU - Weitzel, JN

AU - Thelander, M

AU - Peterlongo, P

AU - Radice, P

AU - Pensotti, V

AU - Dolcetti, R

AU - Bonanni, B

AU - Peissel, B

AU - Zaffaroni, D

AU - Scuvera, G

AU - Manoukian, S

AU - Varesco, L

AU - Capone, GL

AU - Papi, L

AU - Ottini, L

AU - Yannoukakos, D

AU - Konstantopoulou, I

AU - Garber, J

AU - Hamann, U

AU - Donaldson, A

AU - Brady, A

AU - Brewer, C

AU - Foo, C

AU - Evans, DG

AU - Frost, D

AU - Eccles, D

AU - Douglas, F

AU - Cook, J

AU - Adlard, J

AU - Barwell, J

AU - Walker, L

AU - Izatt, L

AU - Side, LE

AU - Kennedy, MJ

AU - Tischkowitz, M

AU - Rogers, MT

AU - Porteous, ME

AU - Morrison, PJ

AU - Platte, R

AU - Eeles, R

AU - Davidson, R

AU - Hodgson, S

AU - Cole, T

AU - Godwin, AK

AU - Isaacs, C

AU - Claes, K

AU - De Leeneer, K

AU - Meindl, A

AU - Gehrig, A

AU - Wappenschmidt, B

AU - Sutter, C

AU - Engel, C

AU - Niederacher, D

AU - Steinemann, D

AU - Plendl, H

AU - Kast, K

AU - Rhiem, K

AU - Ditsch, N

AU - Arnold, N

AU - Varon-Mateeva, R

AU - Schmutzler, RK

AU - Preisler-Adams, S

AU - Markov, NB

AU - Wang-Gohrke, S

AU - de Pauw, A

AU - Lefol, C

AU - Lasset, C

AU - Leroux, D

AU - Rouleau, E

AU - Damiola, F

AU - Dreyfus, H

AU - Barjhoux, L

AU - Golmard, L

AU - Uhrhammer, N

AU - Bonadona, V

AU - Sornin, V

AU - Bignon, YJ

AU - Carter, J

AU - Van Le, L

AU - Piedmonte, M

AU - DiSilvestro, PA

AU - de la Hoya, M

AU - Caldes, T

AU - Nevanlinna, H

AU - Aittomaki, K

AU - Jager, Agnes

AU - van den Ouweland, Ans

AU - Kets, CM

AU - Aalfs, CM

AU - van Leeuwen, FE

AU - Hogervorst, FBL

AU - Meijers-Heijboer, HEJ

AU - Oosterwijk, JC

AU - van Roozendaal, KEP

AU - Rookus, MA

AU - Devilee, P

AU - van der Luijt, RB

AU - Olah, E

AU - Diez, O

AU - Teule, A

AU - Lazaro, C (Conxi)

AU - Blanco, I

AU - Del Valle, J

AU - Jakubowska, A

AU - Sukiennicki, G

AU - Gronwald, J

AU - Lubinski, J

AU - Durda, K

AU - Jaworska-Bieniek, K

AU - Agnarsson, BA

AU - Maugard, C

AU - Amadori, A

AU - Montagna, M

AU - Teixeira, MR

AU - Spurdle, AB

AU - Foulkes, W

AU - Olswold, C

AU - Lindor, NM

AU - Pankratz, VS

AU - Szabo, CI

AU - Lincoln, A

AU - Jacobs, L

AU - Corines, M

AU - Robson, M

AU - Vijai, J

AU - Berger, A

AU - Fink-Retter, A

AU - Singer, CF

AU - Rappaport, C

AU - Kaulich, DG

AU - Pfeiler, G

AU - Tea, MK

AU - Greene, MH

AU - Mai, PL

AU - Rennert, G

AU - Imyanitov, EN

AU - Mulligan, AM

AU - Glendon, G

AU - Andrulis, IL

AU - Tchatchou, S

AU - Toland, AE

AU - Pedersen, IS

AU - Thomassen, Marga

AU - Kruse, TA

AU - Jensen, UB

AU - Caligo, MA

AU - Friedman, E

AU - Zidan, J

AU - Laitman, Y

AU - Lindblom, A

AU - Melin, B

AU - Arver, B

AU - Loman, N

AU - Rosenquist, R

AU - Olopade, OI

AU - Nussbaum, RL

AU - Ramus, SJ

AU - Nathanson, KL

AU - Domchek, SM

AU - Rebbeck, TR

AU - Arun, BK

AU - Mitchell, G

AU - Karlan, BY

AU - Lester, J

AU - Orsulic, S

AU - Stoppa-Lyonnet, D

AU - Thomas, Giju

AU - Simard, J

AU - Couch, FJ

AU - Offit, K

AU - Easton, DF

AU - Chenevix-Trench, G

AU - Antoniou, AC

AU - Mazoyer, S

AU - Phelan, CM

AU - Sinilnikova, OM

AU - Cox, DG

PY - 2015

Y1 - 2015

N2 - Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

AB - Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

U2 - 10.1186/s13058-015-0567-2

DO - 10.1186/s13058-015-0567-2

M3 - Article

C2 - 25925750

SN - 1465-5411

VL - 17

JO - Breast Cancer Research

JF - Breast Cancer Research

ER -