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

2.50
Hdl Handle:
http://hdl.handle.net/11287/594040
Title:
An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers
Authors:
Blein, S.; Bardel, C.; Danjean, V.; McGuffog, L.; Healey, S.; Barrowdale, D.; Lee, A.; Dennis, J.; Kuchenbaecker, K. B.; Soucy, P.; Terry, M. B.; Chung, W. K.; Goldgar, D. E.; Buys, S. S.; Breast Cancer Family, Registry; Janavicius, R.; Tihomirova, L.; Tung, N.; Dorfling, C. M.; van Rensburg, E. J.; Neuhausen, S. L.; Ding, Y. C.; Gerdes, A. M.; Ejlertsen, B.; Nielsen, F. C.; Hansen, T. V.; Osorio, A.; Benitez, J.; Conejero, R. A.; Segota, E.; Weitzel, J. N.; Thelander, M.; Peterlongo, P.; Radice, P.; Pensotti, V.; Dolcetti, R.; Bonanni, B.; Peissel, B.; Zaffaroni, D.; Scuvera, G.; Manoukian, S.; Varesco, L.; Capone, G. L.; Papi, L.; Ottini, L.; Yannoukakos, D.; Konstantopoulou, I.; Garber, J.; Hamann, U.; Donaldson, A.; Brady, A.; Brewer, Carole; Foo, C.; Evans, D. G.; Frost, D.; Eccles, D.; Embrace,; Douglas, F.; Cook, J.; Adlard, J.; Barwell, J.; Walker, L.; Izatt, L.; Side, L. E.; Kennedy, M. J.; Tischkowitz, M.; Rogers, M. T.; Porteous, M. E.; Morrison, P. J.; Platte, R.; Eeles, R.; Davidson, R.; Hodgson, S.; Cole, T.; Godwin, A. K.; 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, R. K.; Preisler-Adams, S.; Markov, N. B.; Wang-Gohrke, S.; de Pauw, A.; Lefol, C.; Lasset, C.; Leroux, D.; Rouleau, E.; Damiola, F.; Gemo Study Collaborators; Dreyfus, H.; Barjhoux, L.; Golmard, L.; Uhrhammer, N.; Bonadona, V.; Sornin, V.; Bignon, Y. J.; Carter, J.; Van Le, L.; Piedmonte, M.; DiSilvestro, P. A.; de la Hoya, M.; Caldes, T.; Nevanlinna, H.; Aittomaki, K.; Jager, A.; van den Ouweland, A. M.; Kets, C. M.; Aalfs, C. M.; van Leeuwen, F. E.; Hogervorst, F. B.; Meijers-Heijboer, H. E.; Hebon,; Oosterwijk, J. C.; van Roozendaal, K. E.; Rookus, M. A.; Devilee, P.; van der Luijt, R. B.; 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, B. A.; Maugard, C.; Amadori, A.; Montagna, M.; Teixeira, M. R.; Spurdle, A. B.; Foulkes, W.; Olswold, C.; Lindor, N. M.; Pankratz, V. S.; Szabo, C. I.; Lincoln, A.; Jacobs, L.; Corines, M.; Robson, M.; Vijai, J.; Berger, A.; Fink-Retter, A.; Singer, C. F.; Rappaport, C.; Kaulich, D. G.; Pfeiler, G.; Tea, M. K.; Greene, M. H.; Mai, P. L.; Rennert, G.; Imyanitov, E. N.; Mulligan, A. M.; Glendon, G.; Andrulis, I. L.; Tchatchou, S.; Toland, A. E.; Pedersen, I. S.; Thomassen, M.; Kruse, T. A.; Jensen, U. B.; Caligo, M. A.; Friedman, E.; Zidan, J.; Laitman, Y.; Lindblom, A.; Melin, B.; Arver, B.; Loman, N.; Rosenquist, R.; Olopade, O. I.; Nussbaum, R. L.; Ramus, S. J.; Nathanson, K. L.; Domchek, S. M.; Rebbeck, T. R.; Arun, B. K.; Mitchell, G.; Karlan, B. Y.; Lester, J.; Orsulic, S.; Stoppa-Lyonnet, D.; Thomas, G.; Simard, J.; Couch, F. J.; Offit, K.; Easton, D. F.; Chenevix-Trench, G.; Antoniou, A. C.; Mazoyer, S.; Phelan, C. M.; Sinilnikova, O. M.; Cox, D. G.
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.
Citation:
Breast Cancer Res. 2015 Apr 25;17:61.
Publisher:
BioMed Central
Journal:
Breast cancer research : BCR
Issue Date:
1-Apr-2015
URI:
http://hdl.handle.net/11287/594040
DOI:
10.1186/s13058-015-0567-2
PubMed ID:
25925750
Additional Links:
http://breast-cancer-research.com/content/17//61
Note:
This article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.
Type:
Journal Article; Research Support, Non-U.S. Gov't
Language:
eng
ISSN:
1465-542X
Appears in Collections:
2015 RD&E publications; Clinical Genetics (Peninsula Genetics)

Full metadata record

DC FieldValue Language
dc.contributor.authorBlein, S.en
dc.contributor.authorBardel, C.en
dc.contributor.authorDanjean, V.en
dc.contributor.authorMcGuffog, L.en
dc.contributor.authorHealey, S.en
dc.contributor.authorBarrowdale, D.en
dc.contributor.authorLee, A.en
dc.contributor.authorDennis, J.en
dc.contributor.authorKuchenbaecker, K. B.en
dc.contributor.authorSoucy, P.en
dc.contributor.authorTerry, M. B.en
dc.contributor.authorChung, W. K.en
dc.contributor.authorGoldgar, D. E.en
dc.contributor.authorBuys, S. S.en
dc.contributor.authorBreast Cancer Family, Registryen
dc.contributor.authorJanavicius, R.en
dc.contributor.authorTihomirova, L.en
dc.contributor.authorTung, N.en
dc.contributor.authorDorfling, C. M.en
dc.contributor.authorvan Rensburg, E. J.en
dc.contributor.authorNeuhausen, S. L.en
dc.contributor.authorDing, Y. C.en
dc.contributor.authorGerdes, A. M.en
dc.contributor.authorEjlertsen, B.en
dc.contributor.authorNielsen, F. C.en
dc.contributor.authorHansen, T. V.en
dc.contributor.authorOsorio, A.en
dc.contributor.authorBenitez, J.en
dc.contributor.authorConejero, R. A.en
dc.contributor.authorSegota, E.en
dc.contributor.authorWeitzel, J. N.en
dc.contributor.authorThelander, M.en
dc.contributor.authorPeterlongo, P.en
dc.contributor.authorRadice, P.en
dc.contributor.authorPensotti, V.en
dc.contributor.authorDolcetti, R.en
dc.contributor.authorBonanni, B.en
dc.contributor.authorPeissel, B.en
dc.contributor.authorZaffaroni, D.en
dc.contributor.authorScuvera, G.en
dc.contributor.authorManoukian, S.en
dc.contributor.authorVaresco, L.en
dc.contributor.authorCapone, G. L.en
dc.contributor.authorPapi, L.en
dc.contributor.authorOttini, L.en
dc.contributor.authorYannoukakos, D.en
dc.contributor.authorKonstantopoulou, I.en
dc.contributor.authorGarber, J.en
dc.contributor.authorHamann, U.en
dc.contributor.authorDonaldson, A.en
dc.contributor.authorBrady, A.en
dc.contributor.authorBrewer, Caroleen
dc.contributor.authorFoo, C.en
dc.contributor.authorEvans, D. G.en
dc.contributor.authorFrost, D.en
dc.contributor.authorEccles, D.en
dc.contributor.authorEmbrace,en
dc.contributor.authorDouglas, F.en
dc.contributor.authorCook, J.en
dc.contributor.authorAdlard, J.en
dc.contributor.authorBarwell, J.en
dc.contributor.authorWalker, L.en
dc.contributor.authorIzatt, L.en
dc.contributor.authorSide, L. E.en
dc.contributor.authorKennedy, M. J.en
dc.contributor.authorTischkowitz, M.en
dc.contributor.authorRogers, M. T.en
dc.contributor.authorPorteous, M. E.en
dc.contributor.authorMorrison, P. J.en
dc.contributor.authorPlatte, R.en
dc.contributor.authorEeles, R.en
dc.contributor.authorDavidson, R.en
dc.contributor.authorHodgson, S.en
dc.contributor.authorCole, T.en
dc.contributor.authorGodwin, A. K.en
dc.contributor.authorIsaacs, C.en
dc.contributor.authorClaes, K.en
dc.contributor.authorDe Leeneer, K.en
dc.contributor.authorMeindl, A.en
dc.contributor.authorGehrig, A.en
dc.contributor.authorWappenschmidt, B.en
dc.contributor.authorSutter, C.en
dc.contributor.authorEngel, C.en
dc.contributor.authorNiederacher, D.en
dc.contributor.authorSteinemann, D.en
dc.contributor.authorPlendl, H.en
dc.contributor.authorKast, K.en
dc.contributor.authorRhiem, K.en
dc.contributor.authorDitsch, N.en
dc.contributor.authorArnold, N.en
dc.contributor.authorVaron-Mateeva, R.en
dc.contributor.authorSchmutzler, R. K.en
dc.contributor.authorPreisler-Adams, S.en
dc.contributor.authorMarkov, N. B.en
dc.contributor.authorWang-Gohrke, S.en
dc.contributor.authorde Pauw, A.en
dc.contributor.authorLefol, C.en
dc.contributor.authorLasset, C.en
dc.contributor.authorLeroux, D.en
dc.contributor.authorRouleau, E.en
dc.contributor.authorDamiola, F.en
dc.contributor.authorGemo Study Collaboratorsen
dc.contributor.authorDreyfus, H.en
dc.contributor.authorBarjhoux, L.en
dc.contributor.authorGolmard, L.en
dc.contributor.authorUhrhammer, N.en
dc.contributor.authorBonadona, V.en
dc.contributor.authorSornin, V.en
dc.contributor.authorBignon, Y. J.en
dc.contributor.authorCarter, J.en
dc.contributor.authorVan Le, L.en
dc.contributor.authorPiedmonte, M.en
dc.contributor.authorDiSilvestro, P. A.en
dc.contributor.authorde la Hoya, M.en
dc.contributor.authorCaldes, T.en
dc.contributor.authorNevanlinna, H.en
dc.contributor.authorAittomaki, K.en
dc.contributor.authorJager, A.en
dc.contributor.authorvan den Ouweland, A. M.en
dc.contributor.authorKets, C. M.en
dc.contributor.authorAalfs, C. M.en
dc.contributor.authorvan Leeuwen, F. E.en
dc.contributor.authorHogervorst, F. B.en
dc.contributor.authorMeijers-Heijboer, H. E.en
dc.contributor.authorHebon,en
dc.contributor.authorOosterwijk, J. C.en
dc.contributor.authorvan Roozendaal, K. E.en
dc.contributor.authorRookus, M. A.en
dc.contributor.authorDevilee, P.en
dc.contributor.authorvan der Luijt, R. B.en
dc.contributor.authorOlah, E.en
dc.contributor.authorDiez, O.en
dc.contributor.authorTeule, A.en
dc.contributor.authorLazaro, C.en
dc.contributor.authorBlanco, I.en
dc.contributor.authorDel Valle, J.en
dc.contributor.authorJakubowska, A.en
dc.contributor.authorSukiennicki, G.en
dc.contributor.authorGronwald, J.en
dc.contributor.authorLubinski, J.en
dc.contributor.authorDurda, K.en
dc.contributor.authorJaworska-Bieniek, K.en
dc.contributor.authorAgnarsson, B. A.en
dc.contributor.authorMaugard, C.en
dc.contributor.authorAmadori, A.en
dc.contributor.authorMontagna, M.en
dc.contributor.authorTeixeira, M. R.en
dc.contributor.authorSpurdle, A. B.en
dc.contributor.authorFoulkes, W.en
dc.contributor.authorOlswold, C.en
dc.contributor.authorLindor, N. M.en
dc.contributor.authorPankratz, V. S.en
dc.contributor.authorSzabo, C. I.en
dc.contributor.authorLincoln, A.en
dc.contributor.authorJacobs, L.en
dc.contributor.authorCorines, M.en
dc.contributor.authorRobson, M.en
dc.contributor.authorVijai, J.en
dc.contributor.authorBerger, A.en
dc.contributor.authorFink-Retter, A.en
dc.contributor.authorSinger, C. F.en
dc.contributor.authorRappaport, C.en
dc.contributor.authorKaulich, D. G.en
dc.contributor.authorPfeiler, G.en
dc.contributor.authorTea, M. K.en
dc.contributor.authorGreene, M. H.en
dc.contributor.authorMai, P. L.en
dc.contributor.authorRennert, G.en
dc.contributor.authorImyanitov, E. N.en
dc.contributor.authorMulligan, A. M.en
dc.contributor.authorGlendon, G.en
dc.contributor.authorAndrulis, I. L.en
dc.contributor.authorTchatchou, S.en
dc.contributor.authorToland, A. E.en
dc.contributor.authorPedersen, I. S.en
dc.contributor.authorThomassen, M.en
dc.contributor.authorKruse, T. A.en
dc.contributor.authorJensen, U. B.en
dc.contributor.authorCaligo, M. A.en
dc.contributor.authorFriedman, E.en
dc.contributor.authorZidan, J.en
dc.contributor.authorLaitman, Y.en
dc.contributor.authorLindblom, A.en
dc.contributor.authorMelin, B.en
dc.contributor.authorArver, B.en
dc.contributor.authorLoman, N.en
dc.contributor.authorRosenquist, R.en
dc.contributor.authorOlopade, O. I.en
dc.contributor.authorNussbaum, R. L.en
dc.contributor.authorRamus, S. J.en
dc.contributor.authorNathanson, K. L.en
dc.contributor.authorDomchek, S. M.en
dc.contributor.authorRebbeck, T. R.en
dc.contributor.authorArun, B. K.en
dc.contributor.authorMitchell, G.en
dc.contributor.authorKarlan, B. Y.en
dc.contributor.authorLester, J.en
dc.contributor.authorOrsulic, S.en
dc.contributor.authorStoppa-Lyonnet, D.en
dc.contributor.authorThomas, G.en
dc.contributor.authorSimard, J.en
dc.contributor.authorCouch, F. J.en
dc.contributor.authorOffit, K.en
dc.contributor.authorEaston, D. F.en
dc.contributor.authorChenevix-Trench, G.en
dc.contributor.authorAntoniou, A. C.en
dc.contributor.authorMazoyer, S.en
dc.contributor.authorPhelan, C. M.en
dc.contributor.authorSinilnikova, O. M.en
dc.contributor.authorCox, D. G.en
dc.date.accessioned2016-01-19T12:38:57Zen
dc.date.available2016-01-19T12:38:57Zen
dc.date.issued2015-04-01en
dc.identifier.citationBreast Cancer Res. 2015 Apr 25;17:61.en
dc.identifier.issn1465-542Xen
dc.identifier.pmid25925750en
dc.identifier.doi10.1186/s13058-015-0567-2en
dc.identifier.urihttp://hdl.handle.net/11287/594040en
dc.description.abstractINTRODUCTION: 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.en
dc.language.isoengen
dc.publisherBioMed Centralen
dc.relation.urlhttp://breast-cancer-research.com/content/17//61en
dc.titleAn original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriersen
dc.typeJournal Articleen
dc.typeResearch Support, Non-U.S. Gov'ten
dc.identifier.journalBreast cancer research : BCRen
dc.description.noteThis article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.en

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