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Multicenter Study
. 2021 Feb 17;12(1):1078.
doi: 10.1038/s41467-020-20496-3.

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Juliette Coignard  1   2   3   4   5   6 , Michael Lush  4 , Jonathan Beesley  7 , Tracy A O'Mara  7 , Joe Dennis  4 , Jonathan P Tyrer  8 , Daniel R Barnes  4 , Lesley McGuffog  4 , Goska Leslie  4 , Manjeet K Bolla  4 , Muriel A Adank  9 , Simona Agata  10 , Thomas Ahearn  11 , Kristiina Aittomäki  12 , Irene L Andrulis  13   14 , Hoda Anton-Culver  15 , Volker Arndt  16 , Norbert Arnold  17   18 , Kristan J Aronson  19 , Banu K Arun  20 , Annelie Augustinsson  21 , Jacopo Azzollini  22 , Daniel Barrowdale  4 , Caroline Baynes  8 , Heiko Becher  23 , Marina Bermisheva  24 , Leslie Bernstein  25 , Katarzyna Białkowska  26 , Carl Blomqvist  27   28 , Stig E Bojesen  29   30   31 , Bernardo Bonanni  32 , Ake Borg  33 , Hiltrud Brauch  34   35   36 , Hermann Brenner  16   36   37 , Barbara Burwinkel  38   39 , Saundra S Buys  40 , Trinidad Caldés  41 , Maria A Caligo  42 , Daniele Campa  43   44 , Brian D Carter  45 , Jose E Castelao  46 , Jenny Chang-Claude  44   47 , Stephen J Chanock  11 , Wendy K Chung  48 , Kathleen B M Claes  49 , Christine L Clarke  50 ; GEMO Study Collaborators; EMBRACE Collaborators; J Margriet Collée  51 , Don M Conroy  8 , Kamila Czene  52 , Mary B Daly  53 , Peter Devilee  54   55 , Orland Diez  56   57 , Yuan Chun Ding  25 , Susan M Domchek  58 , Thilo Dörk  59 , Isabel Dos-Santos-Silva  60 , Alison M Dunning  8 , Miriam Dwek  61 , Diana M Eccles  62 , A Heather Eliassen  63   64 , Christoph Engel  65 , Mikael Eriksson  52 , D Gareth Evans  66   67 , Peter A Fasching  68   69 , Henrik Flyger  70 , Florentia Fostira  71 , Eitan Friedman  72   73 , Lin Fritschi  74 , Debra Frost  4 , Manuela Gago-Dominguez  75   76 , Susan M Gapstur  45 , Judy Garber  77 , Vanesa Garcia-Barberan  78 , Montserrat García-Closas  11 , José A García-Sáenz  78 , Mia M Gaudet  45 , Simon A Gayther  79 , Andrea Gehrig  80 , Vassilios Georgoulias  81 , Graham G Giles  82   83   84 , Andrew K Godwin  85 , Mark S Goldberg  86   87 , David E Goldgar  88 , Anna González-Neira  89 , Mark H Greene  90 , Pascal Guénel  91 , Lothar Haeberle  92 , Eric Hahnen  93   94 , Christopher A Haiman  95 , Niclas Håkansson  96 , Per Hall  52   96 , Ute Hamann  97 , Patricia A Harrington  8 , Steven N Hart  98 , Wei He  52 , Frans B L Hogervorst  9 , Antoinette Hollestelle  99 , John L Hopper  83 , Darling J Horcasitas  100 , Peter J Hulick  101   102 , David J Hunter  64   103   104 , Evgeny N Imyanitov  105 ; KConFab Investigators; HEBON Investigators; ABCTB Investigators; Agnes Jager  99 , Anna Jakubowska  26   106 , Paul A James  107   108 , Uffe Birk Jensen  109 , Esther M John  110   111 , Michael E Jones  111 , Rudolf Kaaks  44 , Pooja Middha Kapoor  44   112 , Beth Y Karlan  113   114 , Renske Keeman  115 , Elza Khusnutdinova  24   116 , Johanna I Kiiski  117 , Yon-Dschun Ko  118 , Veli-Matti Kosma  119   120   121 , Peter Kraft  64   103 , Allison W Kurian  110   111 , Yael Laitman  72 , Diether Lambrechts  122   123 , Loic Le Marchand  124 , Jenny Lester  113   114 , Fabienne Lesueur  1   2   3   5 , Tricia Lindstrom  98 , Adria Lopez-Fernández  125 , Jennifer T Loud  90 , Craig Luccarini  8 , Arto Mannermaa  119   120   121 , Siranoush Manoukian  22 , Sara Margolin  96   126 , John W M Martens  99 , Noura Mebirouk  1   2   3   5 , Alfons Meindl  127 , Austin Miller  128 , Roger L Milne  82   83   84 , Marco Montagna  10 , Katherine L Nathanson  58 , Susan L Neuhausen  25 , Heli Nevanlinna  117 , Finn C Nielsen  129 , Katie M O'Brien  130 , Olufunmilayo I Olopade  131 , Janet E Olson  98 , Håkan Olsson  21 , Ana Osorio  89   132 , Laura Ottini  133 , Tjoung-Won Park-Simon  59 , Michael T Parsons  7 , Inge Sokilde Pedersen  134   135   136 , Beth Peshkin  137 , Paolo Peterlongo  138 , Julian Peto  60 , Paul D P Pharoah  4   8 , Kelly-Anne Phillips  7   83   107 , Eric C Polley  98 , Bruce Poppe  49 , Nadege Presneau  61 , Miquel Angel Pujana  139 , Kevin Punie  140 , Paolo Radice  141 , Johanna Rantala  142 , Muhammad U Rashid  97   143 , Gad Rennert  144 , Hedy S Rennert  144 , Mark Robson  145 , Atocha Romero  146 , Maria Rossing  129 , Emmanouil Saloustros  147 , Dale P Sandler  130 , Regina Santella  148 , Maren T Scheuner  149 , Marjanka K Schmidt  115   150 , Gunnar Schmidt  151 , Christopher Scott  98 , Priyanka Sharma  152 , Penny Soucy  153 , Melissa C Southey  84   154 , John J Spinelli  155   156 , Zoe Steinsnyder  157 , Jennifer Stone  83   158 , Dominique Stoppa-Lyonnet  159   160   161 , Anthony Swerdlow  111   162 , Rulla M Tamimi  63   64   103 , William J Tapper  62 , Jack A Taylor  130   163 , Mary Beth Terry  148 , Alex Teulé  164 , Darcy L Thull  165 , Marc Tischkowitz  166   167 , Amanda E Toland  168 , Diana Torres  97   169 , Alison H Trainer  108   170 , Thérèse Truong  91 , Nadine Tung  171 , Celine M Vachon  172 , Ana Vega  173 , Joseph Vijai  145   157 , Qin Wang  4 , Barbara Wappenschmidt  93   94 , Clarice R Weinberg  174 , Jeffrey N Weitzel  175 , Camilla Wendt  126 , Alicja Wolk  176   177 , Siddhartha Yadav  178 , Xiaohong R Yang  11 , Drakoulis Yannoukakos  71 , Wei Zheng  179 , Argyrios Ziogas  15 , Kristin K Zorn  180 , Sue K Park  181   182   183 , Mads Thomassen  184 , Kenneth Offit  145   157 , Rita K Schmutzler  93   94 , Fergus J Couch  185 , Jacques Simard  15 , Georgia Chenevix-Trench  7 , Douglas F Easton  4   8 , Nadine Andrieu  186   187   188   189 , Antonis C Antoniou  190
Collaborators, Affiliations
Multicenter Study

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Juliette Coignard et al. Nat Commun. .

Erratum in

  • Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.
    Coignard J, Lush M, Beesley J, O'Mara TA, Dennis J, Tyrer JP, Barnes DR, McGuffog L, Leslie G, Bolla MK, Adank MA, Agata S, Ahearn T, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Arnold N, Aronson KJ, Arun BK, Augustinsson A, Azzollini J, Barrowdale D, Baynes C, Becher H, Bermisheva M, Bernstein L, Białkowska K, Blomqvist C, Bojesen SE, Bonanni B, Borg A, Brauch H, Brenner H, Burwinkel B, Buys SS, Caldés T, Caligo MA, Campa D, Carter BD, Castelao JE, Chang-Claude J, Chanock SJ, Chung WK, Claes KBM, Clarke CL; GEMO Study Collaborators; EMBRACE Collaborators; Collée JM, Conroy DM, Czene K, Daly MB, Devilee P, Diez O, Ding YC, Domchek SM, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Eliassen AH, Engel C, Eriksson M, Evans DG, Fasching PA, Flyger H, Fostira F, Friedman E, Fritschi L, Frost D, Gago-Dominguez M, Gapstur SM, Garber J, Garcia-Barberan V, García-Closas M, García-Sáenz JA, Gaudet MM, Gayther SA, Gehrig A, Georgoulias V, Giles GG, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hart SN, He W, Hogervorst FBL, Hollestelle A, Hopper JL, Horcasitas DJ, Hu… See abstract for full author list ➔ Coignard J, et al. Nat Commun. 2021 May 14;12(1):2986. doi: 10.1038/s41467-021-23162-4. Nat Commun. 2021. PMID: 33990587 Free PMC article.

Abstract

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Case-only sample selection.
Sample selection for a BRCA1 and b BRCA2 case-only analysis. *Four studies were excluded because they were included in clinical trials based on breast tumour characteristics as HER-2 receptor status (see Supplementary Table 2).
Fig. 2
Fig. 2. Control-only sample selection.
Sample selection for a BRCA1 and b BRCA2 control-only analysis.
Fig. 3
Fig. 3. Analytical process for known BC susceptibility SNPs.
Strategy followed for analysing the associations for the 179 known BC susceptibility SNPs.
Fig. 4
Fig. 4. Analytical process for identifying novel modifiers.
Strategy followed for identifying potentially novel SNP modifier.
See this image and copyright information in PMC

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