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. 2015 Apr 1;10(4):e0120020.
doi: 10.1371/journal.pone.0120020. eCollection 2015.

Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

Ignacio Blanco  1 , Karoline Kuchenbaecker  2 , Daniel Cuadras  3 , Xianshu Wang  4 , Daniel Barrowdale  2 , Gorka Ruiz de Garibay  5 , Pablo Librado  6 , Alejandro Sánchez-Gracia  6 , Julio Rozas  6 , Núria Bonifaci  5 , Lesley McGuffog  2 , Vernon S Pankratz  7 , Abul Islam  8 , Francesca Mateo  5 , Antoni Berenguer  3 , Anna Petit  9 , Isabel Català  9 , Joan Brunet  10 , Lidia Feliubadaló  1 , Eva Tornero  1 , Javier Benítez  11 , Ana Osorio  11 , Teresa Ramón y Cajal  12 , Heli Nevanlinna  13 , Kristiina Aittomäki  14 , Banu K Arun  15 , Amanda E Toland  16 , Beth Y Karlan  17 , Christine Walsh  17 , Jenny Lester  17 , Mark H Greene  18 , Phuong L Mai  18 , Robert L Nussbaum  19 , Irene L Andrulis  20 , Susan M Domchek  21 , Katherine L Nathanson  21 , Timothy R Rebbeck  22 , Rosa B Barkardottir  23 , Anna Jakubowska  24 , Jan Lubinski  24 , Katarzyna Durda  24 , Katarzyna Jaworska-Bieniek  24 , Kathleen Claes  25 , Tom Van Maerken  25 , Orland Díez  26 , Thomas V Hansen  27 , Lars Jønson  27 , Anne-Marie Gerdes  28 , Bent Ejlertsen  29 , Miguel de la Hoya  30 , Trinidad Caldés  30 , Alison M Dunning  2 , Clare Oliver  2 , Elena Fineberg  2 , Margaret Cook  2 , Susan Peock  2 , Emma McCann  31 , Alex Murray  32 , Chris Jacobs  33 , Gabriella Pichert  33 , Fiona Lalloo  34 , Carol Chu  35 , Huw Dorkins  36 , Joan Paterson  37 , Kai-Ren Ong  38 , Manuel R Teixeira  39 ; Teixeira; Frans B L Hogervorst  40 , Annemarie H van der Hout  41 , Caroline Seynaeve  42 , Rob B van der Luijt  43 , Marjolijn J L Ligtenberg  44 , Peter Devilee  45 , Juul T Wijnen  46 , Matti A Rookus  47 , Hanne E J Meijers-Heijboer  48 , Marinus J Blok  49 , Ans M W van den Ouweland  50 , Cora M Aalfs  51 , Gustavo C Rodriguez  52 , Kelly-Anne A Phillips  53 , Marion Piedmonte  54 , Stacy R Nerenstone  55 , Victoria L Bae-Jump  56 , David M O'Malley  57 , Elena S Ratner  58 , Rita K Schmutzler  59 , Barbara Wappenschmidt  59 , Kerstin Rhiem  59 , Christoph Engel  60 , Alfons Meindl  61 , Nina Ditsch  62 , Norbert Arnold  63 , Hansjoerg J Plendl  64 , Dieter Niederacher  65 , Christian Sutter  66 , Shan Wang-Gohrke  67 , Doris Steinemann  68 , Sabine Preisler-Adams  69 , Karin Kast  70 , Raymonda Varon-Mateeva  71 , Andrea Gehrig  72 , Anders Bojesen  73 , Inge Sokilde Pedersen  74 , Lone Sunde  75 , Uffe Birk Jensen  75 , Mads Thomassen  76 , Torben A Kruse  76 , Lenka Foretova  77 , Paolo Peterlongo  78 , Loris Bernard  79 , Bernard Peissel  80 , Giulietta Scuvera  80 , Siranoush Manoukian  80 , Paolo Radice  81 , Laura Ottini  82 , Marco Montagna  83 , Simona Agata  83 , Christine Maugard  84 , Jacques Simard  85 , Penny Soucy  85 , Andreas Berger  86 , Anneliese Fink-Retter  86 , Christian F Singer  86 , Christine Rappaport  86 , Daphne Geschwantler-Kaulich  86 , Muy-Kheng Tea  86 , Georg Pfeiler  86 ; BCFR; Esther M John  87 , Alex Miron  88 , Susan L Neuhausen  89 , Mary Beth Terry  90 , Wendy K Chung  91 , Mary B Daly  92 , David E Goldgar  93 , Ramunas Janavicius  94 , Cecilia M Dorfling  95 , Elisabeth J van Rensburg  95 , Florentia Fostira  96 , Irene Konstantopoulou  96 , Judy Garber  97 , Andrew K Godwin  98 , Edith Olah  99 , Steven A Narod  100 , Gad Rennert  101 , Shani Shimon Paluch  102 , Yael Laitman  103 , Eitan Friedman  104 ; SWE-BRCA; Annelie Liljegren  105 , Johanna Rantala  106 , Marie Stenmark-Askmalm  107 , Niklas Loman  108 , Evgeny N Imyanitov  109 , Ute Hamann  110 ; kConFab Investigators; Amanda B Spurdle  111 , Sue Healey  111 , Jeffrey N Weitzel  112 , Josef Herzog  112 , David Margileth  113 , Chiara Gorrini  114 , Manel Esteller  115 , Antonio Gómez  116 , Sergi Sayols  116 , Enrique Vidal  116 , Holger Heyn  116 ; GEMO; Dominique Stoppa-Lyonnet  117 , Melanie Léoné  118 , Laure Barjhoux  119 , Marion Fassy-Colcombet  120 , Antoine de Pauw  120 , Christine Lasset  121 , Sandra Fert Ferrer  122 , Laurent Castera  120 , Pascaline Berthet  123 , François Cornelis  124 , Yves-Jean Bignon  125 , Francesca Damiola  119 , Sylvie Mazoyer  119 , Olga M Sinilnikova  126 , Christopher A Maxwell  127 , Joseph Vijai  128 , Mark Robson  128 , Noah Kauff  128 , Marina J Corines  128 , Danylko Villano  128 , Julie Cunningham  129 , Adam Lee  130 , Noralane Lindor  131 , Conxi Lázaro  1 , Douglas F Easton  2 , Kenneth Offit  128 , Georgia Chenevix-Trench  111 , Fergus J Couch  129 , Antonis C Antoniou  2 , Miguel Angel Pujana  5
Collaborators, Affiliations

Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

Ignacio Blanco et al. PLoS One. .

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 pinteraction 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.

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Conflict of interest statement

Competing Interests: PP is an author of this study and is a member of the PLOS ONE Editorial Board; this does not alter the authors' adherence to PLOS ONE Editorial policies and criteria.

Figures

Fig 1
Fig 1. The HMMR locus and breast cancer risk in BRCA1 mutation carriers.
(A) Forest plots showing rs299290 HRs and 95% CIs (retrospective likelihood trend estimation) for participating countries (relatively small sample sets are not shown) ordered by sample size. Left and right panels show results for BRCA1 and BRCA2 mutation carriers, respectively. The sizes of the rectangles are proportional to the corresponding country/study precision. (B) The rs299290-containing region, including the genes, variation and regulatory evidence mentioned in HMECs. Exons are marked by black-filled rectangles and the direction of transcription is marked by arrows in the genomic structure. The chromosome 5 positions (base pairs (bp)) and linkage disequilibrium structure from Caucasian HapMap individuals are also shown.
Fig 2
Fig 2. Candidate amino acid sites under positive selection in RHAMM and BRCA1.
(A) Plot showing the position of potentially selected sites (p (w > 1)) in the amino acid sequence of RHAMM. The relative position of known protein domains is shown. (B) Plot showing the position of potentially selected sites (p (w > 1)) in the amino acid sequence of BRCA1. The relative position of known protein domains is shown.
Fig 3
Fig 3. The AURKA/CSTF1 locus and breast cancer risk in BRCA2 mutation carriers.
(A) Forest plots showing rs2426618 HRs and 95% CIs (retrospective likelihood trend estimation) for participating countries (relatively small sample sets are not shown) ordered by sample size. Left and right panels show results for BRCA1 and BRCA2 mutation carriers, respectively. The sizes of the rectangles are proportional to the corresponding study precision. (B) The rs2426618-containing region, including the genes, variation and regulatory evidence in HMECs. Exons are marked by black-filled rectangles and the direction of transcription is marked by arrows in the genomic structure. The chromosome 20 positions (bp) and linkage disequilibrium structure from Caucasian HapMap individuals are also shown.
Fig 4
Fig 4. Gene expression interactions in breast cancer survival.
(A) Kaplan–Meier survival curves based on categorization of HMMR (probe NM_012484) and AURKA (NM_003600) expression in tertiles (low, medium or high expression). For simplicity, only the tertiles for “high” AURKA are shown. The tumours with high expression levels for both genes were not those with the poorest prognosis. (B) Kaplan–Meier survival curves based on categorization of HMMR (NM_012484) and TUBG1 (NM_016437) expression in tertiles (low, medium or high expression). For simplicity, only the tertiles for “high” HMMR are shown. The cases with high expression levels for both genes were those with the poorest prognosis.
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References

    1. Pujana MA, Han JD, Starita LM, Stevens KN, Tewari M, Ahn JS, et al. Network modeling links breast cancer susceptibility and centrosome dysfunction. Nat Genet. 2007;39: 1338–1349. - PubMed
    1. Kalmyrzaev B, Pharoah PD, Easton DF, Ponder BA, Dunning AM Hyaluronan-mediated motility receptor gene single nucleotide polymorphisms and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2008;17: 3618–3620. 10.1158/1055-9965.EPI-08-0216 - DOI - PubMed
    1. Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet. 2007;39: 870–874. - PMC - PubMed
    1. Maxwell CA, Benitez J, Gomez-Baldo L, Osorio A, Bonifaci N, Fernandez-Ramires R, et al. Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. PLoS Biol. 2011;9: e1001199 10.1371/journal.pbio.1001199 - DOI - PMC - PubMed
    1. Couch FJ, Sinilnikova O, Vierkant RA, Pankratz VS, Fredericksen ZS, Stoppa-Lyonnet D, et al. AURKA F31I polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a consortium of investigators of modifiers of BRCA1/2 study. Cancer Epidemiol Biomarkers Prev. 2007;16: 1416–1421. - PMC - PubMed

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