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Multicenter Study
. 2016 Dec;53(12):800-811.
doi: 10.1136/jmedgenet-2016-103839. Epub 2016 Sep 5.

PALB2, CHEK2 and ATM Rare Variants and Cancer Risk: Data From COGS

Melissa C Southey  1 David E Goldgar  2 Robert Winqvist  3 Katri Pylkäs  3 Fergus Couch  4 Marc Tischkowitz  5 William D Foulkes  6 Joe Dennis  7 Kyriaki Michailidou  7 Elizabeth J van Rensburg  8 Tuomas Heikkinen  9 Heli Nevanlinna  9 John L Hopper  10 Thilo Dörk  11 Kathleen Bm Claes  12 Jorge Reis-Filho  13 Zhi Ling Teo  1 Paolo Radice  14 Irene Catucci  15 Paolo Peterlongo  15 Helen Tsimiklis  1 Fabrice A Odefrey  1 James G Dowty  10 Marjanka K Schmidt  16 Annegien Broeks  16 Frans B Hogervorst  16 Senno Verhoef  16 Jane Carpenter  17 Christine Clarke  18 Rodney J Scott  19 Peter A Fasching  20   21 Lothar Haeberle  20   22 Arif B Ekici  23 Matthias W Beckmann  20 Julian Peto  24 Isabel Dos-Santos-Silva  24 Olivia Fletcher  25 Nichola Johnson  25 Manjeet K Bolla  7 Elinor J Sawyer  26 Ian Tomlinson  27 Michael J Kerin  28 Nicola Miller  28 Federik Marme  29   30 Barbara Burwinkel  29   31 Rongxi Yang  29   31 Pascal Guénel  32   33 Thérèse Truong  32   33 Florence Menegaux  32   33 Marie Sanchez  32   33 Stig Bojesen  34   35 Sune F Nielsen  34   35 Henrik Flyger  36 Javier Benitez  37   38 M Pilar Zamora  39 Jose Ignacio Arias Perez  40 Primitiva Menéndez  41 Hoda Anton-Culver  42 Susan Neuhausen  43 Argyrios Ziogas  42 Christina A Clarke  44 Hermann Brenner  45   46   47 Volker Arndt  45 Christa Stegmaier  48 Hiltrud Brauch  47   49   50 Thomas Brüning  51 Yon-Dschun Ko  52 Taru A Muranen  9 Kristiina Aittomäki  53 Carl Blomqvist  54 Natalia V Bogdanova  11   55 Natalia N Antonenkova  56 Annika Lindblom  57 Sara Margolin  58 Arto Mannermaa  59   60 Vesa Kataja  61   62 Veli-Matti Kosma  59   60 Jaana M Hartikainen  59   60 Amanda B Spurdle  63 kConFab Investigators  64 Australian Ovarian Cancer Study GroupEls Wauters  65   66 Dominiek Smeets  65   66 Benoit Beuselinck  67 Giuseppe Floris  67 Jenny Chang-Claude  68 Anja Rudolph  68 Petra Seibold  68 Dieter Flesch-Janys  69 Janet E Olson  70 Celine Vachon  70 Vernon S Pankratz  70 Catriona McLean  71 Christopher A Haiman  72 Brian E Henderson  72 Fredrick Schumacher  72 Loic Le Marchand  73 Vessela Kristensen  74   75 Grethe Grenaker Alnæs  74 Wei Zheng  76 David J Hunter  77   78 Sara Lindstrom  77   78 Susan E Hankinson  78   79 Peter Kraft  77   78 Irene Andrulis  80   81 Julia A Knight  82   83 Gord Glendon  80 Anna Marie Mulligan  84   85 Arja Jukkola-Vuorinen  86 Mervi Grip  87 Saila Kauppila  88 Peter Devilee  89 Robert A E M Tollenaar  89 Caroline Seynaeve  90   91 Antoinette Hollestelle  90   91 Montserrat Garcia-Closas  92 Jonine Figueroa  93 Stephen J Chanock  93 Jolanta Lissowska  94 Kamila Czene  95 Hatef Darabi  95 Mikael Eriksson  95 Diana M Eccles  96 Sajjad Rafiq  96 William J Tapper  96 Sue M Gerty  96 Maartje J Hooning  91 John W M Martens  91 J Margriet Collée  97 Madeleine Tilanus-Linthorst  98 Per Hall  95 Jingmei Li  99 Judith S Brand  95 Keith Humphreys  95 Angela Cox  100 Malcolm W R Reed  100 Craig Luccarini  101 Caroline Baynes  101 Alison M Dunning  101 Ute Hamann  102 Diana Torres  102   103 Hans Ulrich Ulmer  104 Thomas Rüdiger  105 Anna Jakubowska  106 Jan Lubinski  106 Katarzyna Jaworska  106   107 Katarzyna Durda  106 Susan Slager  70 Amanda E Toland  108 Christine B Ambrosone  109 Drakoulis Yannoukakos  110 Anthony Swerdlow  111   112 Alan Ashworth  92 Nick Orr  92 Michael Jones  111 Anna González-Neira  37 Guillermo Pita  37 M Rosario Alonso  37 Nuria Álvarez  37 Daniel Herrero  37 Daniel C Tessier  113 Daniel Vincent  114 Francois Bacot  114 Jacques Simard  115 Martine Dumont  115 Penny Soucy  115 Rosalind Eeles  116   117 Kenneth Muir  118 Fredrik Wiklund  119 Henrik Gronberg  119 Johanna Schleutker  120   121 Børge G Nordestgaard  122 Maren Weischer  123 Ruth C Travis  124 David Neal  125 Jenny L Donovan  126 Freddie C Hamdy  127 Kay-Tee Khaw  128 Janet L Stanford  129   130 William J Blot  131 Stephen Thibodeau  4 Daniel J Schaid  70 Joseph L Kelley  132 Christiane Maier  133   134 Adam S Kibel  135   136 Cezary Cybulski  137 Lisa Cannon-Albright  138 Katja Butterbach  45 Jong Park  139 Radka Kaneva  140 Jyotsna Batra  141 Manuel R Teixeira  142 Zsofia Kote-Jarai  116 Ali Amin Al Olama  7 Sara Benlloch  7 Stefan P Renner  143 Arndt Hartmann  144 Alexander Hein  143 Matthias Ruebner  143 Diether Lambrechts  145   146 Els Van Nieuwenhuysen  147 Ignace Vergote  147 Sandrina Lambretchs  147 Jennifer A Doherty  148 Mary Anne Rossing  149   150 Stefan Nickels  151 Ursula Eilber  151 Shan Wang-Gohrke  152 Kunle Odunsi  153 Lara E Sucheston-Campbell  153 Grace Friel  153 Galina Lurie  154 Jeffrey L Killeen  155 Lynne R Wilkens  154 Marc T Goodman  156   157 Ingo Runnebaum  158 Peter A Hillemanns  159 Liisa M Pelttari  9 Ralf Butzow  160 Francesmary Modugno  161   162 Robert P Edwards  132 Roberta B Ness  163 Kirsten B Moysich  164 Andreas du Bois  165   166 Florian Heitz  165   166 Philipp Harter  165   166 Stefan Kommoss  166   167 Beth Y Karlan  168 Christine Walsh  168 Jenny Lester  168 Allan Jensen  169 Susanne Krüger Kjaer  169   170 Estrid Høgdall  169   171 Bernard Peissel  172 Bernardo Bonanni  173 Loris Bernard  174 Ellen L Goode  70 Brooke L Fridley  175 Robert A Vierkant  70 Julie M Cunningham  4 Melissa C Larson  70 Zachary C Fogarty  70 Kimberly R Kalli  176 Dong Liang  177 Karen H Lu  178 Michelle A T Hildebrandt  179 Xifeng Wu  179 Douglas A Levine  180 Fanny Dao  180 Maria Bisogna  180 Andrew Berchuck  181 Edwin S Iversen  182 Jeffrey R Marks  183 Lucy Akushevich  184 Daniel W Cramer  185 Joellen Schildkraut  184 Kathryn L Terry  185 Elizabeth M Poole  186   187 Meir Stampfer  78   186 Shelley S Tworoger  186   187 Elisa V Bandera  188 Irene Orlow  189 Sara H Olson  189 Line Bjorge  190   191 Helga B Salvesen  190   191 Anne M van Altena  192 Katja K H Aben  193   194   195 Lambertus A Kiemeney  193 Leon F A G Massuger  192 Tanja Pejovic  196 Yukie Bean  196 Angela Brooks-Wilson  197   198 Linda E Kelemen  199   200 Linda S Cook  201 Nhu D Le  202 Bohdan Górski  137 Jacek Gronwald  137 Janusz Menkiszak  203 Claus K Høgdall  170 Lene Lundvall  204 Lotte Nedergaard  205 Svend Aage Engelholm  206 Ed Dicks  207 Jonathan Tyrer  207 Ian Campbell  208 Iain McNeish  209 James Paul  210 Nadeem Siddiqui  211 Rosalind Glasspool  211 Alice S Whittemore  212 Joseph H Rothstein  212 Valerie McGuire  212 Weiva Sieh  212 Hui Cai  76 Xiao-Ou Shu  76 Rachel T Teten  213 Rebecca Sutphen  213 John R McLaughlin  214 Steven A Narod  215 Catherine M Phelan  216 Alvaro N Monteiro  216 David Fenstermacher  217 Hui-Yi Lin  217 Jennifer B Permuth  216 Thomas A Sellers  216 Y Ann Chen  217 Ya-Yu Tsai  216 Zhihua Chen  217 Aleksandra Gentry-Maharaj  218 Simon A Gayther  219 Susan J Ramus  219 Usha Menon  218 Anna H Wu  219 Celeste L Pearce  219 David Van Den Berg  219 Malcolm C Pike  219   220 Agnieszka Dansonka-Mieszkowska  221 Joanna Plisiecka-Halasa  221 Joanna Moes-Sosnowska  221 Jolanta Kupryjanczyk  221 Paul Dp Pharoah  207 Honglin Song  207 Ingrid Winship  222   223 Georgia Chenevix-Trench  63 Graham G Giles  10   224 Sean V Tavtigian  2 Doug F Easton  7 Roger L Milne  10   224
Affiliations
Free PMC article
Multicenter Study

PALB2, CHEK2 and ATM Rare Variants and Cancer Risk: Data From COGS

Melissa C Southey et al. J Med Genet. .
Free PMC article

Abstract

Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.

Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.

Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.

Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Keywords: Cancer: breast; Cancer: ovary; Cancer: prostate; Genetics; cancer predisposition.

Conflict of interest statement

Conflicts of Interest: None declared.

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