Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

被引：128

作者：

Hauke, Jan ^{[1
]}

Horvath, Judit ^{[2
]}

Gross, Eva ^{[3
]}

Gehrig, Andrea ^{[4
]}

Honisch, Ellen ^{[5
]}

Hackmann, Karl ^{[6
]}

Schmidt, Gunnar ^{[7
]}

Arnold, Norbert ^{[8
]}

Faust, Ulrike ^{[9
]}

Sutter, Christian ^{[10
]}

Hentschel, Julia ^{[11
]}

Wang-Gohrke, Shan ^{[12
]}

Smogavec, Mateja ^{[13
]}

Weber, Bernhard H. F. ^{[14
]}

Weber-Lassalle, Nana ^{[1
]}

Weber-Lassalle, Konstantin ^{[1
]}

Borde, Julika ^{[1
]}

Ernst, Corinna ^{[1
]}

Altmueller, Janine ^{[15
,16
,17
]}

Volk, Alexander E. ^{[18
]}

Thiele, Holger ^{[15
,16
,17
]}

Huebbel, Verena ^{[1
]}

Nuernberg, Peter ^{[15
,16
,17
]}

Keupp, Katharina ^{[1
]}

Versmold, Beatrix ^{[1
]}

Pohl, Esther ^{[1
]}

Kubisch, Christian ^{[18
]}

Grill, Sabine ^{[3
]}

Paul, Victoria ^{[2
]}

Herold, Natalie ^{[1
]}

Lichey, Nadine ^{[2
]}

Rhiem, Kerstin ^{[1
]}

Ditsch, Nina ^{[19
]}

Ruckert, Christian ^{[2
]}

Wappenschmidt, Barbara ^{[1
]}

Auber, Bernd ^{[7
]}

Rump, Andreas ^{[6
]}

Niederacher, Dieter ^{[5
]}

Haaf, Thomas ^{[4
]}

Ramser, Juliane

Dworniczak, Bernd ^{[2
]}

Engel, Christoph ^{[20
,21
]}

Meindl, Alfons ^{[3
]}

Schmutzler, Rita K. ^{[1
]}

Hahnen, Eric ^{[1
]}

机构：

[1] Univ Hosp Cologne, Med Fac, CIO, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany

[2] Univ Hosp Muenster, Inst Human Genet, Munster, Germany

[3] Tech Univ Munich, Klinikum Rechts Isar, Div Tumor Genet, Dept Gynaecol & Obstet, Munich, Germany

[4] Julius Maximilians Univ Wurzburg, Inst Human Genet, Wurzburg, Germany

[5] Heinrich Heine Univ Duesseldorf, Univ Hosp Duesseldorf, Dept Gynaecol & Obstet, Dusseldorf, Germany

[6] Tech Univ Dresden, Inst Clin Genet, Dresden, Germany

[7] Hannover Med Sch, Dept Human Genet, Hannover, Germany

[8] Christian Albrechts Univ Kiel, Univ Hosp Schleswig Holstein, Inst Clin Mol Biol, Dept Gynaecol & Obstet, Campus Kiel, Kiel, Germany

[9] Univ Hosp Tuebingen, Inst Med Genet & Appl Genom, Tubingen, Germany

[10] Heidelberg Univ, Inst Human Genet, Heidelberg, Germany

[11] Univ Leipzig, Inst Human Genet, Hosp & Clin, Leipzig, Germany

[12] Univ Hosp Ulm, Dept Gynaecol & Obstet, Ulm, Germany

[13] Georg August Univ, Univ Med Ctr, Inst Human Genet, Gottingen, Germany

[14] Univ Regensburg, Inst Human Genet, Regensburg, Germany

[15] Univ Cologne, Cologne Ctr Genom, Cologne, Germany

[16] Univ Cologne, Inst Human Genet, Cologne, Germany

[17] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, Cologne, Germany

[18] Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, Hamburg, Germany

[19] Ludwig Maximilians Univ Munchen, Dept Obstet & Gynaecol, Munich, Germany

[20] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany

[21] Univ Leipzig, LIFE Leipzig Res Ctr Civilizat Dis, Leipzig, Germany

来源：

CANCER MEDICINE | 2018年 / 7卷 / 04期

关键词：

Breast cancer predisposition; hereditary breast cancer; GERMLINE MUTATIONS; ATAXIA-TELANGIECTASIA; CONFER SUSCEPTIBILITY; FOUNDER MUTATION; RISK; FAMILIES; CARRIERS; RAD51C; WOMEN; CHEK2-ASTERISK-1100DELC;

D O I：

10.1002/cam4.1376

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95% CI: 2.67-4.94), CDH1 (OR: 17.04, 95% CI: 3.54-82), CHEK2 (OR: 2.93, 95% CI: 2.29-3.75), PALB2 (OR: 9.53, 95% CI: 6.25-14.51), and TP53 (OR: 7.30, 95% CI: 1.22-43.68). NBN germ line mutations were not significantly associated with BC risk (OR: 1.39, 95% CI: 0.73-2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors.

引用

页码：1349 / 1358

页数：10

共 36 条

[1] Protein-truncating variants in moderate-risk breast cancer susceptibility genes: A meta-analysis of high-risk case-control screening studies
Aloraifi, Fatima
McCartan, Damian
McDevitt, Trudi
Green, Andrew J.
Bracken, Adrian
Geraghty, James
[J]. CANCER GENETICS, 2015, 208 (09) : 455 - 463
[2] Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers
Bougeard, Gaelle
Renaux-Petel, Mariette
Flaman, Jean-Michel
Charbonnier, Camille
Fermey, Pierre
Belotti, Muriel
Gauthier-Villars, Marion
Stoppa-Lyonnet, Dominique
Consolino, Emilie
Brugieres, Laurence
Caron, Olivier
Benusiglio, Patrick R.
Bressac-de Paillerets, Brigitte
Bonadona, Valerie
Bonaiti-Pellie, Catherine
Tinat, Julie
Baert-Desurmont, Stephanie
Frebourg, Thierry
[J]. JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (21) : 2345 - U33
[3] A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes
Buys, Saundra S.
Sandbach, John F.
Gammon, Amanda
Patel, Gayle
Kidd, John
Brown, Krystal L.
Sharma, Lavania
Saam, Jennifer
Lancaster, Johnathan
Daly, Mary B.
[J]. CANCER, 2017, 123 (10) : 1721 - 1730
[4] Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer
Couch, Fergus J.
Shimelis, Hermela
Hu, Chunling
Hart, Steven N.
Polley, Eric C.
Na, Jie
Hallberg, Emily
Moore, Raymond
Thomas, Abigail
Lilyquist, Jenna
Feng, Bingjian
McFarland, Rachel
Pesaran, Tina
Huether, Robert
LaDuca, Holly
Chao, Elizabeth C.
Goldgar, David E.
Dolinsky, Jill S.
[J]. JAMA ONCOLOGY, 2017, 3 (09) : 1190 - 1196
[5] Easton D, 2004, AM J HUM GENET, V74, P1175, DOI 10.1086/421251
[6] Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk
Easton, Douglas F.
Pharoah, Paul D. P.
Antoniou, Antonis C.
Tischkowitz, Marc
Tavtigian, Sean V.
Nathanson, Katherine L.
Devilee, Peter
Meindl, Alfons
Couch, Fergus J.
Southey, Melissa
Goldgar, David E.
Evans, Gareth R.
Chenevix-Trench, Georgia
Rahman, Nazneen
Robson, Mark
Domchek, Susan M.
Foulkes, William D.
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2015, 372 (23) : 2243 - 2257
[7] Penetrance analysis of the PALB2 c.1592delT founder mutation
Erkko, Hannele
Dowty, James G.
Nikkila, Jenni
Syrjaekoski, Kirsi
Mannermaa, Arto
Pylkas, Katri
Southey, Melissa C.
Holli, Kaija
Kallioniemi, Anne
Jukkola-Vuorinen, Arja
Kataja, Vesa
Kosma, Veli-Matti
Xia, Bing
Livingston, David M.
Winqvist, Robert
Hopper, John L.
[J]. CLINICAL CANCER RESEARCH, 2008, 14 (14) : 4667 - 4671
[8] A recurrent mutation in PALB2 in Finnish cancer families
Erkko, Hannele
Xia, Bing
Nikkilae, Jenni
Schleutker, Johanna
Syrjaekoski, Kirsi
Mannermaa, Arto
Kallioniemi, Anne
Pylkas, Katri
Karppinen, Sanna-Maria
Rapakko, Katrin
Miron, Alexander
Sheng, Qing
Li, Guilan
Mattila, Henna
Bell, Daphne W.
Haber, Daniel A.
Grip, Mervi
Reiman, Mervi
Jukkola-Vuorinen, Arja
Mustonen, Aki
Kere, Juha
Aaltonen, Lauri A.
Kosma, Veli-Matti
Kataja, Vesa
Soini, Ylermi
Drapkin, Ronny I.
Livingston, David M.
Winqvist, Robert
[J]. NATURE, 2007, 446 (7133) : 316 - 319
[9] Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer Secondary Analysis of the GeparSixto Randomized Clinical Trial
Hahnen, Eric
Lederer, Bianca
Hauke, Jan
Loibl, Sibylle
Kroeber, Sandra
Schneeweiss, Andreas
Denkert, Carsten
Fasching, Peter A.
Blohmer, Jens U.
Jackisch, Christian
Paepke, Stefan
Gerber, Bernd
Kuemmel, Sherko
Schem, Christian
Neidhardt, Guido
Huober, Jens
Rhiem, Kerstin
Costa, Serban
Altmueller, Janine
Hanusch, Claus
Thiele, Holger
Mueller, Volkmar
Nuernberg, Peter
Karn, Thomas
Nekljudova, Valentina
Untch, Michael
von Minckwitz, Gunter
Schmutzler, Rita K.
[J]. JAMA ONCOLOGY, 2017, 3 (10) : 1378 - 1385
[10] Germline Mutations in Triple-Negative Breast Cancer
Hahnen, Eric
Hauke, Jan
Engel, Christoph
Neidhardt, Guido
Rhiem, Kerstin
Schmutzler, Rita K.
[J]. BREAST CARE, 2017, 12 (01) : 15 - 19

← 1 2 3 4 →