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：135

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

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