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Hauke, Jan; Horvath, Judit; Groß, Eva; Gehrig, Andrea; Honisch, Ellen; Hackmann, Karl; Schmidt, Gunnar; Arnold, Norbert; Faust, Ulrike; Sutter, Christian; Hentschel, Julia; Wang‐Gohrke, Shan; Smogavec, Mateja; Weber, Bernhard H. F.; Weber‐Lassalle, Nana; Weber‐Lassalle, Konstantin; Borde, Julika; Ernst, Corinna; Altmüller, Janine; Volk, Alexander E.; Thiele, Holger; Hübbel, Verena; Nürnberg, Peter; Keupp, Katharina; [...]

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

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  • Medientyp: E-Artikel
  • Titel: 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
  • Beteiligte: Hauke, Jan; Horvath, Judit; Groß, Eva; Gehrig, Andrea; Honisch, Ellen; Hackmann, Karl; Schmidt, Gunnar; Arnold, Norbert; Faust, Ulrike; Sutter, Christian; Hentschel, Julia; Wang‐Gohrke, Shan; Smogavec, Mateja; Weber, Bernhard H. F.; Weber‐Lassalle, Nana; Weber‐Lassalle, Konstantin; Borde, Julika; Ernst, Corinna; Altmüller, Janine; Volk, Alexander E.; Thiele, Holger; Hübbel, Verena; Nürnberg, Peter; Keupp, Katharina; [...]
  • Erschienen: Wiley, 2018
  • Erschienen in: Cancer Medicine
  • Sprache: Englisch
  • DOI: 10.1002/cam4.1376
  • ISSN: 2045-7634
  • Schlagwörter: Cancer Research ; Radiology, Nuclear Medicine and imaging ; Oncology
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>The prevalence of germ line mutations in non‐<jats:italic><jats:styled-content style="fixed-case">BRCA</jats:styled-content>1/2</jats:italic> genes associated with hereditary breast cancer (<jats:styled-content style="fixed-case">BC</jats:styled-content>) is low, and the role of some of these genes in <jats:styled-content style="fixed-case">BC</jats:styled-content> predisposition and pathogenesis is conflicting. In this study, 5589 consecutive <jats:styled-content style="fixed-case">BC</jats:styled-content> index patients negative for pathogenic <jats:italic><jats:styled-content style="fixed-case">BRCA</jats:styled-content>1/2</jats:italic> mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (<jats:italic><jats:styled-content style="fixed-case">ATM</jats:styled-content></jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">CDH</jats:styled-content>1</jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">CHEK</jats:styled-content>2</jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">NBN</jats:styled-content></jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">PALB</jats:styled-content>2</jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">RAD</jats:styled-content>51C</jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">RAD</jats:styled-content>51D,</jats:italic> and <jats:italic><jats:styled-content style="fixed-case">TP</jats:styled-content>53</jats:italic>). 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 <jats:italic><jats:styled-content style="fixed-case">CHEK</jats:styled-content>2</jats:italic> gene (2.5%), followed by <jats:italic><jats:styled-content style="fixed-case">ATM</jats:styled-content></jats:italic> (1.5%) and <jats:italic><jats:styled-content style="fixed-case">PALB</jats:styled-content>2</jats:italic> (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 <jats:styled-content style="fixed-case">BC</jats:styled-content> for <jats:italic><jats:styled-content style="fixed-case">ATM</jats:styled-content></jats:italic> (<jats:styled-content style="fixed-case">OR</jats:styled-content>: 3.63, 95%<jats:styled-content style="fixed-case">CI</jats:styled-content>: 2.67–4.94), <jats:italic><jats:styled-content style="fixed-case">CDH</jats:styled-content>1</jats:italic> (<jats:styled-content style="fixed-case">OR</jats:styled-content>: 17.04, 95%<jats:styled-content style="fixed-case">CI</jats:styled-content>: 3.54–82), <jats:italic><jats:styled-content style="fixed-case">CHEK</jats:styled-content>2</jats:italic> (<jats:styled-content style="fixed-case">OR</jats:styled-content>: 2.93, 95%<jats:styled-content style="fixed-case">CI</jats:styled-content>: 2.29–3.75), <jats:italic><jats:styled-content style="fixed-case">PALB</jats:styled-content>2</jats:italic> (<jats:styled-content style="fixed-case">OR</jats:styled-content>: 9.53, 95%<jats:styled-content style="fixed-case">CI</jats:styled-content>: 6.25–14.51), and <jats:italic><jats:styled-content style="fixed-case">TP</jats:styled-content>53</jats:italic> (<jats:styled-content style="fixed-case">OR</jats:styled-content>: 7.30, 95%<jats:styled-content style="fixed-case">CI</jats:styled-content>: 1.22–43.68). <jats:italic><jats:styled-content style="fixed-case">NBN</jats:styled-content></jats:italic> germ line mutations were not significantly associated with <jats:styled-content style="fixed-case">BC</jats:styled-content> risk (<jats:styled-content style="fixed-case">OR</jats:styled-content>:1.39, 95%<jats:styled-content style="fixed-case">CI</jats:styled-content>: 0.73–2.64). Due to their low mutation prevalence, the <jats:italic><jats:styled-content style="fixed-case">RAD</jats:styled-content>51C</jats:italic> and <jats:italic><jats:styled-content style="fixed-case">RAD</jats:styled-content>51D</jats:italic> genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in <jats:italic><jats:styled-content style="fixed-case">CHEK</jats:styled-content>2</jats:italic> and <jats:italic><jats:styled-content style="fixed-case">TP</jats:styled-content>53</jats:italic> in <jats:styled-content style="fixed-case">BC</jats:styled-content> index patients. Compared with the overall sample, only <jats:italic><jats:styled-content style="fixed-case">TP</jats:styled-content>53</jats:italic> mutation carriers show a significantly younger age at first <jats:styled-content style="fixed-case">BC</jats:styled-content> diagnosis. We demonstrate a significant association of deleterious variants in the <jats:italic><jats:styled-content style="fixed-case">CHEK</jats:styled-content>2</jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">PALB</jats:styled-content>2,</jats:italic> and <jats:italic><jats:styled-content style="fixed-case">TP</jats:styled-content>53</jats:italic> genes with bilateral <jats:styled-content style="fixed-case">BC</jats:styled-content>. Both, <jats:italic><jats:styled-content style="fixed-case">ATM</jats:styled-content></jats:italic> and <jats:italic><jats:styled-content style="fixed-case">CHEK</jats:styled-content>2</jats:italic>, were negatively associated with triple‐negative breast cancer (<jats:styled-content style="fixed-case">TNBC</jats:styled-content>) and estrogen receptor (<jats:styled-content style="fixed-case">ER</jats:styled-content>)‐negative tumor phenotypes. A particularly high <jats:italic><jats:styled-content style="fixed-case">CHEK</jats:styled-content>2</jats:italic> mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (<jats:styled-content style="fixed-case">HER</jats:styled-content>2)‐positive tumors.</jats:p>
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