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Hauke, Jan; Harter, Philipp; Ernst, Corinna; Burges, Alexander; Schmidt, Sandra; Reuss, Alexander; Borde, Julika; De Gregorio, Nikolaus; Dietrich, Dimo; El-Balat, Ahmed; Kayali, Mohamad; Gevensleben, Heidrun; Hilpert, Felix; Altmüller, Janine; Heimbach, André; Meier, Werner; Schoemig-Markiefka, Birgid; Thiele, Holger; Kimmig, Rainer; Nürnberg, Peter; Kast, Karin; Richters, Lisa; Sehouli, Jalid; Schmutzler, Rita K;

Sensitivity and specificity of loss of heterozygosity analysis for the classification of rare germline variants in BRCA1/2: results of the observational AGO-TR1 study (NCT02222883)

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  • Medientyp: E-Artikel
  • Titel: Sensitivity and specificity of loss of heterozygosity analysis for the classification of rare germline variants in BRCA1/2: results of the observational AGO-TR1 study (NCT02222883)
  • Beteiligte: Hauke, Jan; Harter, Philipp; Ernst, Corinna; Burges, Alexander; Schmidt, Sandra; Reuss, Alexander; Borde, Julika; De Gregorio, Nikolaus; Dietrich, Dimo; El-Balat, Ahmed; Kayali, Mohamad; Gevensleben, Heidrun; Hilpert, Felix; Altmüller, Janine; Heimbach, André; Meier, Werner; Schoemig-Markiefka, Birgid; Thiele, Holger; Kimmig, Rainer; Nürnberg, Peter; Kast, Karin; Richters, Lisa; Sehouli, Jalid; Schmutzler, Rita K;
  • Erschienen: BMJ, 2022
  • Erschienen in: Journal of Medical Genetics
  • Sprache: Englisch
  • DOI: 10.1136/jmedgenet-2020-107353
  • ISSN: 0022-2593; 1468-6244
  • Schlagwörter: Genetics (clinical) ; Genetics
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:p>Variant-specific loss of heterozygosity (LOH) analyses may be useful to classify <jats:italic>BRCA1/2</jats:italic> germline variants of unknown significance (VUS). The sensitivity and specificity of this approach, however, remains unknown. We performed comparative next-generation sequencing analyses of the <jats:italic>BRCA1/2</jats:italic> genes using blood-derived and tumour-derived DNA of 488 patients with ovarian cancer enrolled in the observational AGO-TR1 trial (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT02222883">NCT02222883</jats:ext-link>). Overall, 94 pathogenic, 90 benign and 24 VUS were identified in the germline. A significantly increased variant fraction (VF) of a germline variant in the tumour indicates loss of the wild-type allele; a decreased VF indicates loss of the variant allele. We demonstrate that significantly increased VFs predict pathogenicity with high sensitivity (0.84, 95% CI 0.77 to 0.91), poor specificity (0.63, 95% CI 0.53 to 0.73) and poor positive predictive value (PPV; 0.71, 95% CI 0.62 to 0.79). Significantly decreased VFs predict benignity with low sensitivity (0.26, 95% CI 0.17 to 0.35), high specificity (1.0, 95% CI 0.96 to 1.00) and PPV (1.0, 95% CI 0.85 to 1.00). Variant classification based on significantly increased VFs results in an unacceptable proportion of false-positive results. A significantly decreased VF in the tumour may be exploited as a reliable predictor for benignity, with no false-negative result observed. When applying the latter approach, VUS identified in four patients can now be considered benign. <jats:bold>Trial registration number</jats:bold><jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" specific-use="clinicaltrial results" xlink:href="NCT02222883">NCT02222883</jats:ext-link>.</jats:p>