Witt Dennis, Sturm Marc, Stäbler Antje, Menden Benita, Ruisinger Lisa, Bosse Kristin, Gruber Ines, Hartkopf Andreas, Gauß Silja, Demidov German, Casadei Nicolas, Atienza Elena Buena, Mehnert Kira, Witt Janna, Gross Caspar, Schütz Leon, Schroeder Christopher, Ossowski Stephan, Dufke Andreas, Haack Tobias B, Riess Olaf, Faust Ulrike
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Breast. 2025 May 15;82:104505. doi: 10.1016/j.breast.2025.104505.
Hereditary breast and ovarian cancer (HBOC) is one of the most frequent genetic cancer predisposition syndromes. Individuals at risk are identified mainly by family history and histopathological criteria. The current standard genetic testing is exome or panel sequencing. However, many high-risk families remain genetically unexplained. Genome sequencing has the potential to increase the diagnostic yield. This single-center real-world study aims to evaluate advantages of short-read genome sequencing (GS) in HBOC families. We report genome sequencing results of 818 index patients, who fulfilled clinical criteria for genetic testing. Data analysis showed less sequencing gaps and a more uniform coverage compared to a large cohort of in-house exomes. Samples were sequenced at an average depth of 41.2x for the HBOC core genes. Pathogenic variants were found in 9 of 13 core genes in 12.2 % of the patients. GS allowed the classification of a BRCA1 duplication and detected a whole-exon inversion in BARD1, as well as a deep intronic CHEK2 variant. Furthermore, we successfully used the BRIDGES-PRS in our HBOC cohort and found a significant effect size compared to the control cohort (p = 4.804, Cohen's-D: 0.476), proving the transferability to a German cohort. GS offers a wealth of information, including the improved detection of structural variants, copy number variants, and parallel detection of complex genetic markers. This has the potential for future analyses, including intronic and intergenic regions. Finally, it also allows for a more streamlined process by converging several tests into one. The approach presented will give guidance for the implementation of GS in HBOC diagnostics.
遗传性乳腺癌和卵巢癌（HBOC）是最常见的遗传性癌症易感性综合征之一。有风险的个体主要通过家族史和组织病理学标准来确定。当前的标准基因检测是外显子组或基因panel测序。然而，许多高危家族在基因方面仍无法解释。基因组测序有提高诊断率的潜力。这项单中心真实世界研究旨在评估短读长基因组测序（GS）在HBOC家族中的优势。我们报告了818例符合基因检测临床标准的索引患者的基因组测序结果。数据分析显示，与大量内部外显子组队列相比，测序间隙更少，覆盖更均匀。HBOC核心基因的样本平均测序深度为41.2倍。在12.2%的患者中，13个核心基因中的9个发现了致病变异。GS能够对BRCA1重复进行分类，并检测到BARD1中的一个全外显子倒位，以及一个CHEK2基因内含子深处的变异。此外，我们在HBOC队列中成功使用了BRIDGES-PRS，与对照队列相比发现了显著的效应量（p = 4.804，科恩D值：0.476），证明了其可转移性至德国队列。GS提供了丰富的信息，包括改进对结构变异、拷贝数变异的检测，以及对复杂遗传标记的并行检测。这对未来的分析具有潜力，包括内含子和基因间区域。最后，它还通过将多项检测整合为一项检测，使检测过程更加简化。所提出的方法将为GS在HBOC诊断中的应用提供指导。
