Schwartz Alison, Manning Danielle K, Koeller Diane R, Chittenden Anu, Isidro Raymond A, Hayes Connor P, Abraamyan Feruza, Manam Monica Devi, Dwan Meaghan, Barletta Justine A, Sholl Lynette M, Yurgelun Matthew B, Rana Huma Q, Garber Judy E, Ghazani Arezou A
Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States.
Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States.
Front Oncol. 2022 Aug 25;12:942741. doi: 10.3389/fonc.2022.942741. eCollection 2022.
Genomic profiles of tumors are often unique and represent characteristic mutational signatures defined by DNA damage or DNA repair response processes. The tumor-derived somatic information has been widely used in therapeutic applications, but it is grossly underutilized in the assessment of germline genetic variants. Here, we present a comprehensive approach for evaluating the pathogenicity of germline variants in cancer using an integrated interpretation of somatic and germline genomic data. We have previously demonstrated the utility of this integrated approach in the reassessment of pathogenic germline variants in selected cancer patients with unexpected or non-syndromic phenotypes. The application of this approach is presented in the assessment of rare variants of uncertain significance (VUS) in Lynch-related colon cancer, hereditary paraganglioma-pheochromocytoma syndrome, and Li-Fraumeni syndrome. Using this integrated method, germline VUS in , , , , and were assessed in 16 cancer patients after genetic evaluation. Comprehensive clinical criteria, somatic signature profiles, and tumor immunohistochemistry were used to re-classify VUS by upgrading or downgrading the variants to likely or unlikely actionable categories, respectively. Going forward, collation of such germline variants and creation of cross-institutional knowledgebase datasets that include integrated somatic and germline data will be crucial for the assessment of these variants in a larger cancer cohort.
肿瘤的基因组图谱通常是独特的，代表了由DNA损伤或DNA修复反应过程定义的特征性突变特征。肿瘤衍生的体细胞信息已广泛应用于治疗领域，但在种系遗传变异评估中却未得到充分利用。在此，我们提出一种综合方法，通过对体细胞和种系基因组数据的综合解读来评估癌症中种系变异的致病性。我们之前已经证明了这种综合方法在重新评估具有意外或非综合征表型的特定癌症患者的致病性种系变异中的效用。该方法的应用体现在对林奇相关结肠癌、遗传性副神经节瘤-嗜铬细胞瘤综合征和李-佛美尼综合征中意义未明的罕见变异（VUS）的评估中。使用这种综合方法，在基因评估后，对16例癌症患者中的、、、和的种系VUS进行了评估。综合临床标准、体细胞特征图谱和肿瘤免疫组化分别用于通过将变异升级或降级为可能或不太可能可操作的类别来重新分类VUS。展望未来，整理此类种系变异并创建包含综合体细胞和种系数据的跨机构知识库数据集对于在更大的癌症队列中评估这些变异至关重要。
