Koeller Diane R, Manning Danielle K, Schwartz Alison, Chittenden Anu, Hayes Connor P, Abraamyan Feruza, Rana Huma Q, Lindeman Neal I, Garber Judy E, Ghazani Arezou A
Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
MethodsX. 2022 Jun 18;9:101761. doi: 10.1016/j.mex.2022.101761. eCollection 2022.
The interpretation of hereditary genetic sequencing variants is often limited due to the absence of functional data and other key evidence to assess the role of variants in disease. Cancer genetics is unique, as two sets of genomic information are often available from a cancer patient: somatic and germline. Despite the progress made in the integrated analysis of somatic and germline findings, the assessment of pathogenicity of germline variants in high penetrance genes remains grossly underutilized. Indeed, standard ACMG/AMP guidelines for interpreting germline sequence variants do not address the evidence derived from tumor data in cancer. Previously, we have demonstrated the utility of somatic tumor data as supporting evidence to elucidate the role of germline variants in patients suspected with VHL syndrome and other cancers. We have leveraged the key elements of cancer genetics in these cases: genes with expected high disease penetrance and those with a known biallelic mechanism of tumorigenicity. Here we provide our optimized protocol for evaluating the pathogenicity of germline variants using informative somatic profiling data. This protocol provides details of case selection, assessment of personal and family evidence, somatic tumor profiles, and loss of heterozygosity (LOH) as supporting evidence for the re-evaluation of germline variants.
由于缺乏功能数据和其他关键证据来评估变异在疾病中的作用，遗传性基因测序变异的解读往往受到限制。癌症遗传学具有独特性，因为癌症患者通常可获得两组基因组信息：体细胞和种系信息。尽管在体细胞和种系研究结果的综合分析方面取得了进展，但高外显率基因中种系变异的致病性评估仍未得到充分利用。事实上，用于解读种系序列变异的标准美国医学遗传学与基因组学学会（ACMG）/美国分子病理学会（AMP）指南并未涉及癌症中来自肿瘤数据的证据。此前，我们已经证明体细胞肿瘤数据作为支持证据，可用于阐明疑似患有VHL综合征和其他癌症患者中种系变异的作用。在这些病例中，我们利用了癌症遗传学的关键要素：预期具有高疾病外显率的基因以及那些具有已知双等位基因致瘤机制的基因。在此，我们提供了优化方案，用于利用信息丰富的体细胞分析数据评估种系变异的致病性。该方案提供了病例选择、个人和家族证据评估、体细胞肿瘤图谱以及杂合性缺失（LOH）作为支持种系变异重新评估证据的详细信息。
