PO.PS01.08 · 人群科学
通过临床仅肿瘤测序鉴定的与遗传性癌症综合征相关的可疑致病性种系变异
Putative pathogenic germline variants associated with hereditary cancer syndromes identified through clinical tumor-only sequencing
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摘要 Abstract
中文摘要
背景：使用新一代测序（NGS）进行临床肿瘤测序被广泛应用于鉴定癌症患者中的可靶向变异和分子生物标志物。由于时间和成本的限制，大多数机构仅对肿瘤组织进行靶向基因组套测序，而非同时对肿瘤和配对的正常样本进行测序。然而，仅肿瘤测序无法可靠地区分患者携带的真正种系变异，尤其是那些与遗传性癌症综合征相关的变异。
方法：我们回顾性收集了 2022 年 12 月至 2025 年 5 月期间首尔国立大学医院（SNUH）癌症患者的临床仅肿瘤测序数据。所有数据均使用由 336 个癌症相关基因组成的定制 SNUH FiRST 癌症组套通过靶向 NGS 生成。根据 ESMO 精准医学工作组的建议以及患者的临床和家族史，对潜在致病性种系变异（PPGV）进行分类。最后，我们使用来自外周血单个核细胞的正常基因组 DNA，通过 Sanger 测序或靶向 NGS 方法确认真正的致病性种系变异。
结果：在研究期间共有 2,513 份肿瘤样本接受了临床靶向癌症组套测序。在这些样本中，在 221 份样本（8.8%）的各种癌症类型中鉴定出 239 个 PPGV。虽然大多数癌症为乳腺癌或卵巢癌，但不同类型的癌症也与 PPGV 相关，包括结肠、胰腺、膀胱、肾脏、前列腺、胆管和子宫的癌症。在 239 个 PPGV 中，129 个（54.0%）通过种系确认检测得到验证。其中，88 个（68.2%）被确认为真正的致病性种系变异，而其余 41 个（31.8%）为体细胞变异。大多数种系变异出现在参与同源重组修复（HRR）的基因中，如 BRCA1、BRCA2、PALB2、BRIP1、RAD51D、CHEK2 和 RAD50；或参与错配修复（MMR）的基因中，如 MLH1、MSH6、MSH2 和 PMS2。在 PPGV 中，85.0% 的 BRCA1 变异被确认为种系变异，而仅有 12.5% 的 PTEN 变异被证实为种系变异。种系变异的平均变异等位基因频率（VAF）为 58.1%，足够高以被视为种系变异。然而，体细胞变异表现出 51.5% 的平均 VAF，若无额外的确认检测则难以与真正的种系变异区分。
结论：临床仅肿瘤测序不仅可以鉴定治疗上可采取行动的突变，还可以推断与遗传性癌症相关的 PPGV。因此，在解读仅肿瘤测序结果以准确诊断和预防遗传性癌症综合征时，必须仔细关注 PPGV。
查看英文原文 English abstract
Background: Clinical tumor sequencing using next-generation sequencing (NGS) is widely applied to identify targetable variants and molecular biomarkers in cancer patients. Due to time and cost constraints, most institutions perform targeted gene panel sequencing only on tumor tissue, rather than on both tumor and matched normal samples. However, tumor-only sequencing cannot reliably distinguish true germline variants carried by the patient, particularly those associated with hereditary cancer syndromes.
Methods: We retrospectively collected clinical tumor-only sequencing data from cancer patients at Seoul National University Hospital (SNUH) between December 2022 and May 2025. All data were generated using targeted NGS with a customized SNUH FiRST Cancer Panel consisting of 336 cancer-related genes. Potential pathogenic germline variants (PPGVs) were classified based on the recommendations of the ESMO Precision Medicine Working Group and the patient's clinical and family history. Finally, we confirmed true pathogenic germline variants using Sanger sequencing or targeted NGS methods with normal genomic DNA from peripheral blood mononuclear cells.
Results: A total of 2,513 tumor samples underwent clinical targeted cancer panel sequencing during the examined period. Of those samples, 239 PPGVs were identified in 221 samples (8.8%) of various cancer types. While most cancers were breast or ovarian, different types of cancer were also associated with PPGVs, including those of the colon, pancreas, bladder, kidneys, prostate, bile ducts, and uterus. Of the 239 PPGVs, 129 (54.0%) were validated through germline confirmation testing. Of those, 88 (68.2%) were confirmed as true pathogenic germline variants, while the remaining 41 (31.8%) were somatic. Most germline variants were found in genes involved in homologous recombination repair (HRR), such as BRCA1, BRCA2, PALB2, BRIP1, RAD51D, CHEK2, and RAD50; or in genes involved in mismatch repair (MMR), such as MLH1, MSH6, MSH2, and PMS2. Among the PPGVs, 85.0% of BRCA1 variants were confirmed as germline, whereas only 12.5% of PTEN variants were verified to be germline. The germline variants showed an average variant allele frequency (VAF) of 58.1%, which is sufficiently high to be considered germline. However, the somatic variants exhibited a mean VAF of 51.5%, making them difficult to distinguish from true germline variants without additional confirmatory testing.
Conclusions: Clinical tumor-only sequencing can not only identify therapeutically actionable mutations but also infer PPGVs associated with hereditary cancers. Therefore, careful attention to PPGVs is essential when interpreting tumor-only sequencing results for the accurate diagnosis and prevention of hereditary cancer syndromes.
利益披露 Disclosure
S. Kim, None..
S. Hwangbo, None..
S. Lee, None..
H. Yun, None.