Department of Otorhinolaryngology-Head and Neck Surgery, National Cancer Center, Goyang, Republic of Korea.
Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
Oral Oncol. 2023 Nov;146:106571. doi: 10.1016/j.oraloncology.2023.106571. Epub 2023 Sep 21.
In biobanking based on patient-derived organoids (PDO), the genetic stability of organoid lines is critical for the clinical relevance of PDO with parental tumors. However, data on mutational heterogeneity and clonal evolution of PDO and their effects on treatment response are insufficient.
To investigate whether head and neck cancer organoids (HNCOs) could maintain the genetic characteristics of their original tumors and elucidate the clonal evolution process during a long-term passage, we performed targeted sequencing, covering 377 cancer-related genes and adopted a sub-clonal fraction model. To explore therapeutic response variability between an early and late passage (>passage 6), we generated dose-response curves for drugs and radiation using two HNCO lines.
Using 3D ex vivo organoid culture protocol, we successfully established 27 HNCOs from 39 patients with an overall success rate of 70% (27/39). Their mutational profiles were highly concordant, with three of the HNCOs analyzed showing greater than 70% concordance. Only one HNCO displayed less than 50% concordance. However, many of these organoid lines displayed clonal evolution during serial passaging, although major cancer driver genes and VAF distributions were shared between early and later passages. We also found that all late passages of HNCOs tended to be more sensitive to radiation than early passages, similar to drug response results.
We report the establishment of HNCO lines derived from 27 patients and demonstrate their genetic concordance with corresponding parental tumors. Furthermore, we show serial changes in mutational profiles of HNCO along with long passage culture and the impact of these clonal evolutions on response to radiotherapy.
在基于患者来源的类器官（PDO）的生物库中，类器官系的遗传稳定性对于具有亲本肿瘤的 PDO 的临床相关性至关重要。然而，关于 PDO 的突变异质性和克隆进化及其对治疗反应的影响的数据还不够充分。
为了研究头颈部癌症类器官（HNCO）是否能够保持其原始肿瘤的遗传特征，并阐明长期传代过程中的克隆进化过程，我们进行了靶向测序，涵盖 377 个与癌症相关的基因，并采用了亚克隆分数模型。为了探索早期和晚期传代（>第 6 代）之间治疗反应的可变性，我们使用两种 HNCO 系生成了药物和辐射的剂量反应曲线。
我们使用 3D 体外类器官培养方案，成功地从 39 名患者中建立了 27 个 HNCO，总体成功率为 70%（27/39）。它们的突变谱高度一致，分析的 3 个 HNCO 显示出超过 70%的一致性。只有一个 HNCO 的一致性低于 50%。然而，许多这些类器官系在连续传代过程中显示出克隆进化，尽管早期和晚期传代之间共享主要的癌症驱动基因和 VAF 分布。我们还发现，所有 HNCO 的晚期传代都比早期传代对辐射更敏感，与药物反应结果相似。
我们报告了从 27 名患者中建立的 HNCO 系，并证明了它们与相应的亲本肿瘤的遗传一致性。此外，我们展示了 HNCO 的突变谱随着长期传代培养而发生的连续变化，以及这些克隆进化对放射治疗反应的影响。
