Most canine ameloblastomas harbor HRAS mutations

Canine acanthomatous ameloblastomas (CAA), analogs of human ameloblastoma, are oral tumors of odontogenic origin for which the genetic drivers have remained undefined. By whole-exome sequencing, we have now discovered recurrent HRAS and BRAF activating mutations respectively in 63% and 8% of CAA. Notably, cell lines derived from CAA with HRAS mutation exhibit marked sensitivity to MAP Kinase (MAPK) pathway inhibitors, which constrain cell proliferation and drive ameloblast differentiation. Our findings newly identify a large-animal spontaneous cancer model to study the progression and treatment of RAS-driven cancer. More broadly, our study highlights the translational potential of canine cancer genome sequencing to benefit both humans and their companion animals.

犬棘层型成釉细胞瘤（Canine acanthomatous ameloblastomas, CAA）是一类与人类成釉细胞瘤类似的牙源性口腔肿瘤，其遗传驱动因素迄今仍未明确。本研究通过全外显子组测序，在63%和8%的CAA病例中分别发现了复发性HRAS与BRAF激活突变。值得关注的是，携带HRAS突变的CAA来源细胞系对MAP激酶（MAP Kinase, MAPK）通路抑制剂呈现显著敏感性，该类抑制剂可抑制细胞增殖并诱导成釉细胞分化。本研究首次确立了可用于研究RAS驱动型癌症进展与治疗的大型动物自发性癌症模型。从更广泛的视角而言，本研究凸显了犬类癌症基因组测序的转化研究潜力，可为人类及其伴侣动物的健康获益提供支持。