Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan.
Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
Cancer Sci. 2021 Feb;112(2):483-489. doi: 10.1111/cas.14699. Epub 2021 Jan 11.
Recent studies of the cancer genome have identified numerous patients harboring multiple mutations (MM) within individual oncogenes. These MM (de novo MM) in cis synergistically activate the mutated oncogene and promote tumorigenesis, indicating a positive epistatic interaction between mutations. The relatively frequent de novo MM suggest that intramolecular positive epistasis is widespread in oncogenes. Studies also suggest that negative and higher-order epistasis affects de novo MM. Comparison of de novo MM and MM associated with drug-resistant secondary mutations (secondary MM) revealed several similarities with respect to allelic configuration, mutational selection and functionality of individual mutations. Conversely, they have several differences, most notably the difference in drug sensitivities. Secondary MM usually confer resistance to molecularly targeted therapies, whereas several de novo MM are associated with increased sensitivity, implying that both can be useful as therapeutic biomarkers. Unlike secondary MM in which specific secondary resistant mutations are selected, minor (infrequent) functionally weak mutations are convergently selected in de novo MM, which may provide an explanation as to why such mutations accumulate in cancer. The third type of MM is MM from different subclones. This type of MM is associated with parallel evolution, which may contribute to relapse and treatment failure. Collectively, MM within individual oncogenes are diverse, but all types of MM are associated with cancer evolution and therapeutic response. Further evaluation of oncogenic MM is warranted to gain a deeper understanding of cancer genetics and evolution.
最近对癌症基因组的研究鉴定了许多个体癌基因中存在多个突变（MM）的患者。这些顺式协同激活突变癌基因并促进肿瘤发生的顺式 MM（新发性 MM）表明突变之间存在正上位性相互作用。相对频繁的新发性 MM 表明，癌基因中广泛存在分子内正上位性。研究还表明，负上位性和更高阶上位性影响新发性 MM。新发性 MM 与耐药性继发性突变相关的 MM（继发性 MM）的比较表明，在等位基因构型、突变选择和单个突变的功能方面具有几个相似性。相反，它们也存在一些差异，最显著的是药物敏感性的差异。继发性 MM 通常对分子靶向治疗产生耐药性，而几种新发性 MM 与敏感性增加相关，这意味着两者都可作为治疗生物标志物。与特定的继发性耐药突变被选择的继发性 MM 不同，新发性 MM 中选择了次要（罕见）功能较弱的突变，这可能解释了为什么这些突变在癌症中积累。第三种 MM 是来自不同亚克隆的 MM。这种类型的 MM 与平行进化有关，这可能导致复发和治疗失败。总之，个体癌基因中的 MM 是多样的，但所有类型的 MM 都与癌症进化和治疗反应有关。进一步评估致癌性 MM 是值得的，以深入了解癌症遗传学和进化。
