当在同一基因中发生两个或多个独立的遗传事件时,肿瘤中的遗传异质性可以显示出显着的选择性。这种现象,称为复合突变,指向选择性压力,这通常会导致对突变特异性药物的治疗耐药。由于复合突变已被描述为发生在亚克隆群体中,它们并不总是通过活检取样捕获。这里,我们提供了预测复合突变的概念证明,以预测哪些患者可能存在亚克隆驱动治疗抵抗的风险.我们发现复合突变发生在5%的癌症患者中,主要影响PIK3CA,EGFR,BRAF,和KRAS基因,这是常见的精准医学目标。此外,我们发现,在非复合背景下,复合突变频率与常见共现突变之间存在强烈且显著的关系.我们还发现,共突变在同一染色体上显著富集。使用细胞系数据独立地确认这些观察结果。最后,我们显示了基于它们的共突变(EGFR的AUC0.62、0.81、0.82和0.91,PIK3CA,KRAS,而BRAF,分别)。该预测模型可以帮助对有发展为引起治疗抗性的突变的风险的患者进行分层。
Genetic heterogeneity in tumors can show a remarkable selectivity when two or more independent genetic events occur in the same gene. This phenomenon, called composite mutation, points toward a selective pressure, which frequently causes therapy resistance to mutation-specific drugs. Since composite mutations have been described to occur in sub-clonal populations, they are not always captured through biopsy sampling. Here, we provide a proof of concept to predict composite mutations to anticipate which patients might be at risk for sub-clonally driven therapy resistance. We found that composite mutations occur in 5% of cancer patients, mostly affecting the PIK3CA, EGFR, BRAF, and KRAS genes, which are common precision medicine targets. Furthermore, we found a strong and significant relationship between the frequencies of composite mutations with commonly co-occurring mutations in a non-composite context. We also found that co-mutations are significantly enriched on the same chromosome. These observations were independently confirmed using cell line data. Finally, we show the feasibility of predicting compositive mutations based on their co-mutations (AUC 0.62, 0.81, 0.82, and 0.91 for EGFR, PIK3CA, KRAS, and BRAF, respectively). This prediction model could help to stratify patients who are at risk of developing therapy resistance-causing mutations.