Background

Colorectal cancer is one of the most common malignancies in both men and women. Despite progress in the treatment of the disease, metastatic colorectal cancer remains lethal with a median survival slightly surpassing 2 years and commonly for some cases a more aggressive course. New therapies are urgently needed based on a better understanding of the molecular pathogenesis of the disease.

Methods

The focus of this investigation is the PIK3CA gene, encoding the alpha catalytic subunit of the enzyme phosphatidylinositol-3 kinase (PI3K). Publicly available data from 3 extensive published series of colorectal carcinomas were analyzed to define the molecular landscape of colorectal adenocarcinomas with and without mutations of PIK3CA. An analysis for discovery of associations with alterations in other critical genes and pathways involved in colorectal cancer was performed. The total mutation burden (TMB) and copy number alteration burden of colorectal cancers with and without mutations of PIK3CA, as well as prognostic implications of alterations of the gene for survival, were examined.

Results

Mutations in PIK3CA are observed in 20% to 25% of colorectal cancers. PIK3CA represents one of the most frequently mutated oncogenes in these cancers. Mutations in PIK3CA are associated with higher rates of mutations in other genes of important cancer-associated pathways such as the tyrosine kinase receptors/K-Ras/BRAF/MAPK and the Wnt/β-catenin pathway. In addition, PIK3CA mutated colorectal cancers display a higher TMB than nonmutated cancers.

Conclusion

Frequent mutations of PIK3CA gene in colorectal carcinomas may represent an opportunity for targeted therapy combination development inhibiting both the PI3K kinase itself and associated pathway defects. Increased TMB may additionally confer immunotherapy sensitivity, which could be augmented by other targeted therapies.

中文翻译：

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结直肠癌中 PIK3CA 突变的概况

背景

结直肠癌是男性和女性最常见的恶性肿瘤之一。尽管该疾病的治疗取得了进展，但转移性结直肠癌仍然是致命的，中位生存期略超过 2 年，并且在某些情况下通常是更具侵袭性的过程。基于对疾病分子发病机制的更好理解，迫切需要新的疗法。

方法

这项研究的重点是PIK3CA基因，它编码酶 phosphatidylinositol-3 激酶 (PI3K) 的 α 催化亚基。分析了来自 3 个广泛发表的结直肠癌系列的公开数据，以确定有和没有PIK3CA突变的结直肠腺癌的分子景观。进行了一项分析，以发现与结直肠癌中涉及的其他关键基因和途径的改变的关联。检测了有和没有PIK3CA突变的结直肠癌的总突变负荷 (TMB) 和拷贝数改变负荷，以及基因改变对生存的预后影响。

结果

在 20% 到 25% 的结直肠癌中观察到PIK3CA突变。PIK3CA代表了这些癌症中最常发生突变的癌基因之一。PIK3CA的突变与其他重要癌症相关途径的基因突变率较高有关，例如酪氨酸激酶受体/K-Ras/BRAF/MAPK 和 Wnt/β-连环蛋白途径。此外，PIK3CA突变的结直肠癌显示出比非突变癌症更高的 TMB。

结论

结直肠癌中PIK3CA基因的频繁突变可能代表了靶向治疗组合开发抑制 PI3K 激酶本身和相关通路缺陷的机会。增加的 TMB 可能另外赋予免疫治疗敏感性，这可以通过其他靶向治疗来增强。