Genetic Heterogeneity and Tissue-specific Patterns of Tumors with Multiple PIK3CA Mutations.
Genetic Heterogeneity and Tissue-specific Patterns of Tumors with Multiple PIK3CA Mutations.
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DOI：
10.1158/1078-0432.ccr-22-2270
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发表时间：
2023-03-14
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全面描述多个PIK3CA(多PIK3CA)突变的组织特异性和分子亚类，并评估它们对潜在治疗结果的影响。我们使用了一个覆盖至少324个癌症相关基因的定向混合捕获的下一代测序面板，对一个由66种肿瘤类型的352,392个样本组成的泛癌队列进行了分析。鉴定和测试分子定义的亚群、等位基因配置、克隆性和突变特征与PI3K抑制剂治疗反应的相关性。在所有PIK3CA突变的肿瘤中，11%发现多个PIK3CA突变，包括9%的低肿瘤突变负荷(TMB)PIK3CA突变的肿瘤，并且在乳腺癌和妇科肿瘤中丰富。多个PIK3CA突变经常是克隆性的，在同一等位基因上顺式突变，并发生在不同肿瘤类型的特定位置。这些突变往往与其他驱动基因的突变以及PI3K途径中的基因互斥。在高TMB的PIK3CA突变肿瘤中，18%是多PIK3CA突变，常带有载脂蛋白B基因编码酶催化多肽(APOBEC)突变特征。尽管包含多个PIK3CA突变肿瘤的特定等位基因组合存在很大差异，尤其是在不同癌症类型之间，但雌激素受体阳性、HER2阴性的不同类别多PIK3CA突变乳腺癌患者对PI3K抑制反应相似。我们的泛肿瘤研究提供了对多个PIK3CA突变的遗传异质性和组织特异性的生物学见解，对指导PI3K抑制策略具有潜在的临床应用价值。
To comprehensively characterize tissue-specific and molecular subclasses of multiple PIK3CA (multi-PIK3CA) mutations and assess their impact on potential therapeutic outcomes. We profiled a pan-cancer cohort comprised of 352,392 samples across 66 tumor types using a targeted hybrid capture-based next-generation sequencing panel covering at least 324 cancer-related genes. Molecularly defined subgroups, allelic configuration, clonality, and mutational signatures were identified and tested for association with PI3K inhibitor therapeutic response. Multi-PIK3CA mutations are found in 11% of all PIK3CA-mutant tumors, including 9% of low tumor mutational burden (TMB) PIK3CA-mutant tumors, and are enriched in breast and gynecologic cancers. Multi-PIK3CA mutations are frequently clonal and in cis on the same allele and occur at characteristic positions across tumor types. These mutations tend to be mutually exclusive of mutations in other driver genes, and of genes in the PI3K pathway. Among PIK3CA-mutant tumors with a high TMB, 18% are multi-PIK3CA mutant and often harbor an apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) mutational signature. Despite large differences in specific allele combinations comprising multi-PIK3CA mutant tumors, especially across cancer types, patients with different classes of multi-PIK3CA mutant estrogen receptor–positive, HER2-negative breast cancers respond similarly to PI3K inhibition. Our pan-tumor study provides biological insights into the genetic heterogeneity and tissue specificities of multi-PIK3CA mutations, with potential clinical utility to guide PI3K inhibition strategies.