Department of Pathology, Johns Hopkins University School of Medicine, Carnegie 469, Pathology, 600 North Wolfe Street, Baltimore, MD, 21287, USA.
Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
Mol Diagn Ther. 2020 Aug;24(4):461-472. doi: 10.1007/s40291-020-00471-w.
Differentiation between intrapulmonary metastasis (IPM) and multiple primary lung cancers (MPLC) in patients with synchronous or metachronous lung tumor nodules is critical but challenging.
We proposed an algorithm to evaluate clonal origin based on trunk (initiating) versus branching drivers and the prevalence of mutations in lung adenocarcinomas.
Driver mutations were examined using next-generation sequencing in five trunk driver genes (BRAF, EGFR, ERBB2, KRAS, and NRAS) and three branching driver genes (ATK1, PIK3CA, and TP53).
Mutational profiling supported same clonality and likely same clonality, respectively, in 39 and 14 of 66 pairs of specimens with known identical clonal origin. Discordance of TP53 mutations (branching drivers) was observed in three pairs. Subsequent analyses of 30 pairs of synchronous or metachronous lung tumor nodules revealed different clonality and likely different clonality in 17 and 2 pairs, respectively, including three pairs with similar histomorphology; same clonality and likely same clonality in three and five pairs, respectively, including two pairs with different histomorphology; and inconclusive or noninformative results in three pairs.
While discordance of trunk drivers indicated MPLC in patients with synchronous or metachronous lung tumor nodules, discordance of branching drivers did not exclude IPM. Concordance of uncommon drivers supported IPM, whereas concordance of common drivers did not exclude MPLC. Additional recommendations from official organizations are needed to guide applications of molecular markers in defining clonality of multiple lung tumor nodules.
在患有同步或异时性肺肿瘤结节的患者中，区分肺内转移（IPM）和多原发肺癌（MPLC）是至关重要但具有挑战性的。
我们提出了一种基于主干（起始）与分支驱动因素以及肺腺癌突变流行率来评估克隆起源的算法。
使用下一代测序技术在五个主干驱动基因（BRAF、EGFR、ERBB2、KRAS 和 NRAS）和三个分支驱动基因（ATK1、PIK3CA 和 TP53）中检查驱动基因突变。
在已知具有相同克隆起源的 66 对标本中，突变谱分析分别支持 39 对和 14 对具有相同的克隆性和可能相同的克隆性。在三对标本中观察到 TP53 突变（分支驱动因素）的不一致性。随后对 30 对同步或异时性肺肿瘤结节进行分析，分别在 17 对和 2 对中发现不同的克隆性和可能的不同克隆性，包括三对具有相似组织形态的标本；分别在 3 对和 5 对中发现相同的克隆性和可能相同的克隆性，包括两对具有不同组织形态的标本；以及三对标本的结果不确定或无信息。
虽然主干驱动因素的不一致性表明同步或异时性肺肿瘤结节患者存在 MPLC，但分支驱动因素的不一致性并不能排除 IPM。罕见驱动因素的一致性支持 IPM，而常见驱动因素的一致性并不排除 MPLC。需要来自官方组织的其他建议来指导分子标志物在定义多个肺肿瘤结节的克隆性中的应用。
