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Abstract：
BACKGROUND: It is clinically challenging to infer the phylogenetic relationship between different tumor lesions of patients with multiple synchronous lung cancers (MSLC), whether these lesions are the result of independently evolved tumor or intrapulmonary metastases.
METHODS: We used the Illumina X10 platform to sequence 128 stage I lung cancer samples collected from 64 patients with MSLC. All samples were analyzed for mutation spectra and phylogenetic inference.
RESULTS: We detected genetic aberrations within genes previously reported to be recurrently altered in lung adenocarcinoma including, EGFR, ERBB2, TP53, BRAF, and KRAS. Other putative driver mutations identified were enriched in RTK-RAS signaling, TP53 signaling, and cell cycle. Also, we found some interesting cases, two cases that carried EGFR L858R and T790M co-mutation in one tumor and another tumor with only EGFR 19del, and 1 case with two KRAS hotspots in the same tumor. Due to the short follow-up time and early stage, further investigation is needed to determine whether this unique mutation profile will affect their progression-free survival (PFS) and overall survival (OS). Regarding genetic evolution analysis among 64 tumor samples, 50 of them display distinct mutational profiles, suggesting these are independently evolved tumors, which is consistent with histopathological assessment. On the other hand, six patients were identified to be intrapulmonary metastasis as the mutations harbored in different lesions are clonally related.
CONCLUSIONS: In summary, unlike intrapulmonary metastases, patients with MSLC harbor distinct genomic profiles in different tumor lesions, and we could distinguish MSLC from intrapulmonary metastases via clonality estimation.
METHODS: We used the Illumina X10 platform to sequence 128 stage I lung cancer samples collected from 64 patients with MSLC. All samples were analyzed for mutation spectra and phylogenetic inference.
RESULTS: We detected genetic aberrations within genes previously reported to be recurrently altered in lung adenocarcinoma including, EGFR, ERBB2, TP53, BRAF, and KRAS. Other putative driver mutations identified were enriched in RTK-RAS signaling, TP53 signaling, and cell cycle. Also, we found some interesting cases, two cases that carried EGFR L858R and T790M co-mutation in one tumor and another tumor with only EGFR 19del, and 1 case with two KRAS hotspots in the same tumor. Due to the short follow-up time and early stage, further investigation is needed to determine whether this unique mutation profile will affect their progression-free survival (PFS) and overall survival (OS). Regarding genetic evolution analysis among 64 tumor samples, 50 of them display distinct mutational profiles, suggesting these are independently evolved tumors, which is consistent with histopathological assessment. On the other hand, six patients were identified to be intrapulmonary metastasis as the mutations harbored in different lesions are clonally related.
CONCLUSIONS: In summary, unlike intrapulmonary metastases, patients with MSLC harbor distinct genomic profiles in different tumor lesions, and we could distinguish MSLC from intrapulmonary metastases via clonality estimation.
摘要：
背景：推断多发性同步肺癌（MSLC）患者的不同肿瘤病变之间的系统发育关系在临床上具有挑战性，这些病变是否是独立发展的肿瘤或肺内转移的结果。
方法：我们使用IlluminaX10平台对从64名MSLC患者收集的128个I期肺癌样品进行测序。分析所有样品的突变光谱和系统发育推断。
结果：我们检测到先前报道在肺腺癌中反复改变的基因中的遗传畸变，包括，EGFR,ERBB2,TP53,BRAF,还有KRAS.鉴定出的其他推定驱动突变在RTK-RAS信号传导中富集，TP53信令,和细胞周期。此外，我们发现了一些有趣的案例,2例携带EGFRL858R和T790M共突变的一个肿瘤和另一个只有EGFR19del的肿瘤，在同一肿瘤中出现两个KRAS热点1例。由于随访时间短，早期，需要进一步的研究来确定这种独特的突变模式是否会影响他们的无进展生存期(PFS)和总生存期(OS).关于64个肿瘤样本的遗传进化分析，其中50个显示出不同的突变特征，表明这些是独立进化的肿瘤，这与组织病理学评估一致。另一方面,6例患者被确定为肺内转移，因为不同病变中的突变是克隆相关的。
结论：总之，不像肺内转移,MSLC患者在不同的肿瘤病变中拥有不同的基因组谱，我们可以通过克隆性估计来区分MSLC和肺内转移。
方法：我们使用IlluminaX10平台对从64名MSLC患者收集的128个I期肺癌样品进行测序。分析所有样品的突变光谱和系统发育推断。
结果：我们检测到先前报道在肺腺癌中反复改变的基因中的遗传畸变，包括，EGFR,ERBB2,TP53,BRAF,还有KRAS.鉴定出的其他推定驱动突变在RTK-RAS信号传导中富集，TP53信令,和细胞周期。此外，我们发现了一些有趣的案例,2例携带EGFRL858R和T790M共突变的一个肿瘤和另一个只有EGFR19del的肿瘤，在同一肿瘤中出现两个KRAS热点1例。由于随访时间短，早期，需要进一步的研究来确定这种独特的突变模式是否会影响他们的无进展生存期(PFS)和总生存期(OS).关于64个肿瘤样本的遗传进化分析，其中50个显示出不同的突变特征，表明这些是独立进化的肿瘤，这与组织病理学评估一致。另一方面,6例患者被确定为肺内转移，因为不同病变中的突变是克隆相关的。
结论：总之，不像肺内转移,MSLC患者在不同的肿瘤病变中拥有不同的基因组谱，我们可以通过克隆性估计来区分MSLC和肺内转移。
