研究背景：肺癌主要的死亡原因不是原发肿瘤，而是远端转移。了解远端转移(DM)的生物学特性有助于对其进行有效预测，同时对于降低复发率至关重要。肿瘤的全基因组分析为揭示肺腺癌远端转移的发病机制和分子诊断提供了新的策略。

Methods: 22 eligible lung adenocarcinoma patients (pts) were enrolled in this study. DNA was extracted from FFPE samples of the primary tumors from 8 pts with distant metastasis (DM) and 14 pts without distant metastasis (non-DM). Comprehensive genomic profiling was performed using a 1.15M size panel covering exon regions of 1,086 genes based on next generation sequencing assay. Tumor gene alterations were analyzed to investigate the difference of molecular features between the lung adenocarcinoma with or without distant metastasis.

研究方法：本研究纳入了22例符合条件的肺腺癌患者(pts)。从8个有远端转移（DM）的患者和14个没有远端转移(非DM)的患者的原发灶FFPE样本中提取DNA。通过基于NGS测序对1086个基因的外显子区域进行了DNA变异分析以探讨肺腺癌有或无远处转移的分子特征的差异。

Result: The most frequently mutated genes were TP53 (73%). Mutations of EGFR were more common in DM pts (7/8 in DM, 6/14 in non-DM). The most frequently amplified gene was RICTOR (55%). Amplification was also detected for other genes such as RAC1 (36%), EGFR (36%), FDPS (32%), CCND1 (18%), HRAS (14%), RNF43 (14%). Interestingly, the amplification of RNA43 and HRAS were only identified in DM pts rather than non-DM pts (p<0.05). In addition, copy number variation of RICTOR, RAC1 and CDKN2B occurred more often in DM pts (p<0.05). 

研究结果：最常见的突变基因是TP53(73%)。EGFR突变在远端转移的患者中更常见(远端转移患者EGFR突变的占比是7/8，没有远端转移的患者EGFR突变的占比是 6/14)。最常见的基因扩增是RICTOR(55%)。RAC1(36%)、EGFR(36%)、FDPS(32%)、CCND1(18%)、HRAS(14%)、RNF43(14%)等其他基因也检测到扩增。有趣的是，RNF43和HRAS的基因扩增仅在远端转移的患者中出现，而在无远端转移的患者中没有被检测到(p<0.05)。此外，在远端转移的患者中，RICTOR、RAC1和CDKN2B的拷贝数变异也较多(p<0.05)。

Conclusion: Comprehensive genomic profiling of lung adenocarcinoma reveals distinctive genomic alterations between DM pts and non-DM pts. Several possible candidate genes that may be helpful for distant metastasis of lung adenocarcinoma were identified in this small cohort. The molecular features of the primary tumor may be used as predictors of distant metastasis in lung adenocarcinoma. Expanded prospective cohorts are warranted to further elucidate these findings.

研究结论：基于目标序列捕获测序的肺腺癌DNA变异图谱揭示了远端转移患者组与无远端转移患者组之间基因组变异的差异。在这些基因里，有几个候选基因可能有助于确定肺腺癌的远端转移，并且原发灶的分子特征可能可以作为肺腺癌远端转移的预测因子，但仍有必要扩大范围来进一步证明这些研究结果。