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. 2018 Sep;23(9):1008-1015.
doi: 10.1634/theoncologist.2017-0629. Epub 2018 Apr 26.

Comprehensive Molecular Characterization of Young Chinese Patients with Lung Adenocarcinoma Identified a Distinctive Genetic Profile

Helei Hou  1 , Hua Zhu  1 , Han Zhao  2 , Weihua Yan  2 , Yongjie Wang  3 , Man Jiang  1 , Bin Liu  4 , Dong Liu  1 , Na Zhou  1 , Chuantao Zhang  1 , Pansong Li  5 , Lianpeng Chang  5 , Yanfang Guan  5 , Zhe Wang  6 , Xiaoping Zhang  6 , Zhuokun Li  7 , Bingliang Fang  8 , Xiaochun Zhang  9
Affiliations

Comprehensive Molecular Characterization of Young Chinese Patients with Lung Adenocarcinoma Identified a Distinctive Genetic Profile

Helei Hou et al. Oncologist. 2018 Sep.

Abstract
in English, Chinese

Background: Occurrence at a younger age has been demonstrated to be associated with a distinct biology in non-small cell lung cancer. However, genomics and clinical characteristics among younger patients with lung adenocarcinoma remain to be determined. Here we studied the potentially targetable genetic alterations by next-generation sequencing (NGS) assay in young Chinese patients with lung adenocarcinoma.

Materials and methods: Seventy-one surgically resected lung adenocarcinoma tissue samples from patients aged less than 45 years were collected with informed consent from all patients. Targeted NGS assays were used to identify actionable genetic alterations in the cancer tissues. Additionally, the genomic and clinicopathologic characteristics of 106 patients with lung adenocarcinoma who received NGS testing over the same period were analyzed retrospectively.

Results: The frequencies of targetable genetic alterations in 177 patients with lung adenocarcinoma were analyzed by defined age categories, which unveiled a distinctive molecular profile in the younger group, aged less than 45 years. Notably, higher frequency of ALK and HER2 genetic alterations were associated with young age. However, a reverse trend was observed for KRAS, STK11 and EGFR exon 20 mutations, which were more frequently identified in the older group, aged more than 46 years. Furthermore, concurrent EGFR/TP53 mutations were much more prevalent in the younger patients (81.6% vs. 46.8%), which might have a poor response to treatment with epidermal growth factor receptor tyrosine kinase inhibitor.

Conclusion: In this study, NGS assay revealed a distinctive genetic profile in younger patients with adenocarcinoma. High frequency of concurrent EGFR/TP53 mutations was found in the younger patients, which especially warranted personalized treatment in this population.

Implications for practice: Further investigation is needed to understand the genomics and clinical characteristics of young patients with lung adenocarcinoma. In the present study, hybrid capture-based next-generation sequencing assays were used to identify targeted genetic alterations in young lung adenocarcinoma patients. Young patients with lung adenocarcinoma, aged less than 45 years, harbored a higher frequency of ALK and HER2 genetic alterations compared with patients aged more than 46 years. Dramatically, concurrent EGFR/TP53 mutations were much more prevalent in younger patients, which had a poor response to treatment with epidermal growth factor receptor kinase inhibitor. These results reveal a distinctive genetic profile in younger patients with adenocarcinoma, which might improve the treatment of this subpopulation.

摘要

背景。非小细胞肺癌发生在年轻的人群已经被证实与独特生物学相关。然而,年纪较轻的肺腺癌患者的基因组和临床特征尚未确定。在本次研究中,我们通过对中国年轻肺腺癌患者实施下一代测序(NGS)试验分析,来探索可能的靶向基因改变。

材料和方法。在所有患者均签署知情同意书的前提下,从年龄小于45岁的患者中共采集了71份手术切除的肺腺癌组织样本。用靶向NGS检测确定癌组织中可能有用的基因改变。此外,还回顾性地分析了同一时期接受NGS检测的106例肺腺癌患者的基因组和临床病理特征。

结果。按规定的年龄组别分析了177例肺腺癌患者的靶向基因改变频率,揭示了45岁以下年轻患者的独特分子谱。值得注意的是,较高的ALK和HER2基因变化发生频率与年纪较轻有关。然而,KRAS、STK11和EGFR外显子20突变的趋势则相反,这些突变在46岁以上的年纪较大人群中更为常见。而且,年纪较轻患者中并发EGFR/TP53突变的发生率要高得多(81.6% vs. 46.8%),这可能对表皮生长因子受体酪氨酸激酶抑制剂治疗的反应较差。

结论。在本次研究中,NGS试验揭示了年纪较轻腺癌患者的独特基因谱。并发EGFR/TP53突变在年轻患者中的发生率较高,这说明此类人群尤其需要个性化的治疗方案。

实践意义: 未来需要展开深入研究,以理解年轻肺腺癌患者的基因组和临床特征。在本次研究中,使用基于杂交捕获的下一代测序试验确定年轻肺腺癌患者的靶向基因改变。45岁以下的年轻肺腺癌患者的ALK和HER2基因改变发生频率高于46岁以上患者。而且,并发EGFR/TP53突变在年轻患者中的发生率明显更高。此类患者对表皮生长因子受体酪氨酸激酶抑制剂治疗的反应较差。这些结果揭示了年纪较轻腺癌患者的独特基因谱,这也许能改善对此类亚组人群的治疗。

Keywords: Genetic profile; Lung adenocarcinoma; Next‐generation sequencing; Young age.

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Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

Figures

Figure 1.
Figure 1.
The genetic profiles in different age groups of patients with lung adenocarcinoma. One hundred seventy‐seven patients with lung adenocarcinoma patients were enrolled, and tissue samples were analyzed by NGS assays. The frequency of targeted genetic alterations across three age groupings was compared to determine an age cutoff point that could differentiate young patients with a distinctive molecular profile. Statistical significance was defined as p < .05.
Figure 2.
Figure 2.
The targeted genetic profiles of younger and older patients with lung adenocarcinoma. (A): The targeted genetic profile of the younger patients, aged less than 45 years. (B): The targeted genetic profile of the older patients, aged more than 45 years. (C): The comparative analysis of the frequency of targeted genetic alterations between the younger and the older group. Statistical significance was defined as p < .05. Abbreviations: amp, amplification; mut, mutation.
Figure 3.
Figure 3.
The distribution of representative targeted genetic alterations between the younger and older patients with lung adenocarcinoma. The comparative analysis of KRAS mutations (A), ALK arrangements (B), EGFR mutations (C), EGFR mutation subtypes (D), HER2‐targeted genetic alterations (E), and STK11 mutations (F) between the younger and the older groups. Statistical significance was defined as p < .05. Abbreviation: WT, wild type.
Figure 4.
Figure 4.
Mutation analysis of the TP53 gene. (A): The comparative analysis of TP53 mutations between the younger and the older groups. (B): Analysis of TP53 mutations between patients with EGFR mutant and ALK‐arranged lung adenocarcinoma. (C): Analysis of concurrent EGFR/TP53 mutations between the younger and the older groups. Statistical significance was defined as p < .05. Abbreviation: WT, wild type.
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