Abstract
Background
The aim of this study was to determine the demographic profile of driver gene alterations, especially low‐frequency gene alterations in Chinese patients with non‐small cell lung cancer (NSCLC).
Methods
A total of 7395 Chinese patients with NSCLC were enrolled in the study. Next‐generation sequencing (NGS) was performed on formalin‐fixed paraffin‐embedded specimens collected via either surgical resection or biopsy.
Results
The frequent genomic alterations found in the study were EGFR mutations (51.7%), KRAS mutations (13.1%), MET alterations (5.6%; 3.2% copy number gains and 0.5% exon 14 skipping mutation), HER2 alterations (7.0%; 2.0% copy number gains and 5.4% mutations), ALK alterations (7.2%; 3.9% rearrangements), RET rearrangements (1.4%), ROS1 rearrangements (0.9%), and NTRK rearrangements (0.6%). The EGFR mutation rate was found to be significantly higher in women than in men (69.1% vs. 38.5%, P < 0.001), while the KRAS mutation (17.5% vs. 7.3%, P < 0.001) and MET alteration rates (6.5% vs. 4.5%, P < 0.001) were significantly higher in men than in women. The EGFR mutation rate tended to decrease with age in the group aged >40 years, while the KRAS mutation rate tended to increase with age. The HER2 mutation (13.9% vs. 6.7%, P < 0.001) and ALK alteration rates (14.3% vs. 6.9%, P < 0.001) were significantly higher in the group aged <40 years than in groups aged 40 years or older.
Conclusions
The frequency of different driver genes was diverse in different age‐gender groups, and the results of this study may assist clinicians in clinical decision‐making and the development of public healthcare strategies in the future.
Key points
Significant findings of the study
This study demonstrated that the frequency of different driver genes was diverse in different age‐gender groups.
What this study adds
It may enable clinicians to make clinical decisions, and assist government, pharmaceutical researchers and insurance companies develop public healthcare strategies.
Keywords: Driver gene, next‐generation sequencing, non‐small cell lung cancer
This study demonstrated that the frequency of different driver genes was diverse in different age‐gender groups, and may assist clinicians in clinical decision‐making, and assist government, pharmaceutical researchers and insurance companies in the development of public healthcare strategies in the future.
Introduction
Lung cancer is the most commonly reported cancer and leading cause of cancer death in China. 1 Non‐small cell lung cancer (NSCLC) accounts for approximately 85% of patients with lung cancer. 2 Targeted therapies have dramatically changed the treatment modalities for NSCLC. The National Comprehensive Cancer Network (NCCN) guideline for NSCLC (Version 1.2020) recommends targeted treatment for EGFR, ALK, ROS1, BRAF, NTRK, RET, HER2, MET amplification and exon 14 skipping mutation. It is well known that patients of East Asian ethnicity have a different prevalence of oncogenic mutations. 3 It is therefore essential that the demographic profile of driver genes in East Asian patients with NSCLC is determined. EGFR mutation has been widely and well researched, while alterations of BRAF, HER2, MET, ROS1, RET, and NTRK have not been previously well described due to their low frequency. Here, we studied the demographic characteristics of driver gene alterations in Chinese patients with NSCLC identified by next‐generation sequencing (NGS). The large sample size of the study made it possible to describe the low‐frequency gene alterations.
Methods
Patients and samples
A total of 7395 Chinese patients were enrolled in the study. Formalin‐fixed paraffin‐embedded (FFPE) specimens were analyzed from patients with NSCLC who underwent either surgical resection or biopsy from 1 January 2018 to 1 October 2019. In order to ensure the quality of DNA extraction, FFPE specimens retrieved within one year were selected, and the specimens were reviewed by experienced pathologists. All the patients involved provided their written informed consent. The study was approved by the Institutional Review Board of Peking Union Medical College Hospital (S‐K1264).
DNA extraction and sequencing library preparation
NGS was performed in the CAP‐accredited laboratory. The tumor content of all samples was confirmed to be at least 10% by pathologists. FFPE sections were deparaffinized with xylene, from which genomic DNA was extracted using the BLACK PREP FFPE DNA kit according to the manufacturer's protocol. The quantity and quality of the extracted DNA were evaluated using a Qubit 3.0 fluorometer and Bioanalyzer 2100 (Agilent Technologies), respectively (Thermo Fisher Scientific). The DNA was fragmented using a Covaris M220 sonication system to obtain 200 bp fragments and purified using Agencourt AMPure XP beads (Beckman Coulter). Library preparations of the fragmented DNA were performed using the KAPA Hyper Prep Kit (KAPA Biosystems), following the manufacturer's protocol. Libraries with different indices were pooled for Hypercap Target Enrichment Kit, and a customized enrichment panel (Roche) covering the exonic regions of 290 genes and the introns of 26 fusion genes. The captured library was further amplified using Illumina p5 (5′ AAT GAT ACG GCG ACC ACC GA 3′) and p7 (5’ CAA GCA GAA GAC GGC ATA CGA GAT 3′) primers in the KAPA Hifi HotStart ReadyMix (KAPA Biosystems), and purified with Agencourt AMPure XP beads. Sequencing libraries were quantified by Bioanalyzer 2100 (Agilent Technologies). The final libraries were sequenced on an Illumina Novaseq 6000 platform to a mean coverage depth of at least 250×, following the manufacturer's instructions.
Bioinformatic analysis
Genomic alterations, including single nucleotide variants (SNVs), short and long insertions/deletions (indels), copy number variations (CNVs), and gene fusions, were subjected to advanced analysis. First, reads were aligned to human genome reference sequence (hg19) by BWA (0.7.17), and duplication reads were removed using Novosort (3.08.00). Second, SNVs and short indels were identified by VarScan (2.4.2) after quality recalibration and realignment using a genome analysis toolkit (GATK) and in‐house pipeline. Short indels were then calibrated using the results from Pindel. A customized algorithm ctCNV was developed to identify and filter CNV. The thresholds of copy number ≥ 2.5 and ≤ 1.5 were used to categorize altered regions as CNV gains (amplification) and copy number losses (deletions). FusionMap (8.0.2.32) was used to detect gene fusion. Gene fusions were required to have at least two support reads with a background P‐value under 0.05. More importantly, reliable somatic alterations were detected in the raw data by comparison with matched blood control samples. At a minimum, five reads and minimum variant allele frequency of 1% were required to support alternative calling.
Statistical analysis
Patients were grouped by age as <40 years, 40–49 years, 50–59 years, 60–69 years, and 70 years or older. Statistical analysis was performed by R language. The χ2‐test was used to analyze the associations of mutational status with gender and age groups. A two‐tailed P‐value of <0.05 was considered statistically significant.
Results
Demographic characteristics
The demographic characteristics are shown in Table 1. With regard to the histological subtype, 5378 cases (72.7%) were lung adenocarcinoma, 855 (11.6%) squamous cell carcinoma, and 1162 (15.7%) NSCLC‐not otherwise specified. The median age of patients was 60 years (range: 8–94), and 56.6% of patients were male.
Table 1.
Genomic profiling of patients in the study
| NSCLC † (n = 7395) | LAD ‡ (n = 5378) | LSCC § (n = 855) | |
|---|---|---|---|
| Median age (range) | 60 (8–94) | 59 (8–94) | 63 (28–93) |
| Gender (M/F) | 4189/3206 | 2678/2700 | 770/85 |
| <40 (M/F: 127/167) | 294/4.0% | 242/5.0% | 10/1.2% |
| 40–49 (M/F:462/567) | 1029/13.9% | 801/14.9% | 65/7.6% |
| 50–59 (M/F: 1200/1082) | 2282/30.9% | 1716/31.9% | 235/27.5% |
| 60–69 (M/F: 1629/990) | 2619/35.4% | 1849/34.4% | 360/42.1% |
| ≥70 (M/F: 771/400) | 1171/15.8% | 770/14.3% | 185/21.6% |
| Smoking history | |||
| Smoking | 2670 | 1725 | 469 |
| Non‐smoking | 3837 | 3006 | 291 |
| Unknown | 888 | 647 | 95 |
| EGFR mutations (%) | 3821/51.7% | 3177/59.1% | 156/18.2% |
| KRAS mutations (%) | 966/13.1% | 757/14.1% | 63/7.4% |
| HER2 alterations (%) | 517/7.0% | 400/7.4% | 45/5.3% |
| HER2 CNGs ¶ (%) | 149/2.0% | 98/1.8% | 23/2.7% |
| ALK alterations (%) | 531/7.2% | 389/7.2% | 59/6.9% |
| MET alterations (%) | 414/5.6% | 304/5.6% | 46/5.4% |
| MET CNGs ¶ (%) | 240/3.2% | 184/3.4% | 23/2.7% |
| BRAF alterations (%) | 298/4.0% | 225/4.2% | 24/2.8% |
| ALK rearrangements (%) | 286/3.9% | 233/4.3% | 11/1.2% |
| RET rearrangements (%) | 103/1.4% | 95/1.8% | 0/0.0% |
| ROS1 rearrangements (%) | 67/0.90% | 55/1.02% | 2/0.2% |
| NTRK rearrangements (%) | 44/0.59% | 33/0.61% | 4/0.5% |
Non‐small cell lung cancer.
Lung adenocarcinoma.
Lung squamous cell carcinoma.
Copy number gains.
Driver gene alterations
The genomic alteration spectra are shown in Table 1. Frequent genomic alterations found were EGFR mutations (51.7%), KRAS mutations (13.1%), MET alterations (5.6%; 3.2% copy number gains and 0.5% exon 14 skipping), HER2 alterations (7.0%; 2.0% copy number gains and 5.4% mutations), ALK alterations (7.2%; 3.9% rearrangements), RET rearrangements (1.4%), ROS1 rearrangements (0.9%), and NTRK rearrangements (0.6%). A total of 5069 (68.5%) patients harbored driver genes. The National Comprehensive Cancer Network (NCCN) guidelines for NSCLC recommend that biomarker testing should include EGFR mutation, ALK rearrangement, ROS1 rearrangement, NTRK gene fusion, MET amplification, MET exon 14 skipping mutation, RET rearrangement, and HER2 mutation (Table 2).
Table 2.
Genomic alteration spectra of non‐small cell lung cancer (NSCLC)
| Genomic alteration (N) | Alteration distribution (N) |
|---|---|
| EGFR mutations (3821) | Exon 18(217), exon 19 (1572), exon 20 (439), exon 21(1757) |
| KRAS mutations (600) | Exon 2(443), exon 3 (63), exon 4 (32) |
| MET alterations (414) | copy number gain (240), exon 14 skipping (36) |
| HER2 mutations (397) | Exon 18 (3), exon 19 (7), exon 20 (227), exon 21(7) |
| BRAF alterations (298) | V600E (75), K601E (32), G469A (19), D22N (13), G469V (8), D594G (8), G466V (6), N588I (6), D594N (6); copy number gain (17); CDC27‐BRAF (2), SND1‐BRAF (2) |
| ALK rearrangements (286) | EML4‐ALK (272), HIP1‐ALK (5), KLC1‐ALK (2), STRN‐ALK (2) |
| RET rearrangements (103) | KIF5B‐RET (81), CCDC6‐RET (16) |
| ROS1 rearrangements (67) | CD74‐ROS1(28), SDC4‐ROS1 (12), SLC34A2‐ROS1 (11), EZR‐ROS1 (10), TPM3‐ROS1 (4), ERC1‐ROS1 (2) |
| NTRK rearrangements (44) | AGBL4‐NTRK (19), ETV6‐NTRK (13), VCL‐NTRK (6), TRIM24‐NTRK (3) |
EGFR was the most frequently determined mutated gene in Chinese patients with NSCLC. Exon 21 L858R (n = 1645) and exon 19 deletions (n = 1526) accounted for 82.9% of all detected EGFR mutations. Other EGFR mutations included T790M (n = 178, 4.6%), exon 20 insertion (n = 148, 3.8%), G719X (n = 143, 3.7%), L861Q (n = 78, 2.0%), S768I (n = 71, 1.8%), E709X (n = 38, 1.0%), and V834L (n = 22, 0.6%). A total of 678 patients (17.7% of patients with EGFR mutations) were identified as having complex EGFR mutations. The most common complex mutation was T790M with another mutation (n = 172, 4.5% of EGFR mutations). Table 3 identifies the 10 complex EGFR mutation types found with the highest frequency.
Table 3.
Complex EGFR mutations identified in non‐small lung cancer (NSCLC)
| Complex mutation type | Number | Percentage of EGFR mutations (n = 3821) |
|---|---|---|
| Exon 19 deletion + T790M | 91 | 2.4% |
| L858R + T790M | 75 | 2.0% |
| G719X + E709X | 30 | 0.8% |
| Exon 19 deletion + L858R | 28 | 0.7% |
| G719X + S768I | 27 | 0.7% |
| L858R + E709X | 18 | 0.5% |
| L858R + V834L | 17 | 0.4% |
| G719X + L861X | 13 | 0.3% |
| L858R + S768I | 11 | 0.3% |
| Exon 19 deletion + K754X | 10 | 0.3% |
HER2 alterations were identified in 517 patients, including HER2 copy number gains (CNGs) in 150 patients, HER2 mutations in 397 patients, and both HER2 CNGs and mutations in 29 patients. HER2 mutations were distributed in ligand binding domain 1 (n = 6), cysteine‐rich domain (n = 28), ligand binding domain 2 (n = 7), growth factor receptor domain (n = 52), transmembrane domain (n = 17), and tyrosine kinase domain (n = 243). The most frequent type of HER2 alteration were exon 20 mutations in the kinase domain (n = 228). Y772_G775dupYVMA was the most common exon 20 variant (n = 144), followed by E770delinsEAYVM (n = 32), G776delinsVC (n = 20), G778_P780dupGSP (n = 9), and G776delinsVV (n = 8). S310F mutations in the HER2 extracellular region were identified in 13 patients.
The most common subtypes of ALK, RET, ROS1 and NTRK rearrangement were EML4‐ALK, KIF5B‐RET, CD74‐ROS1, and AGBL4‐NTRK, respectively.
Correlations between genomic alterations and gender
Correlations of genotype with gender are shown in Fig 1. The EGFR mutation rate was found to be significantly higher in women than in men (69.1% vs. 38.5%, P < 0.001), while the KRAS mutation (17.5% vs. 7.3%, P < 0.001) and MET alteration rates (6.5% vs. 4.5%, P < 0.001) were significantly higher in men than in women. There was no significant difference in the frequency of BRAF mutation, RET rearrangement, ROS1 rearrangement, HER2 alteration, and ALK alteration observed between women and men.
Figure 1.
Comparison of frequency of selected gene mutations in Chinese patients with non‐small cell lung cancer (NSCLC) between men and women. EGFR, EGFR mutations; KRAS, KRAS mutations; HER2, HER2 alterations; ALK, ALK alterations; MET, MET alterations; BRAF, BRAF alterations; RET, RET rearrangements; ROS1, ROS1 rearrangements; *, significant difference. (
) Male, (
) Female.
Correlations between genomic alterations and age
The mutation rates in different age groups are shown in Fig 2. We found that the EGFR mutation rate tended to decrease with age in the group aged >40 years, while the KRAS mutation rate tended to increase with age. The BRAF mutation rate was 1.0% in the group aged <40 years and approximately 4% in the groups aged >40 years. The HER2 mutation (13.9% vs. 6.7%, P < 0.001) and ALK alteration rates (14.3% vs. 6.9%, P < 0.001) were significantly higher in the group aged <40 years than in groups aged 40 years or older. The rates of MET alteration, ROS1 and RET rearrangement were not significantly different between the group aged <40 years and the group aged 40 years or older.
Figure 2.
The frequency of selected gene mutations in Chinese patients with non‐small cell lung cancer (NSCLC) among different age groups. EGFR, EGFR mutations; KRAS, KRAS mutations; HER2, HER2 alterations; ALK, ALK alterations; MET, MET alterations; BRAF, BRAF alterations; RET, RET rearrangements; ROS1, ROS1 rearrangements. (
) <40, (
) 40–50, (
) 50–60, (
) 60–70, (
) >70.
Discussion
NGS technology is now widely used to identify the driver genes of NSCLC with resulting data providing a driver gene profile in Chinese patients with NSCLC. Using this technology enables clinicians to make precise clinical decisions. As 68.5% of patients harboring driver genes can receive matched target agents, it is important to carry out NGS, as in addition to typical EGFR mutations, other genomic alterations can also be focused upon.
The frequency of EGFR mutations, KRAS mutations, HER2 alterations, ROS1 rearrangements, RET rearrangements, BRAF mutations and MET alterations in this study was consistent with that reported previously in a study in Asian patients. 4 , 5 Compared with the Western population, the Chinese patients in this study were found to have a higher frequency of EGFR mutation, but a lower frequency of KRAS mutation. 6 It has been previously reported that NTRK rearrangements have been found to occur in 0.2% of patients with NSCLC in the Western population, 7 and the frequency of NTRK rearrangements was 0.59% in this study.
EGFR mutations include typical and atypical EGFR mutations. With the widespread use of NGS, more and more atypical EGFR mutations can be detected. In clinical practice, women patients who do not smoke are more likely to be recommended for NGS. In addition, NGS could identify more atypical mutations, and might lead to a higher prevalence of EGFR mutations in female patients. Patients with atypical EGFR mutations have been reported to have variable efficacy to EGFR TKIs. As atypical EGFR mutations account for about 20% of all detected EGFR mutations, and 17.7% of patients harbor complex EGFR mutations, efficacy of EGFR TKIs in patients with different atypical and complex EGFR mutations need to be further researched. The EGFR mutation rate in our study tended to decrease with age, apart from in the group aged <40 years, which is consistent with previously reported data,4 which implies that patients in the group aged 40–50 had the highest EGFR mutation rate.
HER2 mutations in NSCLC are dominated by in‐frame insertions in exon 20 of the HER2 kinase domain. 8 HER2 mutation is found in 2%–4% of lung cancer patients. 4 , 9 The frequency of HER2 mutation in this study was 7.0%. The domain structure consists of two ligand binding domains, two cysteine‐rich domains, a short transmembrane domain, a tyrosine kinase domain, and a carboxy terminal tail. 10 The HER2 extracellular domain mutants were activated by two distinct mechanisms, characterized by elevated C‐terminal tail phosphorylation, or by covalent dimerization mediated by intermolecular disulfide bond formation. 11 Different HER2 variants exhibit divergent sensitivities to anti‐HER2 treatments. Afatinib, pyrotinib and poziotinib are regarded as HER2‐TKIs. Certain variants, G778_P780dup and G776delinsVC, derive sustained clinical benefits from afatinib, whereas the predominant variant, A772_G775dupYVMA, is resistant to most anti‐HER2 treatments. 12 In one study, chemotherapy was found to achieve better outcomes than afatinib for YVMA insertions. 13 Further clinical trials involving variable HER2 mutations are required.
Although fluorescence in situ hybridization (FISH) has been established as a gold standard method in the detection of ALK and ROS1 rearrangement, NGS is also a reliable technique. 14 , 15 In addition, NGS has been reported to identify different types of ALK fusions and ALK mutations that mediate resistance to ALK inhibitors. 16 , 17 The ALK rearrangement rate in this study was consistent with that observed in prior studies. 5
Dysregulation of the MET pathway in lung cancer occurs via a variety of mechanisms including gene mutation, amplification, rearrangement, and protein overexpression. 18 MET exon 14 encodes part of the juxtamembrane domain. Juxtamenbrane domain mutations that disrupt splice sites flanking MET exon 14 result in MET exon 14 skipping. The prevalence of MET exon 14 skipping mutations was 0.4% in this study, consistent with a previous report in Chinese patients. 4 MET copy‐number gains arise from two distinct processes: polysomy and amplification. 19 MET amplification is thought to be an oncogenic driver. Copy number gains detected via NGS are reported as continuous variables. Determination of the cutoff related to the efficacy of MET inhibitors requires further clinical data.
It has been previously reported that BRAF mutations have been observed in 2%–4% of patients with NSCLC. 20 However, the association between BRAF mutation status and patient age or sex appears to be less clear. 21 The frequency of BRAF mutation in this study was similar to the frequency reported in other research. Our study showed no significant association between sex and BRAF mutation frequency, but there was a lower frequency in the group aged <40 years than in the group aged 40 years or older. BRAF mutations can be divided into V600E and non‐V600E. A total of 202 of all patients with BRAF‐mutant NSCLC in this study presented with non‐V600E mutations. Vemurafenib monotherapy has been reported to be effective for treating patients with BRAF V600‐mutated NSCLC, but not those with BRAF non‐V600 mutations. 22 Therefore, more effort into the treatment of patients with non‐V600E mutation should be made in the future.
This study has a few limitations. First, it was retrospective, and there may have been a patient selection bias. It has been previously reported that adenocarcinoma accounts for approximately 40% of lung cancers, and squamous cell carcinoma 25% to 30% of lung cancers. 23 In this study, there were 5382 cases (72.9%) of lung adenocarcinoma, and 855 (11.6%) cases of lung squamous cell carcinoma. The frequency of driver gene mutations was found to be much higher in lung adenocarcinoma than in lung squamous cell carcinoma patients. Therefore, it is recommended that NGS is conducted in more patients with lung adenocarcinoma. Second, we did not collect clinical outcome information and were unable to analyze the clinical prognosis of patients with uncommon mutations. Third, we did not analyze the effect of smoking history on the prevalence of driver gene mutations. It has previously been demonstrated that EGFR mutation is highly prevalent in lung cancer patients who were never smokers. 24 Therefore, the smoking history in different sex and age groups may affect the prevalence of driver gene mutations.
This study demonstrated that the frequency of different driver genes was diverse in different age‐gender groups. It is anticipated that the results of this study may assist clinicians in clinical decision‐making, and assist government, pharmaceutical researchers and insurance companies in the development of public healthcare strategies.
Disclosure
The authors have no potential conflicts of interest to disclose.
Acknowledgments
We thank all the patients and their families who contributed to this study. This work was supported by a grant from Project of Development Center for Medical Science and Technology, National Health Commission of the People's Republic of China (No. W2017ZWS17).
Xiaoyan Si and Ruili Pan contributed equally.
Contributor Information
Shaohua Ma, Email: doctor_msh@bjmu.edu.cn.
Xiaotong Zhang, Email: zhangxtpumch@126.com.
Li Zhang, Email: zhanglipumch1026@sina.com.
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