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Article

Epidemiologic Features of NSCLC Gene Alterations in Hispanic Patients from Puerto Rico

by
Ruifang Zheng
1,
Zhiwei Yin
1,
Albert Alhatem
1,
Derek Lyle
2,
Bei You
1,3,
Andrew S. Jiang
4,
Dongfang Liu
1,
Zsolt Jobbagy
1,
Qing Wang
1,
Seena Aisner
1 and
Jie-Gen Jiang
1,3,*
1
Department of Pathology, Immunology & Laboratory Medicine, Rutgers New Jersey Medicine School, Newark, NJ 07103, USA
2
Genoptix Medical Laboratory, 2110 Rutherford Road, Carlsbad, CA 92008, USA
3
The Genomics Center, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
4
College of Medicine, Drexel University, Philadelphia, PA 19129, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(12), 3492; https://doi.org/10.3390/cancers12123492
Submission received: 6 October 2020 / Revised: 18 November 2020 / Accepted: 19 November 2020 / Published: 24 November 2020
Browse Figure
Review Reports Versions Notes

Abstract

:

Simple Summary

We have analyzed the molecular genetic profiles of Hispanic non-small cell lung cancer (NSCLC) patients from Puerto Rico. In addition to the general characteristics, especially on EGFR mutations, we have also reported some novel findings on the incidences of KRAS mutation subgroups, other driver gene alterations, and passenger gene alterations, as well as KRAS/TP53 and KRAS/STK11 co-mutations. Moreover, our study has identified the FGFR2-TACC2 translocation in this population.

Abstract

Targeted therapy has changed the paradigm of advanced NSCLC management by improving the survival rate of patients carrying actionable gene alterations using specific inhibitors. The epidemiologic features of these alterations vary among races. Understanding the racial differences benefits drug development, clinical trial design, and health resource allocation. Compared to Caucasian and Asian populations, current knowledge on Hispanic patients is less and no data of Hispanic patients from Puerto Rico have been reported. We retrieved and analyzed the demographic, clinical, and molecular data of Hispanic NSCLC patients from Puerto Rico with molecular tests performed in the Genoptix Medical Laboratory in Carlsbad, CA, USA between 2011 and 2018. The majority of the NSCLC patients in our study had either adenocarcinoma (75.4%) or squamous cell carcinoma (15.1%). The incidence of EGFR mutations was 24%. They were more common in female and younger patients (<60 years). The deletion of Exon 19 and Exon 21 L858R comprised 55.1% and 31.0% of all EGFR mutations, respectively. The frequency of the T790M mutation was lower compared to that of Hispanic patients reported in the literature (0.5% vs. 2.1%). In addition, 18.7% of the patients were positive for KRAS mutations, which was at the high end of that reported in Hispanic patients. Other driver gene alterations, ALK, MET, RET, ROS1, KRAS, ERBB2, etc., demonstrated similar incidences, as well as gender and age distributions to those previously reported. The KRAS/TP53 and KRAS/STK11 co-mutations were of very low frequencies (3.6%), which could potentially affect the responsiveness to PD1/PD-L1 immunotherapy. Our study demonstrated that the prevalence of NSCLC gene alterations in Hispanic patients from Puerto Rico was comparable to the reported average prevalence in Latin American countries, supporting the intermediate NSCLC gene alteration rate of Hispanic patients between Asian and Caucasian patients. Novel information of the frequencies of KRAS mutation subtypes, driver gene alterations in ROS1, BRAF, and ERBB2, and passenger gene alterations including a rare case with the FGFR2-TACC2 translocation in Hispanic NSCLC patients from Puerto Rico were also described.

1. Introduction

Cancer driver genes refer to the genes whose alterations increase cell proliferation or survival, leading to clonal expansion and tumor growth. KRAS is the first driver gene identified in lung cancer patients. It is also the most commonly mutated gene, and found in approximately 22% of the lung cancer patients in western countries [1]. To date, the driver genes identified in lung cancers include KRAS, EGFR, ALK, MET, BRAF, ROS1, RET, ERBB2, and NTRK, most of which contain actionable alterations except KRAS. The passenger genes, such as TP53, AKT1, PIK3CA, MAP2K1, STKII, KEAP1, etc. are not involved in the disease initiation, but some have a therapeutic or prognostic value. The identification of genetic alterations and specific inhibitors to these alterations has shifted the management of advanced NSCLC from surgical resection and chemotherapy to targeted therapy. Nowadays, molecular studies detecting these genetic alterations are a routine work-up in lung cancer management. These studies provide information not only for treatment, but also for prognosis and drug resistance.
The racial disparity of gene alterations in lung cancer is well known. For example, the incidence of EGFR mutations is higher in Asian patients (~40%), but lower in Caucasian patients (~11%) [2,3]. Studies on the epidemiologic features of lung cancer gene alterations in Hispanic patients are relatively less and of small size except the two conducted by Arrieta et al. [4,5,6,7,8,9,10] in 2011 and 2015. The reported EGFR mutation rate in Hispanic patients was between Asian and Caucasian patients, widely ranging from 13% to 37.3%. Hispanic patients had KRAS (7–20%) and ALK (4.2–10.5%) alteration rates comparable to Asian patients, but lower than Caucasian patients [6]. When breaking down the incidences of the alterations based on countries/regions, we can see a considerable variation though all the patients identified themselves as Hispanics. For example, the EGFR mutation rate is 11% in patients from Argentina, but 67% in patients from Peru. The heterogeneity of the Hispanic population is one of the reasons for this large variation. Hence, studying the epidemiologic features of lung cancer gene alterations in Hispanic patients according to the countries or regions they reside in could probably provide more valuable information than viewing them as a pure ethnic group. In this study, we analyzed the molecular genetic profiles of Hispanic NSCLC patients from Puerto Rico, presented the epidemiologic features of more than 20 genes, which expanded the current information on lung cancer gene alterations in Hispanic patients. In addition to the general characteristics, we also reported some novel findings on the incidences of KRAS mutation subgroups and passenger gene mutations, as well as KRAS/TP53 and KRAS/STKII co-mutations, which were reported to be associated with an adverse prognosis of NSCLC [11,12,13,14].

2. Results

2.1. Patient Demographics and Clinical Diagnosis

The age of the patients ranges from 35 to 95 years, with a mean age of 69 years and a median age of 70 years. Moreover, 52.7% (501/951) are male patients and 47.3% (450/951) are female patients. Of these patients, 80.3% are equal to or older than 60 years. Furthermore, 75.4% (717/951) of the patients were diagnosed with adenocarcinoma, 15.1% (144/951) of them with squamous cell carcinoma, and 6.9% (90/951) of them with other types of NSCLC (Table 1).

2.2. EGFR Mutation

The EGFR status was available in 82% (780/951) of the patients. EGFR mutation(s) was identified in 24% (187/780) of them (Table 2), with Exon 19 deletion (55.1%, 103/187) being the most frequent one, followed by Exon 21 L858R (31.0%, 58/187), Exon 20 insertion (4.8%, 9/187), Exon 21 L861Q (2.7%, 5/187), Exon 18 G719S (2.7%, 5/187), and Exon 20 S768I (1.6%, 3/187) (Figure S1). We compared our data with the largest NSCLC mutation study in the Hispanic/Latino population [5,7] available so far (Table 2). The overall EGFR mutation rate of our patients is comparable to the reported 26.0% (1491/5738). The Exon 19 deletion had a higher rate in our patient population (55.1% vs. 47.1%, p = 0.039). The frequency of Exon 21 L858R was similar to that as previously reported (31.0% vs. 37.3%, p = 0.09). The combined percentage (86.1%) of Exon 19 deletion and Exon 21 L858R was higher in our group of patients, but not significantly different from the reported 84.4% among all the EGFR mutations [5]. Exon 20 S768I had a similar frequency to that in the literature (1.6% vs. 3.1%, p > 0.05) [7]. The EGFR T790M mutation, which confers resistance to the 1st and 2nd generation tyrosine kinase inhibitors (TKIs), showed a lower rate in our study (4/780, 0.5%) than that reported in earlier studies (85/5738, 1.4%) (p < 0.05) [5]. EGFR mutations were detected more often in younger and female patients or patients with adenocarcinoma [2]. Our patients from Puerto Rico demonstrated a similar gender, age, and histologic predilections. Moreover, the female patients having EGFR mutations were 33.2% (124/373) and male patients were 15.5% (63/407) (p < 0.05). The median age of patients with positive EGFR mutation was 68 years. In patients younger than 60 years old, the mutation rate was 30.1% (46/153), higher than the 19.5% (80/410) found in patients older than or equal to 60 years (p < 0.05) (Table 3). Furthermore, the patients with adenocarcinoma having EGFR mutations were 28.2% (169/431), whereas only 5.4% of the patients with squamous cell carcinoma carried EGFR mutations (Table S1). The adenocarcinoma rate is significantly higher than that of squamous cell carcinoma (p < 0.05).

2.3. KRAS Mutation

In our study group, the KRAS mutation rate is 18.7% (77/412), significantly higher compared to the reported frequency (14.0%) in Hispanic patients in Arietta’s paper [5] (Table 2). In contrast to the EGFR mutations, KRAS mutations occurred more often in older patients than in younger patients (29.9% vs. 13.5%, p < 0.05). The KRAS mutation rate was slightly higher in male patients, with a rate of 21% vs. 16.1% in female patients. However, this difference was not statistically significant (Table 3). A strict mutual exclusion of EGFR mutation and KRAS mutation was reported previously, but more recent studies have shown an overlap between KRAS and EGFR in a small number of cases [16,21]. Nine KRAS mutations have been described in the literature, with mutations in codon 12 being the most common ones. Some clinical studies demonstrated that G12V and G12C mutations were associated with poor prognosis [13,14]. In addition, codon 12 mutations were detected in 97.4% (75/77) of our patients, and the frequencies of particular codon 12 mutations were as follows: G12C (40.3%), G12V (18.2%), G12D (23.4%), and G12A (6.5%) (Table 4). The co-existence of KRAS mutations with secondary mutations has been reported to have some distinctive clinical features, e.g., KRAS and STK11 co-mutations are associated with poor overall survival, and patients with concurrent KRAS and p53 mutations are more sensitive to PD1 and PD-L1 immunotherapy [11,12]. In our patients from Puerto Rico, the co-mutations of KRAS/p53 or KRAS/STK11 were 3.6% (2/55) for each combination (Table 4).

2.4. ALK Rearrangement

The ALK rearrangement is a targetable genetic alteration in NSCLC with a low incidence. The reported ALK rearrangement rates in Caucasian, Asian, and Hispanic patients are 1–3%, 2.3–6.7%, and 4.2–10.5%, respectively [8]. In our study, the frequency of ALK rearrangement was 3.9% as detected by FISH (28/710) (Table 2). This is within the range of the ALK rearrangement rate of Asian patients. The ALK rearrangement tends to be present in younger patients, with a median age of 52 years [22]. In our study cohort, the median age of patients with a positive ALK rearrangement was 66.5 years, but it occurred more frequently in relatively young patients, with a rearrangement rate of 7.1% (9/127) in patients younger than 60 years and 3.3% (19/583) in patients older than 60 years (p < 0.05) (Table 3). Though the incidence of ALK rearrangement is reported to have a male predilection [22], we did not see this gender difference in our study (Table 3).

2.5. MET Amplification and Mutation

The MET gene amplification, mutation, rearrangement, and protein overexpression all lead to an elevated MET protein kinase activity and tumor growth [23]. A secondary MET amplification also plays a role in acquired TKI resistance [24]. The MET gene amplification is now used as a biomarker to predict the responsiveness to MET inhibitors. In TKI-naïve NSCLC, the incidence of MET amplification ranges from 2–5%, and reaches 5–20% in NSCLC with resistance to the 1st or 2nd generation of TKIs [2,16,17,18]. An increased MET amplification (≥5 GCN) is an adverse prognostic factor in surgically resected NSCLC [25]. We have tested 172 patients for MET amplification by FISH, 10.5% (18/172) of them had increased MET gene copy numbers (Table 3). The median age of MET amplification patients was 66 years. No age or gender predilection is observed. In the 69 patients tested with NGS results (different from the 172 patients above), five patients carried MET mutations, but none of the mutations have a definite clinical significance (Table S2). The bioinformatics analysis revealed that these mutations have no potential to lead the MET Exon 14 skipping.

2.6. Other Driver Gene Alterations

In our study, 2.2% of the patients had the ROS1 positive rearrangement (7/322), similar to the reported 0.7–3.4% [15]. In addition, 2.1% of the patients had the RET positive rearrangement (4/190), similar to the reported 1.0–3.0% [16]. A total of 94 patients had BRAF tested by NGS and four of them were positive (4.3%), which is also comparable to the reported 1–5% in non-ethnic based studies [19]. ERBB2 was detected by NGS with four positives (6%, 4/69), similar to the documented 2–5% in lung adenocarcinoma (Table 2) [20].

2.7. Overlaps of Driver Gene Alterations

Recent publications have reported overlaps of driver mutations though at a very low rate [26,27], and our data supported these observations. Among the driver genes, BRAF is the only one showing no overlap with others. We observed two cases with overlapping KRAS and EGFR mutations, both co-existed with Exon 19 deletion. ALK, ROS1, RET, and MET each coexist with EGFR in a few cases, KRAS coexisted with MET in two patients, and ROS1 and RET were both positive in one patient (Figure S2).

2.8. Passenger Gene Alterations

Passenger gene alterations were tested in 55 patients by NGS (Table S3). TP53 had the highest mutation rate, 54.55% (30/55). The incidences of mutations in other genes, such as STK11, IGF1, FGFR, etc., ranged from 0% to 11.24% (Table 5). A very interesting finding is that one of the two cases with FGFR2 gene alterations harbored the FGFR2-TACC2 translocation. The patient was an 85-year-old female with a mucinous adenocarcinoma of the lung.

3. Discussion

EGFR mutations in NSCLC have a strong racial disparity: More common in Asian patients (40–51.4%) than Caucasian patients (9.8–11%) [2,3]. The data on the Hispanic population vary over a wide range. Some of the studies demonstrated that the incidences are between Asian and Caucasian patients, ranging from 24.6–35.3% [5,7,8]. Others showed lower EGFR frequencies (13–18%) and no difference from that seen in Caucasian patients [4,8,9,10]. The EGFR mutation rate of patients from Puerto Rico in our study was 24.0%, consistent with the intermediate EGFR mutation rate in Hispanic NSCLC patients. The Exon 19 deletion and Exon 21 L858R mutation are the two most common EGFR mutations, comprising 85–90% of all the EGFR mutations, with Exon 19 deletion slightly more common than Exon 21 L858R [2]. These two mutations are associated with a better prognosis regardless of the treatment [2]. The frequency of Exon 19 deletion in our study was higher than the reported incidence in Arrieta’s paper (55.1% vs. 47.1%) (p < 0.05), and the Exon 21 L858R mutation rate was relatively lower but with no significant difference (31.0% vs. 37.3%, p > 0.05). The combined incidence of Exon 19 deletion and Exon 21 L858R mutation (86.1%) was comparable to that published in the literature. There is no difference between the Exon 19 deletion and Exon 21 L858R mutation regarding their responsiveness to therapy or disease prognosis. Therefore, the above difference may not be clinically significant. The EGFR T790M mutation is one of the mechanisms for the tyrosine kinase inhibitor (TKI) resistance. It can either occur as a primary mutation or as an acquired mutation following the TKI treatment. The T790M mutation can be as high as ~50% in patients treated with TKIs, whereas the treatment-naive mutations are reported to be less than 1% [28,29]. This mutation almost always coexists with either the Exon 19 deletion or the L858R mutation. The Exon 19 deletions are more commonly present with the acquired T790M but the L858R is more likely with the primary T790M [28]. In our study, out of 780 patients with positive EGFR mutations, only four of them (0.4%) have a concomitant T790M, which is within the range of the reported incidence of primary T790M. All the four cases had the Exon 19 deletion. Due to the lack of treatment information, we were not able to determine whether the T790M mutations were primary or acquired. The best interpretation of this low occurrence could be the low prevalence of TKI use in our study population.
Globally, KRAS mutations are the most common mutations in NSCLC and considered a negative prognostic factor [30]. Asian patients have a lower KRAS mutation rate (8–15%) compared to patients from western countries (18–28.1%) [13,31,32]. The frequencies of KRAS mutations in Hispanic/Latino patients are reported between 7–20, comparable to that in the Asian population [5,6,8,33,34]. In our study cohort the KRAS mutation rate was 18.7%. This mutation rate falls into the reported range of Hispanic patients but is significantly higher than that reported in the Arietta’s paper [5]. Most KRAS mutations were located at codons 12, 13, and 61. Some mutation subtypes are associated with an adverse prognosis. G12V and G12C portend an inferior overall survival compared to the G12A and G12D mutations [13,14]. In our study, 97.4% of the patients had codon 12 mutations (75/77), and the frequencies of individual mutations were as follows: G12C (40.3%), G12V (18.2%), G12D (23.4%), and G12A (6.5%). G12V and G12C combined constitute 58.4% (45/77) of all KRAS mutations, and G12A and G12D account for 29.9% (23/77). These numbers were similar to the reported values: G12C (39%), G12V (18–21%), G12D (17–18%), and G12A (10.8%) [13,14].
Though the development of specific inhibitors to KRAS or its downstream signaling molecules has been a difficult journey without success so far, recent studies show that the KRAS co-mutation status in NSCLC is associated with its responsiveness to the PD-1/PD-L1 immunotherapy, as well as the disease prognosis [34]. Lung adenocarcinomas with concurrent KRAS and TP53 mutations are more responsive to PD1/PD-L1 inhibitors, whereas tumors with KRAS and STKII co-mutations exhibit resistance to those inhibitors [11,12]. Patients with KRAS and STKII co-mutations or with the STKII mutation alone also have poor overall survival compared to patients with no concurrent mutations, wild type KRAS, or wild type STKII [12]. Our study cohort included 55 patients with available KRAS, TP53, and STKII mutation statuses available for analysis. Our current observation is the first study reporting data of concurrent KRAS/TP53 and KRAS/STKII mutations in the Hispanic population. Surprisingly, these concurrent mutations in Hispanic NSCLC from Puerto Rico were very rare; only two cases for each combination (3.6%), compared to the published data (52% and 18%, respectively) [14]. Therefore, in Puerto Rican patients, the KRAS co-mutation status may not be a proper biomarker to estimate the responsiveness to immunotherapy. Moreover, the rarity of these co-mutations in Puerto Rican patients makes them an unfavorable population for studying these co-mutations. The low incidences cannot be explained by each individual frequency of KRAS, TP53, and STK11 mutations. The KRAS mutation frequency was relatively lower (18.7 vs. 27%) in our study [14], but the frequencies of STK11 and TP53 mutations were similar to the reported values (11% vs. 8–18% for STK11; 55% vs. 46% for TP53) [16,35,36].
The chromosomal translocation joining in-frame members of the fibroblast growth factor receptor-transforming acidic coiled-coil gene families (FGFR-TACC gene fusions) were first identified in a human glioblastoma multiforme [37]. The most common fusion type is FGFR3-TACC3, which has been discovered in many cancer types including lung cancer. The fusion between FGFR and TACC genes results in a constitutively activated kinase, which induces mitotic and chromosomal segregation defects, subsequently triggering aneuploidy. Clinical data showed promising effects of FGFR inhibitors in malignant tumors harboring FGFR-TACC fusions [37,38,39]. The rearrangement involving FGFR2-TACC2 had never been reported in lung cancer before. Our study identified a novel actionable rearrangement involving FGFR2-TACC2 in one of 55 patients tested by NGS. Figure 1 diagrams the predicted protein structure of the FGFR2-TACC2 fusion from this patient. The patient presented with mucinous adenocarcinoma of the lung. Interestingly, there is another report of a FGFR2-TACC2 translocation identified in a mucinous stomach adenocarcinoma in The Cancer Genome Atlas (TCGA) PanCancer studies (TCGA-BR-8080-01). The findings warrant further investigation of the FGFR2-TACC2 translocation in mucinous adenocarcinoma from different origins.
To the best of our knowledge, our study cohort is the first study on the frequencies of KRAS mutation subtypes, driver gene ROS1 rearrangement, drive gene BRAF and ERBB2 mutations, and passenger gene alterations including the FGFR2-TACC2 translocation in Hispanic NSCLC patients.

4. Materials and Methods

4.1. Patients

We conducted a retrospective study of lung cancer gene alterations in Hispanic NSCLC patients from Puerto Rico, who had lung cancer molecular tests performed between 2011 and 2018, in the Genoptix Medical Laboratory in Carlsbad, CA, USA. The diagnosis of NSCLC is based on the information on the requisition forms provided by the requesting clinicians. The specimens were submitted to the Genoptix Medical Laboratory randomly from twenty medical centers or doctor offices across the whole territory of Puerto Rico. The IRB approval (ID: 6173) to perform a retrospective chart review to collect and analyze clinical data, including laboratory, FISH, mutational, demographic, and pathological data, was issued by the Sterling IRB ethic committee on 11 December 2017.

4.2. Next Generation Sequencing

The Lung NGS panel (amplicon-based, targeted) of 25 genes was conducted on an Illumina MidiSeq instrument using genomic DNA isolated from unstained FFPE slides. The targeted genes include AKT1, ALK, ARAF, BCL2, BRAF, DDR2, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, HRAS, IGF1, KRAS, MAP2K, MDM2, MET, NRAS, PDGFRA, PIK3CA, PTEN, RET, ROS1, STK11, TP53. The alterations within each of those genes were analyzed through the proprietary bioinformatic software and interpreted in conjunction with reference databases such as COSMIC and dbSNP. Quality control metrics included a minimum input of 20 ng, with an optimal input of 100 ng of genomic DNA and average mean sequencing depth of 500× coverage. The limits of detection (LOD) were 5% for SNV, 10% for Indels, ≥6 copies for gene amplifications, and ≤0.3 copies for homozygous gene deletions. Insertions greater than 15 nucleotides and deletions greater than 52 nucleotides may not be detected. Benign sequence variants were not reported.

4.3. Multiplex PCR

Mutations of EGFR, KRAS, and BRAF were detected using multiplex PCR, including Exon 19 deletion, Exon 20 insertion, L858R, S786I, G719X, L861Q, and T790M for EGFR, mutations in codon 12, 13, and 61 for KRAS, and V600E for BRAF.

4.4. FISH

Gene rearrangements of ALK, ROS1, and RET were detected on unstained FFPE slides by a fluorescent break apart (BA) DNA probes and gene amplification of MET was detected on unstained FFPE slides by fluorescent MET and CEP7 DNA probes. Fifty cells for ALK or sixty cells for MET, ROS1, and RET were analyzed for each case. Accordingly, 15% or more of the tumor cells showing split signals of the fluorescent probes was considered positive (Figure S3). Based on the MET-CN and MET/CEP7 ratio, the patients’ MET results were classified as an MET-amplification: MET/CEP7 ≥ 2 or MET-CN ≥ 5. Fusion partners could not be identified in these FISH assays with break apart DNA probes.

4.5. Statistical Analysis

The categorical variables in this study were analyzed using the χ2 test and p < 0.05 was considered statistically significant.

5. Conclusions

In summary, targeted therapy is the trend of medicine. Understanding the epidemiologic features of the genetic alterations in NSCLC in different racial groups improves the efficacy and predictability of the treatment. Our data indicate that Hispanic patients from Puerto Rico showed an intermediate rate of EGFR mutations and ALK rearrangements, similar to that in most Latin American countries. The KRAS mutation rate was at the high end of the reported frequencies in the Hispanic patients, and close to the rate of Caucasian patients. The frequencies of KRAS mutation subtypes, driver gene alterations in ROS1, BRAF, and ERBB2, and passenger gene alterations including a rare case with the FGFR2-TACC2 translocation are novel information in this racial group, which need confirmation by other independent studies.

Supplementary Materials

The following are available online at https://www.mdpi.com/2072-6694/12/12/3492/s1. Table S1: EGFR mutations in different histologic types; Table S2: MET mutations detected by NGS; Table S3: Clinical data of 55 patients with passenger gene mutations; Figure S1: EGFR mutation composition; Figure S2: Overlap of driver gene alterations; Figure S3: Representative FISH figures.

Author Contributions

Conceptualization, J.-G.J.; methodology and formal analysis, R.Z., Z.Y., B.Y., A.S.J. and J.-G.J.; writing—original draft preparation, R.Z., Z.Y., and A.A.; writing—review and editing, J.-G.J., Q.W., Z.J., D.L. (Dongfang Liu), and S.A.; supervision, J.-G.J.; project administration, J.-G.J. and D.L. (Derek Lyle). All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

The authors thank Paris Petersen in the Genoptix Medical Laboratory for searching and collecting data for this study.

Conflicts of Interest

The authors declare no conflict of interest.

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Cancers 12 03492 g001 550
Figure 1. Predicted protein structure of FGFR2-TACC2 fusion. (A) Sequence of the region fused between FGFR2 and TACC2 in genome. (B) Schematic of FGFR2-TACC2 fusion involving exons 1 to 17 of FGFR2 and exons 11 to 17 of TACC2. Red dashed lines indicate breakpoints. FGFR2, fibroblast growth factor receptor 2; TACC2, transforming acidic coiled-coil-containing protein 2; Ig, disulfide linked immunoglobin-like domains; TM, transmembrane domain; TK, intracellular tyrosine kinase domain.
Figure 1. Predicted protein structure of FGFR2-TACC2 fusion. (A) Sequence of the region fused between FGFR2 and TACC2 in genome. (B) Schematic of FGFR2-TACC2 fusion involving exons 1 to 17 of FGFR2 and exons 11 to 17 of TACC2. Red dashed lines indicate breakpoints. FGFR2, fibroblast growth factor receptor 2; TACC2, transforming acidic coiled-coil-containing protein 2; Ig, disulfide linked immunoglobin-like domains; TM, transmembrane domain; TK, intracellular tyrosine kinase domain.
Cancers 12 03492 g001
Table
Table 1. Demographic and pathologic features.
Table 1. Demographic and pathologic features.
VariablesNumber (%)
Gender
Male501 (52.7%)
Female450 (47.3%)
Age (years)
Median (range)70 (35–95)
Mean ± SD69 ± 10.43
<60 years187 (19.7%)
≥60 years764 (80.3%)
Diagnosis
Adenocarcinoma717 (75.4%)
Squamous cell carcinoma144 (15.1%)
Others90 (9.5%)
Table
Table 2. Alteration incidences of the driver genes.
Table 2. Alteration incidences of the driver genes.
GenesIncidenceReported Incidencep-Value
EGFR24.0% (187/780)26.0% (1491/5738) [5]p = 0.2282
Exon 19 deletion55.1% (103/187)47.1% (702/1491) [5]p = 0.0391 †
Exon 21 L858R31.0% (58/187)37.3% (556/1491) [5]p = 0. 0931
Exon 20 S768I1.6% (3/187)3.1% (12/382) [7]p = 0.2824
T790M0.5% (4/780)1.4% (85/5738) [5]p = 0.0268 †
Others10.2% (19/187)N/AN/A
KRAS18.7% (77/411)14.0% (190/1355) [5]p = 0.0195 †
ALK3.9% (28/710)4.2–10.5% [8]N/A
ROS12.2% (7/322)0.7–3.4% [15]N/A
RET2.1% (4/190)1.0–3.0% [16]N/A
MET (Amplification)10.2% (18/172)2–20% [2,16,17,18]N/A
BRAF4.3% (4/94)1–5% [19]N/A
ERBB25.8% (4/69)2–5% [20]N/A
† p < 0.05.
Table
Table 3. Gene alterations in relation to gender and age.
Table 3. Gene alterations in relation to gender and age.
GenesGenderAge
MaleFemalep-ValueMedian (Years)<60 Years≥60 Yearsp-Value
EGFR15.5%33.2%p < 0.00001 †6830.1%19.5%p = 0.0075 †
(63/407)(124/373)(46/153)(80/410)
KRAS21.0%16.1%p = 0.19917213.5%29.9%p = 0.0052 †
(46/219)(31/193)(10/74)(67/224)
ALK3.4%4.6%p = 0.433566.57.1%3.3%p = 0.0446 †
(13/381)(15/329)(9/127)(19/583)
MET7.4%14.3%p = 0.14066620.0%8.8%p = 0.0920
(7/95)(11/77)(5/25)(13/147)
† p < 0.05.
Table
Table 4. KRAS mutation subtypes and co-mutations.
Table 4. KRAS mutation subtypes and co-mutations.
Gene MutationsPercentage
KRAS
Condon 1297.4% (75/77)
G12C40.3% (31/77)
G12V18.2% (14/77)
G12D23.4% (18/77)
G12A6.5% (5/77)
KRAS + TP533.6% (2/55)
KRAS + STK113.6% (2/55)
Table
Table 5. Frequencies of passenger gene alterations.
Table 5. Frequencies of passenger gene alterations.
GenesPositive (n)Tested (n)Percentage (%)
TP53305554.6
STK1165510.9
FGFR165510.9
PIK3CA5559.1
IGF15559.1
DDR24557.3
MDM23555.5
PTEN2553.6
FGFR22 #553.6
FGFR32553.6
HRAS1551.8
PDGFRA1551.8
BCL21551.8
AKT10550
ARAF0550
MAP2K10550
#: One case with the FGFR2-TACC2 fusion.
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Zheng, R.; Yin, Z.; Alhatem, A.; Lyle, D.; You, B.; Jiang, A.S.; Liu, D.; Jobbagy, Z.; Wang, Q.; Aisner, S.; et al. Epidemiologic Features of NSCLC Gene Alterations in Hispanic Patients from Puerto Rico. Cancers 2020, 12, 3492. https://doi.org/10.3390/cancers12123492

AMA Style

Zheng R, Yin Z, Alhatem A, Lyle D, You B, Jiang AS, Liu D, Jobbagy Z, Wang Q, Aisner S, et al. Epidemiologic Features of NSCLC Gene Alterations in Hispanic Patients from Puerto Rico. Cancers. 2020; 12(12):3492. https://doi.org/10.3390/cancers12123492

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Zheng, Ruifang, Zhiwei Yin, Albert Alhatem, Derek Lyle, Bei You, Andrew S. Jiang, Dongfang Liu, Zsolt Jobbagy, Qing Wang, Seena Aisner, and et al. 2020. "Epidemiologic Features of NSCLC Gene Alterations in Hispanic Patients from Puerto Rico" Cancers 12, no. 12: 3492. https://doi.org/10.3390/cancers12123492

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