EGFR variant profiles in lung adenocarcinoma from different regions of Brazil: A multi- institutional study using a rapid RT‒PCR platform

EGFR variant profiles in lung adenocarcinoma from different regions of Brazil: A multi- institutional study using a rapid RT‒PCR platform | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article EGFR variant profiles in lung adenocarcinoma from different regions of Brazil: A multi- institutional study using a rapid RT‒PCR platform Rodrigo de Andrade Natal, Ana Luiza Araújo Jernigan, Marília de Oliveira Scliar, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6606895/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Lung cancer is the second most diagnosed cancer and activating EGFR variants are involved in the pathogenesis of a significant subset of lung adenocarcinomas. Given that Brazil is the largest and most populous country in South America with high ancestry’s admixture, this study aimed to evaluate the frequency of the EGFR variant and its subtypes in lung adenocarcinoma in three distinct Brazilian regions and to correlate these findings with clinicopathological features. Methods A retrospective electronic search was performed to select patients with lung adenocarcinoma who underwent EGFR profiling via a rapid RT‒PCR molecular platform from different regions of Brazil. Results The EGFR variant was present in 21% of the patients, with the highest mutation frequency observed in the northeastern region (NE), followed by the southeastern (SE) and southern (S) regions. Compared with male patients, female patients presented a greater EGFR variant frequency, except in S. Exon 19 deletion (exon 19 del) and p.Leu858Arg were the most common variants found. In addition, the NE had a greater frequency of exon 19 del, whereas the SE had p.Gly719Ala/Cys/Ser. Conclusion The highest frequency of the EGFR variant was observed in the NE, whereas the lowest rate was observed in the S. Furthermore, the NE presented the highest frequency of exon 19 del, whereas the SE presented p.Gly719Ala/Cys/Ser, regardless of gender. Lung adenocarcinoma EGFR variant Brazilian regions Figures Figure 1 1. Introduction Lung cancer is the second most diagnosed cancer, accounting for approximately 11% of all new cancer diagnoses, and is the leading cause of cancer deaths worldwide, accounting for up to 18% of all deaths [ 1 ]. Similarly, in Brazil, lung cancer is the second most common cancer in men and the fourth most common in women [ 2 ]. However, owing to underdiagnosis and underreporting, the frequency of lung cancer in Brazil may be significantly underestimated. Furthermore, there are regional variations in the incidence of lung cancer, with the southern region (S) having the highest incidence, followed by the midwestern (MW), northeastern (NE), northern (N), and southeastern (SE) regions [ 3 ]. Despite some improvements in survival rates over recent decades, lung cancer still has a poor prognosis, with 5-year survival rates ranging from 4–17% depending on the stage and histological subtype [ 4 ]. There are two primary histological subtypes of lung cancer, namely non-small cell lung cancer (NSCLC), which accounts for up to 85% of cases, and small-cell lung cancer, which accounts for the remaining 15% and has a poorer prognosis than the former [ 5 ]. NSCLC can be further subclassified into squamous cell carcinoma and adenocarcinoma, which account for 20% and 40% of cases, respectively [ 2 ]. Although the activating EGFR variant is involved in the pathogenesis of a significant subset of lung adenocarcinomas [ 6 ], it also serves as a prognostic and predictive factor. Variants in EGFR are clustered within exons 18 through 21, which are part of the tyrosine kinase binding domain [ 7 ]. Patients with a deletion in exon 19 (exon 19 del) and a point mutation, p. Lys858Arg, in exon 21 tend to respond very well to EGFR tyrosine kinase inhibitors (EGFR-TKIs) [ 8 ]. However, p.Thr790Met in exon 20 is associated with poor prognosis and is the most common cause of acquired resistance to first- and second-generation EGFR-TKIs [ 9 , 10 ]. The frequency of EGFR variants in lung adenocarcinomas varies depending on geographic region. The activating variants are present in approximately 49–60% in Asia, but only 12–33% of other continents [ 11 – 13 ]. These findings suggest a strong association with genetic origin and environmental factors. As a result, it has become essential to consider the epidemiology of EGFR variants when making decisions, such as which EGFR-TKIs should be used in any given population [ 13 ]. In Brazil, the frequency of the EGFR variant ranges from 19–30% [ 14 – 17 ], which is higher than that in European countries and the USA [ 12 ] but lower than that in some Latin American countries, such as Mexico and Peru [ 18 ]. However, Brazil is the largest and most populous country compared with these other countries. Then, based on geographic location, the population derives from a distinct mixture of Amerindian, European, and African ancestries, which may lead to genetic differences and regional variations [ 19 ]. Although a single study revealed no differences in variant frequency across different regions [ 20 ], it did not address different variant subtypes. Therefore, this study aimed to evaluate the frequency of the EGFR variant and its subtypes in lung adenocarcinoma in three distinct Brazilian regions (S, SE, and NE) and to correlate these findings with clinicopathological features. 2. Materials and methods 2.2 Patient selection We conducted a retrospective electronic search to select patients with lung adenocarcinoma submitted to EGFR profiling via a rapid RT‒PCR platform (Idylla system, EGFR assay – Biocartis, Mechelen, Belgium) from January 2019 to February 2022. Overall, 920 samples were retrieved, and the results were reviewed. The data were collected from three different regions of Brazil: São Paulo/Rede D’OR (SE), Ceará/ARGOS Patologia (NE), and Santa Catarina/Grupo Infolaudo & Medicina Diagnóstica (S). Age, sex, testing date, EGFR variant subtype, and collection site were obtained from electronic pathology reports. Patients with inconclusive results were excluded from the study. This study was conducted according to the principles of the Declaration of Helsinki and approved by the Instituto D’Or Research and Ethics Committee (institutional ethics committee). 2.3 Statistical analysis Statistical analyses were performed via R Studio [ 21 ]. Data for a continuous variable were expressed as mean and standard deviation (sd) of the mean. \(\:{\chi\:}^{2}\) test and Fisher’s exact test were used to compare two categorical variables. Woof-test on homogeneity of odds ratio and Cochran‒Mantel‒Haenszel test, with post-hoc analysis conducted by \(\:{\chi\:}^{2}\) -test, were applied to observe independence between two categorical variables while controlling for a third confounding categorical variable. Shapiro-Wilk test was used to evaluate the normality of the distributions of continuous variables. Mann-Whitney test and Kruskal-Wallis test with Dunn post-hoc test were applied to compare continuous variables according to categorical variables. p < 0.05 was considered statistically significant. 3. Results Table 1 shows the clinicopathological features of the 920 patients. The mean age of the patients was 67.0 years (sd = 12.7 years), with a slight female predominance versus males (51% vs 49%). Most of the patients were from the S (43%), followed by the SE (38%) and NE (19%). Regarding the tissue site of collection, testing occurred more commonly in the primary tumor than in its metastases (79% vs 21%). EGFR variants were detected in 21% of the patients, with the highest variant frequency observed in the NE (32%), followed by the SE (27%) and the S (11%) (Fig. 1 A). The most common EGFR variants were exon 19 del (45%) and p.Leu858Arg (43%). There was no statistical difference between the patient’s age and gender (p = 0.13), site of collection (p = 0.45), or EGFR variant (p = 0.61). Patient’s age differed across regions (p < 0.05), with the NE being older than the S (p adj < 0.05), and no difference was observed between the other groups. Female patients were predominant in the NE and SE (p < 0.05). Regarding EGFR variant, female patients presented a greater frequency (p < 0.05), with exon 19 del and p.Leu858Arg being the most common alterations (p < 0.05). Furthermore, when the associations between EGFR variants by region were evaluated, a greater frequency was observed in the NE and SE regions (p < 0.05). Although this contingency ( EGFR variant vs region) might be influenced by the asymmetric distribution of gender between those different regions, in this case, it was observed as independent (p < 0.05), even after correction for gender (p adj < 0.05). In addition, NE had a greater frequency of exon 19 deletion, whereas SE had a greater frequency of p.Gly719Ala/Cys/Ser (Fig. 1 B). 4. Discussion Our transversal analysis of genomic data obtained from rapid RT‒PCR molecular protocols revealed different frequencies of the EGFR variant in lung adenocarcinomas across the three distinct regions of Brazil. The highest frequency was observed in NE, whereas the lowest was in S. Furthermore, female patients presented a greater variant frequency than males, particularly in patients with exon 19 del and p.Lys858Arg, regardless of the region. Similarly, the NE displayed the highest frequency of exon 19 del, whereas the SE region presented p.Gly719Ala/Cys/Ser. In agreement with previous studies that reported a range from 19–30% [ 14 – 17 ], we demonstrated that the Brazilian EGFR variant frequency was 21%. Furthermore, when only SE data were used, the mutation frequency was 27%, which was higher than the Brazilian mean but still within the range of these previous studies [ 14 – 17 ], since it mainly included patients from this region. However, the frequencies of the EGFR variants were quite broad, which may reflect differences in patient selection and areas within the SE itself (Table 2 ). Moreover, it demonstrated a higher frequency of the p.Lys858Arg. Table 01 Clinicopathological features of patients submitted to EGFR profiling evaluation: Northeast Southeast South Total n (%) 171 (19) 350 (38) 399 (43) 920 Age – years (sd) 68.5 (14.2) 67.3 (13.0) 66.1 (11.6) 67.0 (12.7) Gender Female (%) 97 (21) 193 (41) 180 (38) 470 Male (%) 74 (16) 157 (35) 219 (49) 450 EGFR mutation (%) 55 (29) 93 (49) 42 (22) 190 Exon 19 deletion (%) 29 (53) 39 (42) 18 (43) 86 p.Lys858Arg (%) 20 (37) 41 (44) 21 (50) 82 Exon 20 insertion (%) 3 (5) 5 (5) 2 (5) 10 Other (%) 3 (5) 8 (9) 1 (2) 12 Table 2 EGFR variant frequency and ancestries composition according to region [ 14 – 17 , 19 , 23 – 25 , 33 ] Northeast Southeast South EGFR mutation 22.0–26.0% 22.0–30.0% 19.0% Exon 19 del 36.0% 39.0–60.0% 40.0% p.Lys858Arg 46.0% 11.0–33.0% 29.0% Exon 20 ins 6.0% 4.0–6.0% 10.0% Ancestries European 74.0% 78.0% 76.0–89.0% African 14.0% 15.0% 3.0–15.0% Amerindian 11.0% 7.0% 8.0% Conversely, S had the lowest EGFR variant frequency (11%). This difference may be attributed to demographic characteristics, such as gender, smoking behavior, and genetic background. This region has the highest proportion of European genetic ancestry due to the immigration of West Europeans, such as Germans and Italians [ 19 , 22 , 23 ]. This background might explain the similarity in the frequency of EGFR variants between S and Western European countries, where the frequency was between 9% and 16% [ 12 ] (Table 2 ). A previous Brazilian study reported a greater frequency of the EGFR variant in S than our results did [ 24 ]. This discrepancy might be due to the distinct methodology, since this comparative study used massively parallel sequencing, which revealed variants that were not detectable by our targeted RT‒PCR based system [ 24 ]. Although the p.Lys858Arg frequency was higher in this previous study (50.0% vs 29.0%), the frequencies of exon 19 del and exon 21 insertions (exon 21 ins) were similar [ 24 ]. Although there is a well-established degree of genetic overlap between southern and southeastern regions, due to European immigration [ 19 ], there was a distinct frequency of EGFR variant in these regions. The higher frequency in the southeastern region might be attributed to the influx of immigrants from Asian countries such as Japan, Korea, and China [ 16 ], which is the region with the highest known frequency of the EGFR variant [ 11 – 13 ]. The highest frequency of the EGFR variant occurred in NE (32%), although previous studies reported a lower frequency, ranging from 22–26% [ 25 , 26 ]. In addition, the exon 19 del and p.Lys858Arg variants had very different frequencies; as our results revealed a predominance of the former, the previous study had a predominance of the latter [ 25 , 26 ]. Recent studies have indicated an inverse correlation between smoking behavior and a lower incidence of EGFR mutation [ 27 – 29 ], even in the Brazilian population [ 15 , 20 ]. In this way, S exhibited the highest prevalence of smoking behavior [ 30 ], the highest incidence of lung cancer [ 3 ], and the lowest frequency of the EGFR mutation. In contrast, the NE, which has the lowest rate of smoking behavior [ 30 ], presented the highest frequency of the EGFR mutation. Furthermore, the highest frequency of the EGFR variant was detected in female patients, and the predominance of p.Leu858Arg and exon 19 del, which is well established in the literature [ 16 , 17 , 31 ], was consistent with our findings. Importantly, the prevalence of the various EGFR variants varied according to region, regardless of gender. Exon 19 del was the predominant variant in NE, whereas p.Gly719Ala/Cys/Ser was unique in SE. This localization for each variant, beyond the genetic diversity in Brazilian territories, has significant implications for treatment. Exon 19 del and p.Leu858Arg respond well to first-, second-, and third-generation EGFR-TKIs (e.g., erlotinib, gefitinib, icotinib, and osimertinib), whereas pGly719Ala/Cys/Ser responds well to second- and third-generation EGFR-TKIs (e.g., afatinib and osimertinib) [ 32 ]. In summary, our study revealed significant differences in the frequency of EGFR variants across the three Brazilian regions evaluated. These differences may be attributed to the distinct migratory processes that occur in each of these regions and distinct smoking behavior. A more comprehensive understanding of the genetic profile of patients in each region is essential to better understand the pathogenesis and incidence of lung adenocarcinoma, as well as the selection of the most appropriate therapy and drug distribution across the country. Declarations Competing interests The authors have no conflicts of interest to declare. Human Ethics and Consent to Participate declarations This study was approved by the Ethics Committee from Instituto D’OR de Pesquisa e Ensino (CAAE: 77607124.7.0000.0087). Due to its descriptive nature and the assurance of absolute anonymity, the authors were exempt from obtaining signed informed consent from the participants. Funding Not applicable. Authors' contributions RAN: Conceptualization, study design and coordination, data curation, formal analysis, data interpretation, writing–original draft, and writing–review and editing. ALAJ: Data curation. MOS: Formal analysis and data interpretation. CK: Data curation. FRT: Data curation. JCS: Data curation. FAS: Writing–review. MPM: Data curation. IWC: Conceptualization, study design and coordination, data interpretation, and writing–review and editing. All authors reviewed the manuscript. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6606895","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":458059994,"identity":"752ab15a-515f-4d40-ac0f-fb1a2fdf49d6","order_by":0,"name":"Rodrigo de Andrade Natal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABE0lEQVRIiWNgGAWjYHACA4YEGPNBBZA4ABSBAB5CWpgZGBLOEKuFAaYlsY0ILebtzds+PPhlw2DOfv7gh8R59+T4jjdvfFzBYCen28B77AMWLTJnjhXPSOxLY7DsSWaWSNxWbCwJFDE8w5BsbHaAL3kGFi0SEjnGDIk9hxkMDiQzALUkJG64kWMm2cBwIHHbAR5jbA5DaDn/mPlH4pyE+g333xChJeEHUMuNZDaJxIaEBIMbPAS08BwrZkhsSOMxuPHYzCLhWILhzDNpxYYNBkC/HOZLxqqFvXkz448/NnIG5xMf3/hQkyDPd/zwxocNFXZyZsd7D2MNZRBgbMOIAlDUMOPUAAR/8EmOglEwCkbBiAcApXBk8LW6IMsAAAAASUVORK5CYII=","orcid":"","institution":"Instituto D’Or de Pesquisa e Ensino (IDOR)","correspondingAuthor":true,"prefix":"","firstName":"Rodrigo","middleName":"de Andrade","lastName":"Natal","suffix":""},{"id":458059995,"identity":"3d274390-ce6e-48aa-90b4-c2f1f745993e","order_by":1,"name":"Ana Luiza Araújo Jernigan","email":"","orcid":"","institution":"Instituto D’Or de Pesquisa e Ensino (IDOR)","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"Luiza Araújo","lastName":"Jernigan","suffix":""},{"id":458059996,"identity":"64109972-5e62-4a12-a6b7-c9d4cf4ef9dd","order_by":2,"name":"Marília de Oliveira Scliar","email":"","orcid":"","institution":"Instituto D’Or de Pesquisa e Ensino (IDOR)","correspondingAuthor":false,"prefix":"","firstName":"Marília","middleName":"de Oliveira","lastName":"Scliar","suffix":""},{"id":458059997,"identity":"2f261dd2-1414-4350-9140-0990aea5ac7d","order_by":3,"name":"Clovis Klock","email":"","orcid":"","institution":"Grupo Infolaudo \u0026 Medicina diagnóstica","correspondingAuthor":false,"prefix":"","firstName":"Clovis","middleName":"","lastName":"Klock","suffix":""},{"id":458059999,"identity":"a755d115-dc5a-4805-b882-a22536e4fe1c","order_by":4,"name":"Fábio Rocha Távora","email":"","orcid":"","institution":"ARGOS Patologia","correspondingAuthor":false,"prefix":"","firstName":"Fábio","middleName":"Rocha","lastName":"Távora","suffix":""},{"id":458060001,"identity":"b014446c-def8-4928-80c7-59dea237505e","order_by":5,"name":"Juliana Cordeiro Sousa","email":"","orcid":"","institution":"ARGOS Patologia","correspondingAuthor":false,"prefix":"","firstName":"Juliana","middleName":"Cordeiro","lastName":"Sousa","suffix":""},{"id":458060002,"identity":"8d02d464-807a-45e4-92c6-2f48495ffa94","order_by":6,"name":"Fernando Augusto Soares","email":"","orcid":"","institution":"Instituto D’Or de Pesquisa e Ensino (IDOR)","correspondingAuthor":false,"prefix":"","firstName":"Fernando","middleName":"Augusto","lastName":"Soares","suffix":""},{"id":458060003,"identity":"901f1294-d2f4-4445-9ced-81c8d08baa3e","order_by":7,"name":"Mariana Petaccia Macedo","email":"","orcid":"","institution":"Instituto D’Or de Pesquisa e Ensino (IDOR)","correspondingAuthor":false,"prefix":"","firstName":"Mariana","middleName":"Petaccia","lastName":"Macedo","suffix":""},{"id":458060004,"identity":"b4336072-5e94-460f-9bf5-5f499f5c37d7","order_by":8,"name":"Isabela Werneck Cunha","email":"","orcid":"","institution":"Instituto D’Or de Pesquisa e Ensino (IDOR)","correspondingAuthor":false,"prefix":"","firstName":"Isabela","middleName":"Werneck","lastName":"Cunha","suffix":""}],"badges":[],"createdAt":"2025-05-07 01:23:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6606895/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6606895/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83210969,"identity":"0920753c-5736-4353-a315-29dc372d2078","added_by":"auto","created_at":"2025-05-21 08:25:34","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":259390,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Graphicalrepresentation of \u003cem\u003eEGFR\u003c/em\u003e variant frequency across the three regions evaluated, with the highest frequency in the northeastern (NE) region and the lowest in the southern (S) region. (B) Number of patients distributed by region and gender, highlighting a high number of female patients, the presence of p.Gly719Ala/Cys/Ser only in the southeastern (SE) region and a disproportionately high number of exon 19 del in the NE region.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6606895/v1/6d3e65c4227e834cafaf3ed8.jpg"},{"id":83212966,"identity":"01cb360b-9710-4ee8-af15-dec91c8b1b3c","added_by":"auto","created_at":"2025-05-21 08:41:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":851236,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6606895/v1/b77aa700-367a-44a3-8acd-d5c27618b6ae.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"EGFR variant profiles in lung adenocarcinoma from different regions of Brazil: A multi- institutional study using a rapid RT‒PCR platform","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eLung cancer is the second most diagnosed cancer, accounting for approximately 11% of all new cancer diagnoses, and is the leading cause of cancer deaths worldwide, accounting for up to 18% of all deaths [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Similarly, in Brazil, lung cancer is the second most common cancer in men and the fourth most common in women [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, owing to underdiagnosis and underreporting, the frequency of lung cancer in Brazil may be significantly underestimated. Furthermore, there are regional variations in the incidence of lung cancer, with the southern region (S) having the highest incidence, followed by the midwestern (MW), northeastern (NE), northern (N), and southeastern (SE) regions [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite some improvements in survival rates over recent decades, lung cancer still has a poor prognosis, with 5-year survival rates ranging from 4\u0026ndash;17% depending on the stage and histological subtype [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. There are two primary histological subtypes of lung cancer, namely non-small cell lung cancer (NSCLC), which accounts for up to 85% of cases, and small-cell lung cancer, which accounts for the remaining 15% and has a poorer prognosis than the former [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. NSCLC can be further subclassified into squamous cell carcinoma and adenocarcinoma, which account for 20% and 40% of cases, respectively [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough the activating \u003cem\u003eEGFR\u003c/em\u003e variant is involved in the pathogenesis of a significant subset of lung adenocarcinomas [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], it also serves as a prognostic and predictive factor. Variants in \u003cem\u003eEGFR\u003c/em\u003e are clustered within exons 18 through 21, which are part of the tyrosine kinase binding domain [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Patients with a deletion in exon 19 (exon 19 del) and a point mutation, p. Lys858Arg, in exon 21 tend to respond very well to \u003cem\u003eEGFR\u003c/em\u003e tyrosine kinase inhibitors (EGFR-TKIs) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, p.Thr790Met in exon 20 is associated with poor prognosis and is the most common cause of acquired resistance to first- and second-generation EGFR-TKIs [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe frequency of \u003cem\u003eEGFR\u003c/em\u003e variants in lung adenocarcinomas varies depending on geographic region. The activating variants are present in approximately 49\u0026ndash;60% in Asia, but only 12\u0026ndash;33% of other continents [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. These findings suggest a strong association with genetic origin and environmental factors. As a result, it has become essential to consider the epidemiology of \u003cem\u003eEGFR\u003c/em\u003e variants when making decisions, such as which EGFR-TKIs should be used in any given population [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn Brazil, the frequency of the \u003cem\u003eEGFR\u003c/em\u003e variant ranges from 19\u0026ndash;30% [\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], which is higher than that in European countries and the USA [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] but lower than that in some Latin American countries, such as Mexico and Peru [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, Brazil is the largest and most populous country compared with these other countries. Then, based on geographic location, the population derives from a distinct mixture of Amerindian, European, and African ancestries, which may lead to genetic differences and regional variations [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Although a single study revealed no differences in variant frequency across different regions [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], it did not address different variant subtypes. Therefore, this study aimed to evaluate the frequency of the \u003cem\u003eEGFR\u003c/em\u003e variant and its subtypes in lung adenocarcinoma in three distinct Brazilian regions (S, SE, and NE) and to correlate these findings with clinicopathological features.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Patient selection\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective electronic search to select patients with lung adenocarcinoma submitted to \u003cem\u003eEGFR\u003c/em\u003e profiling via a rapid RT‒PCR platform (Idylla system, EGFR assay \u0026ndash; Biocartis, Mechelen, Belgium) from January 2019 to February 2022. Overall, 920 samples were retrieved, and the results were reviewed. The data were collected from three different regions of Brazil: S\u0026atilde;o Paulo/Rede D\u0026rsquo;OR (SE), Cear\u0026aacute;/ARGOS Patologia (NE), and Santa Catarina/Grupo Infolaudo \u0026amp; Medicina Diagn\u0026oacute;stica (S). Age, sex, testing date, \u003cem\u003eEGFR\u003c/em\u003e variant subtype, and collection site were obtained from electronic pathology reports. Patients with inconclusive results were excluded from the study.\u003c/p\u003e \u003cp\u003e This study was conducted according to the principles of the Declaration of Helsinki and approved by the Instituto D\u0026rsquo;Or Research and Ethics Committee (institutional ethics committee).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed via R Studio [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Data for a continuous variable were expressed as mean and standard deviation (sd) of the mean. \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\chi\\:}^{2}\\)\u003c/span\u003e\u003c/span\u003e test and Fisher\u0026rsquo;s exact test were used to compare two categorical variables. Woof-test on homogeneity of odds ratio and Cochran‒Mantel‒Haenszel test, with post-hoc analysis conducted by \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\chi\\:}^{2}\\)\u003c/span\u003e\u003c/span\u003e-test, were applied to observe independence between two categorical variables while controlling for a third confounding categorical variable. Shapiro-Wilk test was used to evaluate the normality of the distributions of continuous variables. Mann-Whitney test and Kruskal-Wallis test with Dunn post-hoc test were applied to compare continuous variables according to categorical variables. \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the clinicopathological features of the 920 patients. The mean age of the patients was 67.0 years (sd\u0026thinsp;=\u0026thinsp;12.7 years), with a slight female predominance versus males (51% \u003cem\u003evs\u003c/em\u003e 49%). Most of the patients were from the S (43%), followed by the SE (38%) and NE (19%). Regarding the tissue site of collection, testing occurred more commonly in the primary tumor than in its metastases (79% \u003cem\u003evs\u003c/em\u003e 21%). \u003cem\u003eEGFR\u003c/em\u003e variants were detected in 21% of the patients, with the highest variant frequency observed in the NE (32%), followed by the SE (27%) and the S (11%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). The most common \u003cem\u003eEGFR\u003c/em\u003e variants were exon 19 del (45%) and p.Leu858Arg (43%).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThere was no statistical difference between the patient\u0026rsquo;s age and gender (p\u0026thinsp;=\u0026thinsp;0.13), site of collection (p\u0026thinsp;=\u0026thinsp;0.45), or \u003cem\u003eEGFR\u003c/em\u003e variant (p\u0026thinsp;=\u0026thinsp;0.61). Patient\u0026rsquo;s age differed across regions (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), with the NE being older than the S (p\u003csub\u003eadj\u003c/sub\u003e\u0026lt; 0.05), and no difference was observed between the other groups. Female patients were predominant in the NE and SE (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eRegarding \u003cem\u003eEGFR\u003c/em\u003e variant, female patients presented a greater frequency (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), with exon 19 del and p.Leu858Arg being the most common alterations (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Furthermore, when the associations between \u003cem\u003eEGFR\u003c/em\u003e variants by region were evaluated, a greater frequency was observed in the NE and SE regions (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Although this contingency (\u003cem\u003eEGFR\u003c/em\u003e variant \u003cem\u003evs\u003c/em\u003e region) might be influenced by the asymmetric distribution of gender between those different regions, in this case, it was observed as independent (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), even after correction for gender (p\u003csub\u003eadj\u003c/sub\u003e\u0026lt; 0.05). In addition, NE had a greater frequency of exon 19 deletion, whereas SE had a greater frequency of p.Gly719Ala/Cys/Ser (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eOur transversal analysis of genomic data obtained from rapid RT‒PCR molecular protocols revealed different frequencies of the \u003cem\u003eEGFR\u003c/em\u003e variant in lung adenocarcinomas across the three distinct regions of Brazil. The highest frequency was observed in NE, whereas the lowest was in S. Furthermore, female patients presented a greater variant frequency than males, particularly in patients with exon 19 del and p.Lys858Arg, regardless of the region. Similarly, the NE displayed the highest frequency of exon 19 del, whereas the SE region presented p.Gly719Ala/Cys/Ser.\u003c/p\u003e \u003cp\u003eIn agreement with previous studies that reported a range from 19\u0026ndash;30% [\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], we demonstrated that the Brazilian \u003cem\u003eEGFR\u003c/em\u003e variant frequency was 21%. Furthermore, when only SE data were used, the mutation frequency was 27%, which was higher than the Brazilian mean but still within the range of these previous studies [\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], since it mainly included patients from this region. However, the frequencies of the \u003cem\u003eEGFR\u003c/em\u003e variants were quite broad, which may reflect differences in patient selection and areas within the SE itself (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Moreover, it demonstrated a higher frequency of the p.Lys858Arg.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 01\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinicopathological features of patients submitted to \u003cem\u003eEGFR\u003c/em\u003e profiling evaluation:\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNortheast\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSoutheast\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSouth\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e171 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e350 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e399 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e920\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge \u0026ndash; years (sd)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68.5 (14.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67.3 (13.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66.1 (11.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e67.0 (12.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e97 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e193 (41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e180 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e470\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e157 (35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e219 (49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e450\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eEGFR\u003c/em\u003e mutation (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e93 (49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e190\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExon 19 deletion (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ep.Lys858Arg (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExon 20 insertion (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cem\u003eEGFR\u003c/em\u003e variant frequency and ancestries composition according to region [\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNortheast\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSoutheast\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSouth\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eEGFR\u003c/em\u003e mutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22.0\u0026ndash;26.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22.0\u0026ndash;30.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExon 19 del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e36.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39.0\u0026ndash;60.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e40.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ep.Lys858Arg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.0\u0026ndash;33.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExon 20 ins\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.0\u0026ndash;6.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAncestries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e74.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e78.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e76.0\u0026ndash;89.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAfrican\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.0\u0026ndash;15.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmerindian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eConversely, S had the lowest \u003cem\u003eEGFR\u003c/em\u003e variant frequency (11%). This difference may be attributed to demographic characteristics, such as gender, smoking behavior, and genetic background. This region has the highest proportion of European genetic ancestry due to the immigration of West Europeans, such as Germans and Italians [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. This background might explain the similarity in the frequency of \u003cem\u003eEGFR\u003c/em\u003e variants between S and Western European countries, where the frequency was between 9% and 16% [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA previous Brazilian study reported a greater frequency of the \u003cem\u003eEGFR\u003c/em\u003e variant in S than our results did [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. This discrepancy might be due to the distinct methodology, since this comparative study used massively parallel sequencing, which revealed variants that were not detectable by our targeted RT‒PCR based system [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Although the p.Lys858Arg frequency was higher in this previous study (50.0% \u003cem\u003evs\u003c/em\u003e 29.0%), the frequencies of exon 19 del and exon 21 insertions (exon 21 ins) were similar [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough there is a well-established degree of genetic overlap between southern and southeastern regions, due to European immigration [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], there was a distinct frequency of \u003cem\u003eEGFR\u003c/em\u003e variant in these regions. The higher frequency in the southeastern region might be attributed to the influx of immigrants from Asian countries such as Japan, Korea, and China [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], which is the region with the highest known frequency of the \u003cem\u003eEGFR\u003c/em\u003e variant [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe highest frequency of the \u003cem\u003eEGFR\u003c/em\u003e variant occurred in NE (32%), although previous studies reported a lower frequency, ranging from 22\u0026ndash;26% [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In addition, the exon 19 del and p.Lys858Arg variants had very different frequencies; as our results revealed a predominance of the former, the previous study had a predominance of the latter [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecent studies have indicated an inverse correlation between smoking behavior and a lower incidence of \u003cem\u003eEGFR\u003c/em\u003e mutation [\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], even in the Brazilian population [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In this way, S exhibited the highest prevalence of smoking behavior [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], the highest incidence of lung cancer [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and the lowest frequency of the \u003cem\u003eEGFR\u003c/em\u003e mutation. In contrast, the NE, which has the lowest rate of smoking behavior [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], presented the highest frequency of the \u003cem\u003eEGFR\u003c/em\u003e mutation.\u003c/p\u003e \u003cp\u003eFurthermore, the highest frequency of the \u003cem\u003eEGFR\u003c/em\u003e variant was detected in female patients, and the predominance of p.Leu858Arg and exon 19 del, which is well established in the literature [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], was consistent with our findings. Importantly, the prevalence of the various \u003cem\u003eEGFR\u003c/em\u003e variants varied according to region, regardless of gender. Exon 19 del was the predominant variant in NE, whereas p.Gly719Ala/Cys/Ser was unique in SE. This localization for each variant, beyond the genetic diversity in Brazilian territories, has significant implications for treatment. Exon 19 del and p.Leu858Arg respond well to first-, second-, and third-generation EGFR-TKIs (e.g., erlotinib, gefitinib, icotinib, and osimertinib), whereas pGly719Ala/Cys/Ser responds well to second- and third-generation EGFR-TKIs (e.g., afatinib and osimertinib) [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn summary, our study revealed significant differences in the frequency of \u003cem\u003eEGFR\u003c/em\u003e variants across the three Brazilian regions evaluated. These differences may be attributed to the distinct migratory processes that occur in each of these regions and distinct smoking behavior. A more comprehensive understanding of the genetic profile of patients in each region is essential to better understand the pathogenesis and incidence of lung adenocarcinoma, as well as the selection of the most appropriate therapy and drug distribution across the country.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee from Instituto D\u0026rsquo;OR de Pesquisa e Ensino (CAAE: 77607124.7.0000.0087). Due to its descriptive nature and the assurance of absolute anonymity, the authors were exempt from obtaining signed informed consent from the participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRAN: Conceptualization, study design and coordination, data curation, formal analysis, data interpretation, writing\u0026ndash;original draft, and writing\u0026ndash;review and editing. ALAJ: Data curation. MOS: Formal analysis and data interpretation. CK: Data curation. FRT: Data curation. JCS: Data curation. FAS: Writing\u0026ndash;review. MPM: Data curation. IWC: Conceptualization, study design and coordination, data interpretation, and writing\u0026ndash;review and editing. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Availability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F, Global Cancer Statistics 2020. GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. 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PLoS ONE. 2011;6:e17063. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1371/JOURNAL.PONE.0017063\u003c/span\u003e\u003cspan address=\"10.1371/JOURNAL.PONE.0017063\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":false,"email":"[email protected]","identity":"surgical-and-experimental-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"saep","sideBox":"Learn more about [Surgical and Experimental Pathology](http://surgexppathol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/SAEP/default.aspx","title":"Surgical and Experimental Pathology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Lung adenocarcinoma, EGFR variant, Brazilian regions","lastPublishedDoi":"10.21203/rs.3.rs-6606895/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6606895/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eLung cancer is the second most diagnosed cancer and activating \u003cem\u003eEGFR\u003c/em\u003e variants are involved in the pathogenesis of a significant subset of lung adenocarcinomas. Given that Brazil is the largest and most populous country in South America with high ancestry\u0026rsquo;s admixture, this study aimed to evaluate the frequency of the \u003cem\u003eEGFR\u003c/em\u003e variant and its subtypes in lung adenocarcinoma in three distinct Brazilian regions and to correlate these findings with clinicopathological features.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA retrospective electronic search was performed to select patients with lung adenocarcinoma who underwent \u003cem\u003eEGFR\u003c/em\u003e profiling via a rapid RT‒PCR molecular platform from different regions of Brazil.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe \u003cem\u003eEGFR\u003c/em\u003e variant was present in 21% of the patients, with the highest mutation frequency observed in the northeastern region (NE), followed by the southeastern (SE) and southern (S) regions. Compared with male patients, female patients presented a greater \u003cem\u003eEGFR\u003c/em\u003e variant frequency, except in S. Exon 19 deletion (exon 19 del) and p.Leu858Arg were the most common variants found. In addition, the NE had a greater frequency of exon 19 del, whereas the SE had p.Gly719Ala/Cys/Ser.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe highest frequency of the \u003cem\u003eEGFR\u003c/em\u003e variant was observed in the NE, whereas the lowest rate was observed in the S. Furthermore, the NE presented the highest frequency of exon 19 del, whereas the SE presented p.Gly719Ala/Cys/Ser, regardless of gender.\u003c/p\u003e","manuscriptTitle":"EGFR variant profiles in lung adenocarcinoma from different regions of Brazil: A multi- institutional study using a rapid RT‒PCR platform","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-21 08:25:29","doi":"10.21203/rs.3.rs-6606895/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-07T10:40:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-06T09:28:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-02T13:55:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"49018618881292241616425044963581753431","date":"2025-05-23T09:22:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"105442212150677837380433574365865596619","date":"2025-05-17T15:42:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"26255120764128901196380400150718851534","date":"2025-05-15T16:00:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-15T15:39:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-13T01:15:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-13T01:14:29+00:00","index":"","fulltext":""},{"type":"submitted","content":"Surgical and Experimental Pathology","date":"2025-05-07T01:13:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":false,"email":"[email protected]","identity":"surgical-and-experimental-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"saep","sideBox":"Learn more about [Surgical and Experimental Pathology](http://surgexppathol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/SAEP/default.aspx","title":"Surgical and Experimental Pathology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a8fd2006-c164-4dac-a7ba-256ce2e6cd31","owner":[],"postedDate":"May 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-06T11:08:25+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-21 08:25:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6606895","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6606895","identity":"rs-6606895","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}