Analysis of Predictive Biomarkers in Patients With Lung Adenocarcinoma From Southern Brazil Reveals a Distinct Profile From Other Regions of the Country

Andreis, Tiago Finger; Correa, Bruno S; Vianna, Fernanda S.L.; de‐Paris, Fernanda; Siebert, Marina; Leistner‐Segal, Sandra; Hahn, Eriza Cristina; Ulbrich, Jane Maria; Rivero, Luis Fernando; Oliveira, Francine Hehn de; Lorandi, V.; Ashton‐Prolla, Patrícia; Macedo, Gabriel S.

doi:10.1200/jgo.19.00174

Cited by 15 publications

(26 citation statements)

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“…This lower frequency of KRAS mutations could be a result of a lower frequency of smokers in that cohort and a high EGFR mutation frequency, as the two mutation types are usually mutually exclusive. In the Brazilian population, KRAS mutation frequencies of 14.6-30.2% have been reported (12,13,26,27). These differences could be partially explained by differences in detection methods and population characteristics.…”

Section: Discussionmentioning

confidence: 99%

Mutational Portrait of Lung Adenocarcinoma in Brazilian Patients: Past, Present, and Future of Molecular Profiling in the Clinic

et al. 2020

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Objectives: Approximately 60% of lung adenocarcinomas (LAs) carry mutations that can guide treatment with tyrosine-kinase inhibitors (TKI) and other targeted therapies. Data on activating mutations in EGFR and other tyrosine-kinase receptor (TKR) genes in highly admixed populations, such as that of Brazil, are scarce. In this study, we comprehensively analyzed the actionable alteration profile of LA in Brazilian patients. Materials and Methods: EGFR driver mutation data were collected from a large Brazilian LA cohort covering an 8-year period of molecular testing in a single institution. Tests were performed using three distinct methods, and demographic and histopathological data were analyzed. For a subset of patients, driver mutations in KRAS, NRAS, and BRAF and gene fusions involving TKR genes (before TKI treatment) and EGFR T790M (after TKI treatment) were assessed. Results: EGFR mutations were detected in 25% of 1,316 LAs evaluated, with exon 19 deletions and exon 21 L858R TKI sensitizing mutations representing 72.5% of all mutations. Mutation rates were higher in women and non-smokers (p < 0.001). Next-generation sequencing was very sensitive, with a lower rate of inconclusive results compared with Sanger sequencing and pyrosequencing. EGFR/RAS/BRAF hotspot gene panels were applied in 495 LA cases and detected oncogenic mutations in 51.3% of samples, most frequently in EGFR (22.4%) and KRAS (26.9%). In subgroups of 36 and 35 patients, gene fusions were detected in 11.1% of tumors and EGFR T790M resistance mutations were detected in 59% of plasma samples from patients previously treated with TKI, respectively. Conclusion: This report provides the first comprehensive actionable alteration portrait of LA in Brazil. The high rate of actionable alterations in EGFR and other driver genes in LA reinforces the need to incorporate TKI guided by molecular diagnostics into clinical routines for patients in both public and private healthcare systems.

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Section: Discussionmentioning

confidence: 99%

Mutational Portrait of Lung Adenocarcinoma in Brazilian Patients: Past, Present, and Future of Molecular Profiling in the Clinic

et al. 2020

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“…In the present study, we identified seven LUAD tumors harboring the founder TP53 variant among 586 samples recruited from patients in southern Brazil, a cohort described in detail elsewhere ( Andreis et al, 2019 ). Remarkably, all variant-positive tumors were diagnosed over age 50 years.…”

Section: Discussionmentioning

confidence: 99%

“…A total of 586 LC samples derived from a cohort described in a previous study from our group ( Andreis et al, 2019 ) were analyzed. Patients were originally recruited for somatic mutation testing in EGFR (exons 18–21), KRAS (exons 2 and 3), BRAF (exons 11 and 15), and NRAS (exons 2 and 3) genes from different hospitals and clinics distributed in 22 healthcare centers located in the three states of the southern region of Brazil: Rio Grande do Sul ( N = 496), Santa Catarina ( N = 20), and Paraná ( N = 70).…”

Section: Methodsmentioning

confidence: 99%

“…However, histological subtype data were available for only a small proportion (72/586) of patients. The mutation status of EGFR , BRAF , KRAS , and NRAS genes was evaluated using technical procedures as previously reported ( Andreis et al, 2019 ). Genotyping was performed in a central laboratory, a diagnostic precision medicine program established in a tertiary care hospital in southern Brazil.…”

Section: Methodsmentioning

confidence: 99%

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Prevalence of the Brazilian TP53 Founder c.1010G>A (p.Arg337His) in Lung Adenocarcinoma: Is Genotyping Warranted in All Brazilian Patients?

et al. 2021

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In Southern and Southeastern Brazil, there is a germline pathogenic variant with incomplete penetrance located in the oligomerization domain of TP53, c.1010G>A (p.Arg337His). Due to a founder effect, the variant is present in 0.3% of the general population of the region. Recently, this variant was identified in 4.4 and 8.9% of two apparently unselected, single center case series of Brazilian lung adenocarcinoma (LUAD) patients from the Southeastern and Central regions of the country, respectively. In the present study, our aim was to examine TP53 c.1010G>A allele and genotype frequencies in LUAD samples obtained from patients diagnosed in Southern Brazil. A total of 586 LUAD samples (tumor DNA) recruited from multiple centers in the region were tested, and the mutant allele was identified using TaqMan® assays in seven cases (7/586, 1.2%) which were submitted to next generation sequencing analyses for confirmation. Somatic EGFR mutations were more frequent in TP53 c.1010G>A carriers than in non-carriers (57.1 vs. 17.6%, respectively). Further studies are needed to confirm if TP53 c.1010G>A is a driver in LUAD carcinogenesis and to verify if there is a combined effect of EGFR and germline TP53 c.1010G>A. Although variant frequency was higher than observed in the general population, it is less than previously reported in LUAD patients from other Brazilian regions. Additional data, producing regional allele frequency information in larger series of patients and including cost-effectiveness analyses, are necessary to determine if TP53 c.1010G>A screening in all Brazilian LUAD patients is justified.

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“…TCGA comprehensively mapped mutations and transcriptome changes, as well as their frequency in large sample sets of lung AD and SCC, and demonstrated that mutations in oncogenes such as EGFR, K-RAS, ALK and BRAF occur in >60% of lung AD cases [7], with driver mutations targetable by tyrosine kinase inhibitors [8]. The frequency of alterations of these driver genes in the Brazilian population is slightly different and associated with a genetic ancestry admixture [9][10][11]. Although the development of molecularly targeted therapies including EGFR tyrosine kinase inhibitors have benefited only a small fraction (15%) of patients with lung AD.…”

Section: Introductionmentioning

confidence: 99%

Deregulated microRNAs Are Associated with Patient Survival and Predicted to Target Genes That Modulate Lung Cancer Signaling Pathways

Souza

Cinegaglia

Felix

et al. 2020

Cancers

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(1) Background: Although the advances in diagnostic and treatment strategies, lung cancer remains the leading cause of cancer-related deaths, worldwide, with survival rates as low as 16% in developed countries. Low survival rates are mainly due to late diagnosis and the lack of effective treatment. Therefore, the identification of novel, clinically useful biomarkers is still needed for patients with advanced disease stage and poor survival. Micro(mi)RNAs are non-coding RNAs and potent regulators of gene expression with a possible role as diagnostic, prognostic and predictive biomarkers in cancer. (2) Methods: We applied global miRNA expression profiling analysis using TaqMan® arrays in paired tumor and normal lung tissues (n = 38) from treatment-naïve patients with lung adenocarcinoma (AD; n = 23) and lung squamous cell carcinoma (SCC; n = 15). miRNA target genes were validated using The Cancer Genome Atlas (TCGA) lung AD (n = 561) and lung SCC (n = 523) RNA-Seq datasets. (3) Results: We identified 33 significantly deregulated miRNAs (fold change, FC ≥ 2.0 and p < 0.05) in tumors relative to normal lung tissues, regardless of tumor histology. Enrichment analysis confirmed that genes targeted by the 33 miRNAs are aberrantly expressed in lung AD and SCC, and modulate known pathways in lung cancer. Additionally, high expression of miR-25-3p was significantly associated (p < 0.05) with poor patient survival, when considering both tumor histologies. (4) Conclusions: miR-25-3p may be a potential prognostic biomarker in non-small cell lung cancer. Genes targeted by miRNAs regulate EGFR and TGFβ signaling, among other known pathways relevant to lung tumorigenesis.

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Analysis of Predictive Biomarkers in Patients With Lung Adenocarcinoma From Southern Brazil Reveals a Distinct Profile From Other Regions of the Country

Cited by 15 publications

References 50 publications

Mutational Portrait of Lung Adenocarcinoma in Brazilian Patients: Past, Present, and Future of Molecular Profiling in the Clinic

Mutational Portrait of Lung Adenocarcinoma in Brazilian Patients: Past, Present, and Future of Molecular Profiling in the Clinic

Prevalence of the Brazilian TP53 Founder c.1010G>A (p.Arg337His) in Lung Adenocarcinoma: Is Genotyping Warranted in All Brazilian Patients?

Deregulated microRNAs Are Associated with Patient Survival and Predicted to Target Genes That Modulate Lung Cancer Signaling Pathways

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