Mutational profile of Brazilian lung adenocarcinoma unveils association of EGFR mutations with high Asian ancestry and independent prognostic role of KRAS mutations

Leal, Letícia Ferro; Paula, Flávia Escremim de; Marchi, Pedro De; Viana, Luciano de Souza; Pinto, Gustavo Dix Junqueira; Carlos, Carolina Dias; Berardinelli, Gustavo Nóriz; Miziara, Juliana Muniz; Silva, Carlos Maciel da; Silva, Eduardo Caetano Albino da; Pereira, Rui; Oliveira, Marco Antônio de; Scapulatempo‐Neto, Cristovam; Reis, Rui Manuel

doi:10.1038/s41598-019-39965-x

Cited by 37 publications

(57 citation statements)

References 46 publications

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“…These markers were selected due to their high allele frequency divergence between different ancestral or geographically distant populations, including more than 1,000 individuals from 40 reference populations from the Human Genome Diversity Project (HGDP)-Centre d/Etude du Polymorphisme (CEPH), plus individuals from Angola, Portugal, Taiwan, and indigenous Brazilian, which allowed to establish the ancestral proportions in high admixture individuals and populations, like the Brazilian one (14). Moreover, they were assembled in a simple multiplex reaction following a short amplicon strategy, adequate for challenging samples such as FFPE (15,26,27). The primer sequences and PCR conditions were according to Giolo et al (14).…”

Section: Genetic Ancestry Determinationmentioning

confidence: 99%

Role of Genetic Ancestry in 1,002 Brazilian Colorectal Cancer Patients From Barretos Cancer Hospital

et al. 2020

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Background: Colorectal cancer (CRC) is the third most frequent and the second deadliest cancer worldwide. The ethnic structure of the population has been gaining prominence as a cancer player. The purpose of this study was to determine the genetic ancestry of Brazilian CRC patients. Moreover, we intended to interrogate its impact on patients' clinicopathological features.Methods: Retrospective observational cohort study with 1,002 patients with CRC admitted from 2000 to 2014 at Barretos Cancer Hospital. Following tumor DNA isolation, genetic ancestry was assessed using a specific panel of 46 ancestry informative markers. Survival rates were obtained by the Kaplan-Meier method, and the log-rank test was used to compare the survival curves. Multivariable Cox proportional regression models were used to estimate hazard ratios (HRs). Results:We observed considerable admixture in the genetic composition, with the following average proportions: European 74.2%, African 12.7%, Asian 6.5%, and Amerindian 6.6%. The multivariate analysis for cancer-specific survival showed that clinical stage, lymphovascular invasion, and the presence of recurrence were associated with an increased relative risk of death from cancer (p < 0.05). High African proportion was associated with younger age at diagnosis, while high Amerindian proportion was associated with the mucinous histological subtype.Conclusions: This represents the larger assessment of genetic ancestry in a population of Brazilian patients with CRC. Brazilian CRC patients exhibited similar clinicopathological features as described in Western countries.Impact: Genetic ancestry components corroborated the significant admixture, and importantly, patients with high African proportion develop cancer at a younger age.

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Section: Genetic Ancestry Determinationmentioning

confidence: 99%

Role of Genetic Ancestry in 1,002 Brazilian Colorectal Cancer Patients From Barretos Cancer Hospital

et al. 2020

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“…Although we did not find mutations associated with miRNA changes, likely due to our small sample set, we identified common, mutually exclusive driver mutations in EGFR, K-RAS and N-RAS. In Brazilian patients, mutational frequency of driver genes was reported in a large number of lung adenocarcinoma cases (n = 444), with EGFR mutated in 22.7% and K-RAS in 20.4% of the cases [9].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, DNA was isolated from representative sections of tumor FFPE resected samples, using the QIAmp DNA micro kit (Qiagen, Hilden, Germany) following the manufacturer's instructions as previously reported [9]. DNA was used for analysis of driver mutations by the SNaPShot assay.…”

Section: Rna and Dna Extractionmentioning

confidence: 99%

“…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%

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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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“…14 A subset (n = 444) of this series comprised of EGFR-mutated patients has been previously reported. 14…”

Section: Dna Isolation and Egfr Mutational Statusmentioning

confidence: 99%

EGF+61 A>G polymorphism does not predict response to first‐generation EGFR tyrosine kinase inhibitors in lung cancer patients

Leal¹,

Laus

Cavagna

et al. 2020

Thoracic Cancer

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Epidermal growth factor (EGF) and its receptor (EGFR) play a paramount role in lung carcinogenesis. The polymorphism in the EGF promoter region EGF +61A>G (rs4444903) has been associated with cancer susceptibility, but its role in lung cancer patients treated with tyrosine kinase inhibitors (TKIs) remains unknown. Here, we aimed to evaluate the predictive and prognostic role of EGF +61A>G SNP in lung cancer from Brazilian EGFR-mutated TKI-treated patients. Herein, patients carrying EGFR-sensitizing mutations submitted to TKI treatment (gefitinib/erlotinib) were analyzed (n = 111) for EGF+61A>G genotype by TaqMan genotyping assay. TKI treatment was classified as partial response (PR), stable disease (SD), and disease progression (DP), according to RECIST1.1. Association analysis was assessed by chi-square and Fisher's test (univariate) and multinomial model (multivariate) and survival analysis by Kaplan-Meier method and log-rank test. The EGF+61A>G genotype frequencies observed were: AA = 31.5% (n = 35), AG = 49.6% (n = 55) and GG = 18.9% (n = 21). The allelic frequencies were 56.3% for A, and 43.7% for G and the population was in Hardy-Weinberg equilibrium (P = 0.94). EGF+61A>G codominant model (AA vs. AG vs. GG) was associated with a response to TKIs (P = 0.046), as well as a recessive model (AA vs. AG + GG; P = 0.023). The multinomial regression showed an association between the codominant model (AG) and recessive model (AG + GG) with SD compared with DP (P = 0.01;OR = 0.08; 95% CI = 0.01-0.60 and P = 0.02; OR = 0.12; 95% CI = 0.20-0.72, respectively). No association between genotypes and progression-free or overall survival was observed. In conclusion, the EGF+61 polymorphism (AG and AG + GG) was independently associated with stable disease in lung cancer patients although it was not associated with the overall response rate to first-generation TKIs or patient outcome.

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Mutational profile of Brazilian lung adenocarcinoma unveils association of EGFR mutations with high Asian ancestry and independent prognostic role of KRAS mutations

Cited by 37 publications

References 46 publications

Role of Genetic Ancestry in 1,002 Brazilian Colorectal Cancer Patients From Barretos Cancer Hospital

Role of Genetic Ancestry in 1,002 Brazilian Colorectal Cancer Patients From Barretos Cancer Hospital

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

EGF+61 A>G polymorphism does not predict response to first‐generation EGFR tyrosine kinase inhibitors in lung cancer patients

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