High Prevalence of EGFR Mutations in Lung Adenocarcinomas From Brazilian Patients Harboring the TP53 p.R337H Variant

Barbosa, Malu Viter R.; Lima, Vladmir Cláudio Cordeiro de; Formiga, Maria Nirvana; Paula, Cláudia Alessandra Andrade de; Torrezan, Giovana Tardin; Carraro, Dirce Maria

doi:10.1016/j.cllc.2019.11.012

Cited by 18 publications

(27 citation statements)

References 12 publications

(14 reference statements)

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“…In this sense, a greater proportion of Asian ancestry (7.3%) was recently reported to be associated with EGFR mutation in a Brazilian cohort from São Paulo state (13). In addition, a high prevalence of EGFR activating-mutations was recently detected in LA diagnosed in Brazilian patients with Li-Fraumeni syndrome harboring the Brazilian TP53 R337H founder mutation; however these patients comprised only 2.7% of our cohort (14). Interestingly, in the previously reported series of Brazil a considerably variation in terms of mutation rate was observed −19% in South of Brazil and 21.9-30% in Southeast (more specifically in São Paulo city) that has a higher proportion of Amerindian and Asian ancestries.…”

Section: Discussionmentioning

confidence: 63%

“…Since 2009, abundant evidence for the benefit of TKIs in the treatment of EGFR-mutant NSCLC has accumulated. Nevertheless, health insurance companies in Brazil did not reimburse for molecular tests until sometime later, and such (11)(12)(13)(14). Studies conducted in other Latin American countries suggest that EGFR mutation rates are higher on this continent than in European countries and the USA, which are around 10-15% (6,8,9), especially in countries with greater contributions of mestizo/indigenous ancestries (11).…”

Section: Discussionmentioning

confidence: 99%

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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: 63%

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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“…42 Notably, 3 patients were exposed to thoracic irradiation during the treatment of a previous breast cancer. 42 All 164 p.R337H patients had family histories of cancer, with 3 having more than 1 case of lung cancer. However, none of them fulfilled the classic LFS criteria as reported.…”

Section: The Intricate Cancer Phenotype Among Carriers Of the Foundermentioning

confidence: 99%

“…However, none of them fulfilled the classic LFS criteria as reported. 42 An analysis of the same group of families followed at the A. C. Camargo Cancer Center (São Paulo State) revealed 11 cases of thyroid carcinoma in 5 independent families. 43 The overall mean age at diagnosis was 44 years (3 men and 8 women).…”

Section: The Intricate Cancer Phenotype Among Carriers Of the Foundermentioning

confidence: 99%

“…Thyroid (mostly papillary carcinomas), kidney, skin, and lung cancers are reported among carriers of the p.R337H variant. [41][42][43][44] Overlapping syndromes TP53 p.R337H has been observed in patients tested for HBOC. 38,39 Abbreviations: ACT, adrenocortical tumor; CPC, choroid plexus carcinoma; HBOC, hereditary breast and ovarian cancer syndrome; LFS, Li-Fraumeni syndrome.…”

Section: Othersmentioning

confidence: 99%

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What 20 years of research has taught us about the TP53 p.R337H mutation

Pinto

Zambetti

2020

Cancer

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The p53 tumor suppressor transcriptionally regulates a myriad of genes involved in cell cycle control, DNA repair, cell survival, and cell metabolism and represents one of the most well-studied inhibitors of tumorigenesis. Since the discovery of TP53 in 1979, somatic mutations have been shown to be extremely common; more than 50% of human cancers carry loss-of-function mutations in TP53. Inherited or germline TP53 mutations are rare and are involved in complex hereditary cancer predisposition disorders, and affected family members can develop diverse tumor types and multiple primary cancers at young ages. In Brazil, a fascinating history of p53 and cancer predisposition began in the year 2000 with identification of the TP53 p.R337H mutation in close association with the development of adrenocortical tumors. In these past 20 years, much has been learned about the genetics and biochemistry of this mutation, which is widespread in Brazil because of a founder effect. This review highlights the contributions of TP53 p.R337H research over the last 20 years, the findings of which have sparked passionate debate among researchers worldwide, to understanding cancer predisposition in Brazilian individuals and families. Cancer 2020;126:4678-4686.

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Three Primary Tumors Including EGFR-mutated Non–Small Cell Lung Cancer as First Presentation in Patient With Li-Fraumeni Syndrome

Gower

Kim

Spector

et al. 2021

Clinical Lung Cancer

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High Prevalence of EGFR Mutations in Lung Adenocarcinomas From Brazilian Patients Harboring the TP53 p.R337H Variant

Cited by 18 publications

References 12 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

What 20 years of research has taught us about the TP53 p.R337H mutation

Three Primary Tumors Including EGFR-mutated Non–Small Cell Lung Cancer as First Presentation in Patient With Li-Fraumeni Syndrome

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