Concomitant TP53 mutation in early-stage resected EGFR-mutated non-small cell lung cancer: a narrative approach in a genetically admixed Brazilian cohort

TP53 mutations are frequent in non-small cell lung cancer (NSCLC) and have been associated with poor outcome. The prognostic and predictive relevance of EGFR/TP53 co-mutations in NSCLC is controversial. We analyzed lung tissue specimens from 70 patients with NSCLC using next-generation sequencing to determine EGFR and TP53 status and the association between these status with baseline patient and tumor characteristics, adjuvant treatments, relapse, and progression-free (PFS) and overall survival (OS) after surgical resection. We found the EGFR mutation in 32.9% of patients (20% classical mutations and 12.9% uncommon mutations). TP53 missense mutations occurred in 25.7% and TP53/EGFR co-mutations occurred in 43.5% of patients. Stage after surgical resection was significantly associated with OS (P=0.028). We identified an association between progression-free survival and poor outcome in patients with distant metastases (P=0.007). We found a marginally significant difference in OS between genders (P=0.057) and between mutant and wild type TP53 (P=0.079). In univariate analysis, distant metastases (P=0.027), pathological stage (IIIA-IIIB vs I-II; P=0.028), and TP53 status (borderline significance between wild type and mutant; P=0.079) influenced OS. In multivariable analysis, a significant model for high risk of death and poor OS (P=0.029) selected patients in stage IIIA-IIIB, with relapse and distant metastases, non-responsive to platin-based chemotherapy and erlotinib, with tumors harboring EGFR uncommon mutations, with TP53 mutant, and with EGFR/TP53 co-mutations. Our study suggested that TP53 mutation tends to confer poor survival and a potentially negative predictive effect associated with a non-response to platinum-based chemotherapy and erlotinib in early-stage resected EGFR-mutated NSCLC.

Clinical outcome of Brazilian patients with non-small cell lung cancer in early stage harboring rare mutations in epidermal growth factor receptor

The common epidermal growth factor receptor (EGFR) mutations, such as the L858R point mutation in exon 21 and the in-frame deletional mutation in exon 19, have been definitively associated with response to EGFR-tyrosine kinase inhibitors (EGFR-TKI). However, the clinical outcome and response to treatment for many other rarer mutations are still unclear. In this study, we report the results of Brazilian patients in stage IB-IIIA non-small cell lung cancer (NSCLC) following complete resection with minimal residual disease and EGFR mutations treated with adjuvant chemotherapy and/or EGFR-TKIs. The frequency of EGFR mutations was investigated in 70 cases of early stage NSCLC. Mutations in exons 18 and 20, uncommon mutations in exons 19 and 21, as well as in exons 3, 7, 14, 16, 22, 27, and 28, and/or the presence of different mutations in a single tumor (complex mutations) are considered rare. EGFR mutations were detected in 23 tumors (32.9%). Fourteen cases carried rare mutations and were treated with platinum-based chemotherapy and two cases were treated with erlotinib. The clinical outcome is described case by case with references to the literature. Notably, we found two rare EGFR mutations and one of them with an unknown response to chemotherapy and/or EGFR-TKIs. We have provided complementary information concerning the clinical outcome and treatment of patients with early stage NSCLC for several rare EGFR mutations not previously or only rarely reported. Description of cases harboring rare mutations can support the decision-making process in this subset of patients.

Amino acids change liver growth factors gene expression in malnourished rats.

BACKGROUND: Glutamine and proline are metabolized the liver and may collaborate on its regeneration. Parenteral nutrition (PN) containing either glutamine or proline was given to partially hepatectomized rats. The total RNA content and growth factor gene expression in hepatic remnants was measured, to determine the effects of these amino acid supplementation on the expression of growth factors during liver regeneration. METHODS: Wistar rats nourished (HN) and malnourished (HM) were hepatectomized and divided in two groups: 20 receiving PN enriched with Alanyl-Glutamine (HN-Gln and HM-Gln) and 20 PN enriched with proline+alanine (HN-Pro and HM-Pro). The control groups comprised 7 nourished (CN) and 7 malnourished (CM) rats that didn't undergo surgery. Growth factor and thymidine kinase mRNA levels were measured by RT-PCR. RESULTS: In nourished rats, total hepatic RNA levels were lower in the HN-Gln and HN-Pro groups (0.75 and 0.63 microg/mg tissue, respectively) than in control group (1.67 microg/mg tissue) (P<0.05). In malnourished rats, total hepatic RNA content was higher in the HM-Pro group than HN-Pro, HM-Gln, and CM (3.18 vs. 0.63, 0.93 and 1.10 microg/mg, respectively; P<0.05). Hepatocyte growth factor mRNA was more abundant in the HM-Gln group when compared to CM (0.31 vs. 0.23 arbitrary units) and also in HM-Pro in relation to HM-Gln, HN-Pro, and CM(0.46 vs. 0.33 and 0.23, respectively, P<0.05). CONCLUSIONS: Proline or glutamine supplementation in malnourished rats improves total RNA content in the remnant hepatic tissue. Amino acids administration increased HGF gene expression after partial hepatectomy in malnourished rats, with a greater effect of proline than glutamine.

Amino acids change liver growth factors gene expression in malnourished rats / Los aminoácidos alteran la expresión genética de factores de crecimiento hepático en ratas macho desnutridas

Background: Glutamine and proline are metabolized the liver and may collaborate on its regeneration. Parenteral nutrition (PN) containing either glutamine or proline was given to partially hepatectomized rats. The total RNA content and growth factor gene expression in hepatic remnants was measured, to determine the effects of these amino acid supplementation on the expression ofgrowth factors during liver regeneration. Methods: Wistar rats nourished (HN) and malnourished (HM) were hepatectomized and divided in two groups: 20 receiving PN enriched with Alanyl-Glutamine (HN-Gln and HM-Gln) and 20 PN enriched with proline+alanine (HN-Pro and HM-Pro). The control groups comprised 7 nourished (CN) and 7 malnourished (CM) rats that didn't undergo surgery. Growth factor and thymidine kinase mRNA levels were measured by RT-PCR. Results: In nourished rats, total hepatic RNA levels were lower in the HN-Gln and HN-Pro groups (0.75 and 0.63 μg/mg tissue, respectively) than in control group (1.67 μg/mg tissue) (P < 0.05). In malnourished rats, total hepatic RNA content was higher in the HM-Pro group than HN-Pro, HM-Gln, and CM (3.18 vs. 0.63, 0.93 and 1.10 μg/mg, respectively; P < 0.05). Hepatocyte growth factor mRNA was more abundant in the HM-Gln group when compared to CM (0.31 vs. 0.23 arbitrary units) and also in HM-Pro in relation to HM-Gln, HN-Pro, and CM(0.46 vs. 0.33 and 0.23, respectively, P < 0.05). Conclusions: Proline or glutamine supplementation in malnourished rats improves total RNA content in the remnant hepatic tissue. Amino acids administration increased HGF gene expression after partial hepatectomy in malnourished rats, with a greater effect of proline than glutamine (AU)

Introducción: La glutamina y la prolina de metabolizan en el hígado y pueden contribuir a la regeneración de este. Se administró nutrición parenteral con glutamina o prolina a ratas sometidas a hepatectomía parcial. Se midieron el contenido de ARN total así como la expresión genética del factor de crecimiento en el tejido hepático remanente, con el objetivo de determinar los efectos que provocaban estos aminoácidos en la expresión genética de factores de crecimiento durante el proceso de regeneración del hígado. Métodos: ratas macho Wistar nutridas (HN) y desnutridas (HM) se sometieron a hepatectomía parcial y se dividieron en dos grupos: 20 recibieron nutrición parenteral enriquecida con Alanil-Glutamina (HN-Gln y HM-Gln) y 20 nutrición parenteral enriquecida con prolina+alanina (HNPro y HM-Pro). Los grupos de control estaban formados por 7 ratas nutridas (CN) y 7 desnutridas (CM) que no se sometieron a la cirugía. Los niveles de factor de crecimiento y timidina quinasa mRNA se midieron por RT-PCR. Resultados: En las ratas nutridas, lo niveles de ARN hepático total fueron inferiores en los grupos que recibieron HNGln y HN-Pro (0,75 y 0,63 mg/mg tejido, respectivamente) que en el grupo control (1,67 mg/mg tejido) (P < 0,05). En las ratas desnutridas, el contenido total de ARN hepático fue superior en el grupo que recibió HM-Pro que el que recibió HN-Pro, HM-Gln y CM (3,18 vs 0,63, 0,93 y 1,10 mg/mg, respectivamente; P < 0,05). El mRNA del factor de crecimiento de hepatocitos fue más abundante en el grupo que recibió HM-Gln con respecto a CM (0,31 vs 0,23 unidades arbitrarias), así como en HM-Pro con relación a HM-Gln, HN-Pro y CM (0,46 vs 0,33 y 0,23, respectivamente, P < 0,05). Discusión: La suplementación de prolina o glutamina en ratas macho desnutridas mejora el contenido total de ARN en el tejido hepático remanente. Al administrarse aminoácidos aumentó la expresión genética del HGF tras someter las ratas desnutridas a una hepatectomía parcial, obteniéndose un resultado mejor con prolina que con glutamina (AU)