Data documento
18/10/2024

Título
Gene expression profiles (GEPs) of immuno-oncologic pathways as predictors of response to checkpoint inhibitors in advanced NSCLC

Autor(es)
Pedro De Marchi - Leticia Ferro Leal - Luciane Sussuchi da Silva - Rodrigo de Oliveira Cavagna - Flavio Augusto Ferreira da Silva - Vinicius Duval da Silva - Eduardo Ca da Silva - Augusto O Saito - Vladmir C Cordeiro de Lima - Rui Manuel Reis.

Palavras chave
GEP; Gama interferon; Immunotherapy; Lung-tumor signature; NSCLC; Non-small cell lung cancer; PD-L1; TIS; anti-CTLA-4; anti-PD-(L)1; gene expression profile.

Resumo
Background: Immune checkpoint inhibitors (ICIs) revolutionized non-small-cell lung cancer (NSCLC) treatment. However, improving patients selection for this therapy is needed. Gene expression profile (GEP) is a promising biomarker tool. We assessed the predictive value of 48 onco-immune GEPs in an NSCLC real-world scenario. Methods: Retrospective cohort of Brazilian NSCLC patients treated with ICIs in any line. GEP was assessed in FFPE tumor tissue using the nCounter PanCancer IO360 panel, comprising 770 cancer immune genes. Results: The median age of the 135 patients was 61 years old, most male (57.8 %), history of smoking (83.6 %), ECOG-PS 0-1 (88.7 %), clinical stage IV (91.9 %) and adenocarcinoma (65.1 %). First-line ICI in 40 % of cases, alone or in combination with chemotherapy. The median follow-up was 28 months, overall survival after starting immunotherapy (post-immunotherapy survival - PIS) was 17.8 months, and real-world progression-free survival was 5.5 months. The GEP analysis was possible in 66 patients. We found that 14 different GEPs associated with PIS, namely IDO1, PD-L2, Cytotoxicity, Cytotoxic Cells, IFN Downstream, CTLA4, PD-L1, TIGIT, Lymphoid, Immunoproteasome, Exhausted CD8, IFN Gamma, TIS and APM. TIS and IFN-γ were the most significant GEPs associated with favorable outcomes. The median PIS for patients with high TIS expression was 29.2 versus 15.5 months (HR 0.42; 95 %CI; 0.17-0.67; p<0.05) for those with low expression. Similar results were observed for IFN-γ. Conclusions: The TIS (tumor inflammation signature) and IFN-γ signatures constitute predictive biomarkers to identify patients with NSCLC patients who would possibly benefit from ICI therapies.

Citação
Gene expression profiles (GEPs) of immuno-oncologic pathways as predictors of response to checkpoint inhibitors in advanced NSCLC. De Marchi P, Leal LF, da Silva LS, Cavagna RO, da Silva FAF, da Silva VD, da Silva EC, Saito AO, de Lima VCC, Reis RM.Transl Oncol. 2024 Jan;39:101818. doi: 10.1016/j.tranon.2023.101818. Epub 2023 Oct 31.PMID: 37918166

Data documento
19/03/2025

Título
Immune-checkpoint gene expression and BCG response in non-muscle invasive bladder cancer

Autor(es)
Zucca LER, Laus AC - Sorroche BP - Paro E Sussuchi L - Marques RF - Teixeira GR - Berardinelli GN - Arantes LMRB - Reis RM - Cárcano FM.

Palavras chave
Urinary bladder neoplasms1 - BCG vaccine 2 - Gene expression profiling3 - Immunity active4

Resumo
Methods One-hundred-six patients diagnosed with non-muscle invasive bladder cancer and treated with intravesical BCG were included and divided into two groups, BCG-responsive (n = 47) and -unresponsive (n = 59). Immunohistochemistry was used to evaluate PD-L1 expression and MSI was assessed by a commercial multiplex PCR kit. The mRNA expression profile of 15 immune checkpoints was performed using the nCounter technology. For in silico validation, two distinct cohorts sourced from the Gene Expression Omnibus (GEO) database were used. Results Among the 106 patients, only one (<1 %) exhibited MSI instability. PD-L1 expression was present in 9.4 % of cases, and no association was found with BCG-responsive status. We found low gene expression of canonic actionable immune checkpoints PDCD1 (PD-1), CD274 (PD-L1), and CTLA4, while high expression was observed for CD276 (B7-H3), CD47, TNFRSF14, IDO1 and PVR (CD155) genes. High IDO1 expression levels was associated with worst overall survival. The PDCD1, CTLA4 and TNFRSF14 expression levels were associated with BCG responsiveness, whereas TIGIT and CD276 were associated with unresponsiveness. Finally, CD276 was validated in silico cohorts. Conclusion In NMIBC, MSI is rare and PD-L1 expression is present in a small subset of cases. Expression levels of PDCD1, CTLA4, TNFRSF14, TIGIT and CD276 could constitute predictive biomarkers of BCG responsiveness.

Citação
Zucca LER, Laus AC, Sorroche BP, Paro E, Sussuchi L, Marques RF, Teixeira GR, Berardinelli GN, Arantes LMRB, Reis RM, Cárcano FM. Transl Oncol. 2024 Aug;46:102003. doi: 10.1016/j.tranon.2024.102003. Epub 2024 Jun 4. PMID: 38838438

Data documento
07/05/2024

Título
Significance of Chr9p22.1-p21.3 Deletion in Cancer Development: A Pan-cancer In Silico Analysis

Autor(es)
Gonçalves PG, Reis RM, Bidinotto LT.

Palavras chave
locus - In silico analysis - TCGA - gene expression - prognostic value

Resumo
Background/aim: Deletions in chr9p22.1-21.3 locus have been related to the development of several types of cancer, mainly due to the presence of CDKN2A and CDKN2B genes. However, there are several other genes in the region with potential importance in tumorigenesis. We, therefore, aimed to analyze in silico the potential prognostic significance of alterations in copy number and expression of genes present in the chr9p22.1-21.3 locus in 33 TCGA datasets (approximately 10,000 patients). Materials and methods: We analyzed which of the 27 genes are expressed in the datasets. Additionally, we associated the deletion of the locus with survival (log rank analysis) and hazard ratio (HR) (univariate cox regression). Finally, we performed univariate, multivariate, and overall survival analyses in 13 datasets considering the expression of 10 genes present in the locus. Results: We identified 10 genes of the chr9p22.1-21.3 locus expressed in the datasets (MLLT3, FOCAD, PTPLAD2, KLHL9, IFNE, MTAP, CDKN2A, CDKN2B, DMRTA1 and ELAVL2). Moreover, we found that deletion in at least 1 of these genes was associated with poor survival and increased HR in 13 datasets: adrenocortical carcinoma (ACC), glioblastoma (GBM), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), low-grade glioma (LGG), lung adenocarcinoma (LUAD), mesothelioma (MESO), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), sarcoma (SARC) and uterine corpus endometrial carcinoma (UCEC). Finally, we found an association of survival/HR and altered expression of MLLT3 in the MESO dataset, of FOCAD in the READ dataset, of PTPLAD2 in the KIRP dataset, of KLHL9 in the LGG and UCEC datasets, of IFNE in ACC, GBM, KIRC and LUAD datasets, of MTAP in LGG, LUAD and MESO datasets, of CDKN2A in the HNSC, KIRC and MESO datasets, of CDKN2B in the LGG and READ datasets, of DMRTA1 in SARC datasets and of ELAVL2 in the LGG dataset (p<0.01 for all associations). Conclusion: Besides CDKN2A and CDKN2B, numerous other genes are possibly related to cancer development, requiring further investigation.

Citação
Gonçalves PG, Reis RM, Bidinotto LT. Significance of Chr9p22.1-p21.3 Deletion in Cancer Development: A Pan-cancer In Silico Analysis. Anticancer Res. 2022 Nov;42(11):5291-5304. doi: 10.21873/anticanres.16036. PMID: 36288884.

Data documento
02/05/2024

Título
The digital expression profile of BMP7, CDKN2C, HIST1H3G, and PKMYT1 genes improves high‐grade cervical lesion detection in liquid‐based cytology

Autor(es)
Causin RL, - Sussuchi da Silva L, - Leal LF, - Possati-Resende JC, - Evangelista AF, - Matsushita GM, - Scapulatempo-Neto C, - Tavares Guerreiro Fregnani JH, - Antônio de Oliveira M, - Musselwhite LW, - Chiquitelli Marques MM, - Reis RM.

Palavras chave
biomarkers - cervical cancer - cervical intraepithelial neoplasia - gene expression - liquid‐based cytology

Resumo
Background: Some studies reported that differential gene expression could be used as a biomarker for high‐grade cervical lesion identification. The aim was to evaluate the gene expression profile of cervical intraepithelial neoplasia (CIN) to identify a gene expression signature of CIN2+ in liquid‐based cytology (LBC) samples. Methods: LBC samples (n = 85) obtained from women who underwent colposcopy were included with benign (n = 13), CIN1 (n = 26), CIN2 (n = 16), and CIN3 (n = 30) diagnoses. After RNA isolation, gene expression profiling was performed using the nCounter PanCancer Pathways, which consists of 730 cancer‐related genes. The genes identified were in silico expression evaluated using the UALCAN database. An accurate prediction model to discriminate CIN2+ from

Descrição

Citação
Causin RL, Sussuchi da Silva L, Leal LF, Possati-Resende JC, Evangelista AF, Matsushita GM, Scapulatempo-Neto C, Tavares Guerreiro Fregnani JH, Antônio de Oliveira M, Musselwhite LW, Chiquitelli Marques MM, Reis RM. The digital expression profile of BMP7, CDKN2C, HIST1H3G, and PKMYT1 genes improves high-grade cervical lesion detection in liquid-based cytology. Cancer Cytopathol. 2023 Jul;131(7):454-464. doi: 10.1002/cncy.22704. Epub 2023 Apr 17. PMID: 37069588.