Relevance of PD-L1 Non-Coding Polymorphisms on the Prognosis of a Genetically Admixed NSCLC Cohort

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Machado-Rugolo, Juliana ^{[1, 2]} ; Prieto, Tabatha Gutierrez ^[1] ; Fabro, Alexandre Todorovic ^[3] ; Parra Cuentas, Edwin Roger ^[4] ; Sa, Vanessa Karen ^[5] ; Baldavira, Camila Machado ^[1] ; Rainho, Claudia Aparecida ^[6] ; Castelli, Erick C. ^{[7, 8]} ; Farhat, Cecilia ^[1] ; Takagaki, Teresa Yae ^[9] ; Nagai, Maria Aparecida ^{[10, 11]} ; Capelozzi, Vera Luiza ^[1]

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^[1] Univ Sao Paulo, Dept Pathol, Lab Genom & Histomorphometry, Med Sch USP, Sao Paulo - Brazil

^[2] Sao Paulo State Univ UNESP, Clin Hosp HCFMB, Hlth Technol Assessment Ctr, Med Sch, Botucatu, SP - Brazil

^[3] Univ Sao Paulo FMRP USP, Ribeirao Preto Sch Med, Dept Pathol & Legal Med, Ribeirao Preto - Brazil

^[4] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 - USA

^[5] AC Camargo Canc Ctr, Ctr Int Pesquisa CIPE, Lab Genom & Mol Biol, Sao Paulo, SP - Brazil

^[6] Sao Paulo State Univ UNESP, Inst Biosci, Dept Chem & Biol Sci, Botucatu, SP - Brazil

^[7] Sao Paulo State Univ UNESP, Expt Res Unit UNIPEX, Mol Genet & Bioinformat Lab, Med Sch, Botucatu, SP - Brazil

^[8] Sao Paulo State Univ UNESP, Dept Pathol, Med Sch, Botucatu, SP - Brazil

^[9] Univ Sao Paulo, Clin Hosp, Heart Inst Incor, Div Pneumol, Med Sch USP, Sao Paulo, SP - Brazil

^[10] Canc Inst Sao Paulo ICESP, Ctr Translat Res Oncol, Lab Mol Genet, Sao Paulo - Brazil

^[11] Univ Sao Paulo, Dept Radiol & Oncol, Med Sch USP, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PHARMACOGENOMICS & PERSONALIZED MEDICINE; v. 14, p. 239-252, 2021.
• Citações Web of Science: 0

Resumo

Purpose: Although non-small cell lung cancer (NSCLC) remains a deadly disease, new predictive biomarkers have emerged to assist in managing the disease, of which one of the most promising is the programmed death-ligand 1 (PD-L1). Each, PD-L1 variant seem to modulate the function of immune checkpoints differently and affect response to adjuvant treatment and outcome in NSCLC patients. We thus investigated the influence of these PD-L1 genetic variations in genetically admixed NSCLC tissue samples, and correlated these values with clinicopathological characteristics, including prognosis. Materials and Methods: We evaluated PD-L1 non-coding genetic variants and protein expression in lung adenocarcinomas (ADC), squamous cell carcinomas (SqCC), and large cell carcinomas (LCC) in silico. Microarray paraffin blocks from 70 samples of ADC (N=33), SqCC (N=24), and LCC (N=13) were used to create PD-L1 multiplex immunofluorescence assays with a Cell Signaling E1L3N clone. Fifteen polymorphisms of the PD-L1 gene were investigated by targeted sequencing and evaluated in silico using dedicated tools. Results: Although PD-L1 polymorphisms seemed not to interfere with protein expression, PD-L1 expression varied among different histological subtypes, as did clinical outcomes, with the rs4742098A>G, rs4143815G>C, and rs7041009G>A variants being associated with relapse (P=0.01, P=0.05, P=0.02, respectively). The rs7041009 GG genotype showed a significant correlation with younger and alive patients compared to carriers of the A allele (P=0.02 and P<0.01, respectively). The Cox regression model showed that the rs7041009 GG genotype may influence OS (P<0.01) as a co-dependent factor associated with radiotherapy and recurrence in NSCLC patients. Furthermore, the Kaplan-Meier survival curves showed that rs7041009 and rs4742098 might impact PPS in relapsed patients. In silico approaches identified the variants as benign. Conclusion: PD-L1 non-coding variants play an important role in modulating immune checkpoint function and may be explored as immunotherapy biomarkers. We highlight the rs7041009 variant, which impacts OS and PPS in NSCLC patients. (AU)

• Processo FAPESP: 18/20403-6 - Marcadores biomoleculares de proliferação e remodelamento em doenças respiratórias agudas e crônicas: promissores alvos terapêuticos
• Beneficiário: Vera Luiza Capelozzi
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/14277-4 - Prognóstico e evolução clínica de novos e vigentes biomarcadores genéticos e protéicos em câncer de pulmão
• Beneficiário: Vera Luiza Capelozzi
• Modalidade de apoio: Auxílio à Pesquisa - Regular