RESUMEN
Background: Despite having revolutionized the treatment paradigm for advanced melanoma, not all patients benefit from immune checkpoint inhibitor therapy. To date, there are no predictive biomarkers for response or the occurrence of immune-related adverse events (irAEs) to programmed cell death protein 1 (PD-1) inhibitors. Our aim was to investigate the predictive and prognostic role of single nucleotide variants (SNVs) of genes involved in the PD-1 axis. Methods: We analysed, in metastatic melanoma patients treated with nivolumab or pembrolizumab, five PD-1 SNVs, namely PD1.3 G>A (rs11568821), PD1.5 C>T (rs2227981), PD1.6 G>A (rs10204525), PD1.7 T>C(rs7421861), PD1.10 C>G (rs5582977) and three programmed death-ligand 1 (PD-L1) SNVs: +8293 C>A (rs2890658), PD-L1 C>T (rs2297136) and PD-L1 G>C (rs4143815). Association of SNV genotypic frequencies with best overall response to PD-1 inhibitors and development of irAEs were estimated through a modified Poisson regression. A Cox regression modelling approach was applied to evaluate the SNV association with OS. Results: A total of 125 patients with advanced melanoma were included in the analysis. A reduction in irAEs risk was observed in patients carrying the PD-L1 +8293 C/A genotype compared with those carrying the C/C genotype (risk ratio = 0.45; 95% CL 0.22-0.93; P = 0.031). A trend for a reduction in irAEs was also observed with the PD1.5 T allele (risk ratio = 0.70, 95% confidence limits 0.48-1.01 versus C allele). None of the SNVs was associated with response to therapy. Finally, a survival benefit was observed in patients harbouring the PD1.7 C/C genotype (hazard ratio = 0.37; 95% confidence limits 0.14-0.96; P = 0.028) in the homozygous model. Conclusions: Our study showed that PD-1.5 and PD-L1 +8293 SNVs may play a role as a predictive biomarker of development of irAEs to PD-1 inhibitors. PD1.7 SNV may also be associated with a reduction of the risk of death, although further translational research is needed to confirm these results.
RESUMEN
BACKGROUND: Breast cancer patients have a cumulative lifetime risk of 2%-15% of developing a contralateral metastatic or ex novo primary cancer. From prognostic and therapeutic viewpoints, it is important to differentiate metastatic from second primary. To distinguish these entities, we investigated whether the pattern of X chromosome inactivation could determine whether the two tumors derived from different progenitor cells. MATERIALS AND METHODS: The clonality of bilateral breast cancer was evaluated through the X-inactivation analysis using the human androgen receptor gene (HUMARA) polymorphism and the histopathologic and molecular results were compared. A different or an identical pattern of X inactivation was considered as indicator of a second primary cancer or not informative, respectively. We considered morphological indicators of a new primary cancer the absence of concordance in the histological type or a better histological differentiation. RESULTS: Ten patients with bilateral breast cancer were evaluated. Morphological criteria indicated that eight were second primary, a conclusion confirmed by the X-inactivation analysis. Two cases classified as recurrence according to morphological criteria were classified as second tumor by molecular analysis. CONCLUSION: Our results show that the HUMARA clonality assay can improve the histological parameters in differentiating metastatic cancer from second primary cancer.
Asunto(s)
Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Carcinoma/diagnóstico , Carcinoma/patología , Técnicas de Diagnóstico Molecular/métodos , Estadificación de Neoplasias/métodos , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Carcinoma/genética , Carcinoma/mortalidad , Células Clonales/patología , Diagnóstico Diferencial , Femenino , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Metástasis de la Neoplasia , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/patología , Reacción en Cadena de la Polimerasa/métodos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Análisis de Supervivencia , Estudios de Validación como AsuntoAsunto(s)
Caspasas/genética , Proteínas de Unión al ADN/metabolismo , Neuroblastoma/enzimología , Fosfoproteínas/metabolismo , Regiones Promotoras Genéticas , Caspasa 8 , Caspasas/efectos de los fármacos , Caspasas/metabolismo , Proteínas de Unión al ADN/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica , Humanos , Factor 1 Regulador del Interferón , Interferones/farmacología , Neuroblastoma/genética , Fosfoproteínas/efectos de los fármacos , Factor de Transcripción STAT1 , Transducción de Señal/genética , Transactivadores/metabolismo , Células Tumorales CultivadasRESUMEN
The p73 gene is a p53 homologue localized at 1p36.3, a chromosomal region frequently deleted in neuroblastoma. p73 was originally considered an oncosuppressor gene. However, it was soon realized that its mode of action did not resemble that of a classic anti-oncogene. The recent discovery of N-terminal truncated isoforms, with oncogenic properties, showed that p73 has a 'two in one' structure. Indeed, the full-length variants are strong inducers of apoptosis while the truncated isoforms inhibit the pro-apoptotic activity of p53 and of the full-length p73. This review summarizes some aspects of p73 biology with particular reference to its possible role in neuroblastoma.
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Proteínas de Unión al ADN/fisiología , Neuroblastoma/metabolismo , Proteínas Nucleares/fisiología , Empalme Alternativo , Apoptosis/fisiología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Genes Supresores de Tumor , Humanos , Neuroblastoma/genética , Neuroblastoma/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Pronóstico , Tasa de Supervivencia , Proteína Tumoral p73 , Proteínas Supresoras de TumorRESUMEN
The p73 gene is a p53 homologue which induces apoptosis and inhibits cell proliferation. Although p73 maps at 1p36.3 and is frequently deleted in neuroblastoma (NB), it does not act as a classic oncosuppressor gene. In developing sympathetic neurons of mice, p73 is predominantly expressed as a truncated anti-apoptotic isoform (DeltaNp73), which antagonizes both p53 and the full-length p73 protein (TAp73). This suggests that p73 may be part of a complex tumor-control mechanism. To determine the role of DeltaNp73 in NB we analyzed the pattern of expression of this gene in vivo and evaluated the prognostic significance of its expression. Our results indicate that DeltaNp73 expression is associated with reduced apoptosis in a NB tumor tissue. Expression of this variant in NB patients significantly correlates with age at diagnosis and VMA urinary excretion. Moreover it is strongly associated with reduced survival (HR=7.93; P<0.001) and progression-free survival (HR=5.3; P<0.001) and its role in predicting a poorer outcome is independent from age, primary tumor site, stage and MYCN amplification (OS: HR=5.24, P=0.012; PFS: HR=4.36, P=0.005). In conclusion our data seem to indicate that DeltaNp73 is a crucial gene in neuroblastoma pathogenesis.
Asunto(s)
Apoptosis/fisiología , Neuroblastoma/diagnóstico , Niño , Preescolar , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Genes Supresores de Tumor , Humanos , Lactante , Recién Nacido , Neuroblastoma/mortalidad , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/genética , Pronóstico , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/genética , Tasa de Supervivencia , Proteína Tumoral p73 , Proteínas Supresoras de TumorAsunto(s)
Islas de CpG/genética , Metilación de ADN , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Neuroblastoma/genética , Proteínas Nucleares/genética , Animales , Apoptosis , Islas de CpG/fisiología , Proteínas de Unión al ADN/metabolismo , Silenciador del Gen , Genes Supresores de Tumor , Humanos , Neuroblastoma/metabolismo , Proteínas Nucleares/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteína Tumoral p73 , Proteínas Supresoras de TumorRESUMEN
p73 is a p53 homolog that, in vitro, inhibits cell growth and induce apoptosis. In some tumors p73 is monoallelically expressed and this raised the possibility that this gene is subjected to imprinting. Silencing of p73 in acute leukemia and in Burkitt's lymphoma occurs in association with the aberrant methylation of the first exon of the gene. We have analysed the methylation pattern of the p73 promoter and of upstream and downstream sequences in neuroblastoma. Our results demonstrate that p73 expression in this tumor is not regulated by methylation. We concluded that it is unlikely that p73 is imprinted in neuroblastoma and that the methylation-dependent silencing of this gene, thus far, is a characteristic of hematologic malignancies. Oncogene (2000) 19, 4553 - 4556.
Asunto(s)
Metilación de ADN , Proteínas de Unión al ADN/genética , Genes Supresores de Tumor , Neuroblastoma/genética , Proteínas Nucleares/genética , Secuencia de Bases , Islas de CpG , Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Células HL-60 , Humanos , Datos de Secuencia Molecular , Proteínas Nucleares/metabolismo , Reacción en Cadena de la Polimerasa/métodos , Regiones Promotoras Genéticas , Proteína Tumoral p73 , Proteínas Supresoras de TumorAsunto(s)
Mapeo Cromosómico/métodos , Clonación Molecular , Línea Celular , Humanos , Mutagénesis InsercionalRESUMEN
We report the refined chromosomal localization of the putative tumor suppressor gene TP73 (alias p73) within the genomic region between the anonymous loci D1Z2 and D1S47. The region measures less than 6 Mb and covers a genetic distance of 16 cM. The present mapping considerably restricts the previous cytogenetic localization of TP73.
