Tratamiento del cáncer de próstata en función de la esperanza de vida, la comorbilidad y las guías de práctica clínica

En un número anterior de la revista de Anales del Sistema Sanitario de Navarra, Barceló y col realizaron una interesante y útil revisión de los pacientes con cáncer de próstata tratados en un gran centro hospitalario español durante un año, centrándose en sus características basales, el tratamiento realizado y el grado de seguimiento de las Guías de Práctica Clínica (GPC) y las complicaciones asociadas a los tratamientos realizados

Genomic characterization of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced lung cancer

Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n=3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (p(combined)=5.66x10(-5); ORcombined=2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (p(combined)=1.02x10(-4); ORcombined=2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10D mRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p=0.01 and p<0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I-II NSCLC (p=0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco-induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco-induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC

Caracterización, mediante estudio de asociación del genoma (Genome-Wide Association Study, GWAS), de individuos con fenotipos extremos de sensibilidad y resistencia a desarrollar cáncer de pulmón no microcítico

El cáncer de pulmón es la primera causa de muerte por tumores en el mundo. En 2018, en Europa, la incidencia fue de 470.000 nuevos casos y la tasa de muerte de 53 casos por cada 100.000 individuos, [1] en EE.UU se estimó una incidencia de 234.000 casos [2]. En España, la tasa de mortalidad en 2018 fue de 47.9 muertes por cada 100.000 habitantes [3]. Existen dos subtipos principales de cáncer de pulmón, el carcinoma no microcítico de pulmón (CNMP), que supone el 85% de los casos y el carcinoma microcítico de pulmón (CMP) con una frecuencia del 15%. A su vez, en el CNMP se distinguen diferentes tipos histológicos, siendo los más frecuentes el adenocarcinoma (40%), los tumores epidermoides (25-30%) y los carcinomas de células grandes (10-15%) [4]

Caracterización, mediante estudio de asociación del genoma (Genome-Wide Association Study, GWAS), de individuos con fenotipos extremos de sensibilidad y resistencia a desarrollar cáncer de pulmón no microcítico

El cáncer de pulmón es la primera causa de muerte por tumores en el mundo. En 2018, en Europa, la incidencia fue de 470.000 nuevos casos y la tasa de muerte de 53 casos por cada 100.000 individuos, [1] en EE.UU se estimó una incidencia de 234.000 casos [2]. En España, la tasa de mortalidad en 2018 fue de 47.9 muertes por cada 100.000 habitantes [3]. Existen dos subtipos principales de cáncer de pulmón, el carcinoma no microcítico de pulmón (CNMP), que supone el 85% de los casos y el carcinoma microcítico de pulmón (CMP) con una frecuencia del 15%. A su vez, en el CNMP se distinguen diferentes tipos histológicos, siendo los más frecuentes el adenocarcinoma (40%), los tumores epidermoides (25-30%) y los carcinomas de células grandes (10-15%) [4]

Tratamiento del cáncer de próstata en función de la esperanza de vida, la comorbilidad y las guías de práctica clínica

En un número anterior de la revista de Anales del Sistema Sanitario de Navarra, Barceló y col realizaron una interesante y útil revisión de los pacientes con cáncer de próstata tratados en un gran centro hospitalario español durante un año, centrándose en sus características basales, el tratamiento realizado y el grado de seguimiento de las Guías de Práctica Clínica (GPC) y las complicaciones asociadas a los tratamientos realizados

Genomic characterization of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced lung cancer

Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n=3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (p(combined)=5.66x10(-5); ORcombined=2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (p(combined)=1.02x10(-4); ORcombined=2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10D mRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p=0.01 and p<0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I-II NSCLC (p=0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco-induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco-induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC

Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer

Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor-suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib-desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low-dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC