Pharmacogenetics of taxanes: identification and characterization of molecular mechanisms underlying toxicity and lack of response

Tesis doctoral inédita. Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 15-02-201

Molecular genetic heterogeneity in undifferentiated endometrial carcinomas

Undifferentiated and dedifferentiated endometrial carcinomas are rare and highly aggressive subtypes of uterine cancer, not well characterized at a molecular level. To investigate whether dedifferentiated carcinomas carry molecular genetic alterations similar to those of pure undifferentiated carcinomas, and to gain insight into the pathogenesis of these tumors, we selected a cohort of 18 undifferentiated endometrial carcinomas, 8 of them with a well-differentiated endometrioid carcinoma component (dedifferentiated endometrioid carcinomas), and studied them by immunohistochemistry and massive parallel and Sanger sequencing. Whole-exome sequencing of the endometrioid and undifferentiated components, as well as normal myometrium, was also carried out in one case. According to The Cancer Genome Atlas classification, we distributed 95% of the undifferentiated carcinomas in this series as follows: (a) hypermutated tumors with loss of any mismatch repair protein expression and microsatellite instability (eight cases, 45%); (b) ultramutated carcinomas carrying mutations in the exonuclease domain of POLE (two cases, 11%); (c) high copy number alterations (copy-number high) tumors group exhibiting only TP53 mutations and high number of alterations detected by FISH (two cases, 11%); and (d) low copy number alterations (copy-number low) tumors with molecular alterations typical of endometrioid endometrial carcinomas (five cases, 28%). Two of the latter cases, however, also had TP53 mutations and higher number of alterations detected by FISH and could have progressed to a copy-number high phenotype. Most dedifferentiated carcinomas belonged to the hypermutated group, whereas pure undifferentiated carcinomas shared molecular genetic alterations with copy-number low or copy-number high tumors. These results indicate that undifferentiated and dedifferentiated endometrial carcinomas are molecularly heterogeneous tumors, which may have prognostic value

Digitaalisten palvelujen vaikutukset sosiaali- ja terveydenhuollossa

Selvityksen tavoitteena oli luoda ajantasainen kuva digipalvelujen vaikutuksista sosiaali- ja terveydenhuollossa eri toimijoiden näkökulmista. Digipalveluja hyödynnetään etenkin terveydenhuollossa, erityisesti avosairaanhoidossa asiakaspolun eri vaiheissa. Myös kotihoidossa digipalveluita hyödynnetään runsaasti. Muissa sosiaalihuollon palveluissa digipalveluja havaittiin vähemmän, erityisesti vammais- ja hoivapalveluissa. Sosiaalihuollon digipalvelut ovat myös enemmän pistemäisiä; sähköisiä hakemuksia ja lomakkeita. Digipalvelujen käyttäjät ovat pääosin tyytyväisiä palveluihin. Asiakkaille kriittistä on digipalvelujen saavutettavuus ja integraatio, etenkin jos henkilöllä on useita pitkäaikaisia sairauksia, vammoja tai toiminnanvajausta. Ammattilaisten kokemukset digipalveluista ovat osin positiivisia, mutta huolia työmäärän lisääntymisestä esiintyy. Käyttöönotoissa tulisi tehdä enemmän työtä digipalvelujen viimekätisten hyötyjen ja vaikutusten saavuttamiseksi. Palvelujärjestelmän johto kokee, että digipalvelujen vaikutusten ja vaikuttavuuden arviointia tulisi lisätä, mutta mittaaminen on haasteellista. Yksi ratkaisu on sitoa mittaaminen voimakkaammin tavoitteisiin, mikä edellyttäisi selkeämpää tavoiteasetantaa. Digipalvelujen vaikuttavuus ei juurikaan näy lainsäädännössä, ja lainsäädännössä on useita kehittämistarpeita. Lain tulkinnat aiheuttavat haasteita digipalvelujen käytölle.Tämä julkaisu on toteutettu osana valtioneuvoston selvitys- ja tutkimussuunnitelman toimeenpanoa. (tietokayttoon.fi) Julkaisun sisällöstä vastaavat tiedon tuottajat, eikä tekstisisältö välttämättä edusta valtioneuvoston näkemystä

The Variant rs1867277 in FOXE1 Gene Confers Thyroid Cancer Susceptibility through the Recruitment of USF1/USF2 Transcription Factors

In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30–1.70; P = 5.9×10−9). Functional assays of rs1867277 (NM_004473.3:c.−283G>A) within the FOXE1 5′ UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/αCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era

Virtsarakkosyövän avohoito lisääntyi ja kustannusten kasvu tasoittui

Lähtökohdat :Tarkastelemme virtsarakkosyövän vuosittaisia diagnoosi- ja toimenpidemääriä sekä levinnyttä tautia sairastavien elossaoloa. Selvitämme myös potilaiden palvelunkäytön kustannuksia ja Kelan maksamia korvauksia. Menetelmät : Tämä retrospektiivinen tutkimus pohjautuu kansallisiin rekistereihin. Aineisto koostuu suomalaisista virtsarakkosyöpäpotilaista vuosilta 2011–2019. Heidät luokiteltiin kolmeen ryhmään: pinnallinen, paikallisesti edennyt ja levinnyt tauti. Tulokset : Avohoitokäyntien määrä erikoissairaanhoidossa lisääntyi. Palvelujen käytön kokonaiskustannukset vuonna 2019 olivat 17 % suuremmat kuin vuonna 2011. Hoidon kustannukset kasvoivat vuosina 2015–2018 vain 2 %, vaikka hoidossa olevien määrä kasvoi samaan aikaan noin 10 %. Keskimääräinen kustannus potilasta kohden pieneni pinnallista ja paikallisesti edennyttä syöpää sairastavilla potilailla, mutta kasvoi levinnyttä syöpää sairastavilla. Päätelmät : Rakkosyöpäpotilaiden hoito noudattaa yleistä suuntausta, eli avohoito on lisääntynyt merkittävästi. Resurssien käyttöä, kustannuksia ja hoidon vaikutuksia tulee seurata, jotta voidaan valita vaikuttava hoito.Peer reviewe

Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy.

BACKGROUND Peripheral neuropathy is the dose limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat solid tumours. This toxicity exhibits great inter-individual variability of unknown origin. The present study aimed to identify genetic variants associated with paclitaxel induced neuropathy via a whole genome approach. METHODS A genome-wide association study (GWAS) was performed in 144 white European patients uniformly treated with paclitaxel/carboplatin and for whom detailed data on neuropathy was available. Per allele single nucleotide polymorphism (SNP) associations were assessed by Cox regression, modelling the cumulative dose of paclitaxel up to the development of grade 2 sensory neuropathy. RESULTS The strongest evidence of association was observed for the ephrin type A receptor 4 (EPHA4) locus (rs17348202, p=1.0×10(-6)), and EPHA6 and EPHA5 were among the top 25 and 50 hits (rs301927, p=3.4×10(-5) and rs1159057, p=6.8×10(-5)), respectively. A meta-analysis of EPHA5-rs7349683, the top marker for paclitaxel induced neuropathy in a previous GWAS (r(2)=0.79 with rs1159057), gave a hazard ratio (HR) estimate of 1.68 (p=1.4×10(-9)). Meta-analysis of the second hit of this GWAS, XKR4-rs4737264, gave a HR of 1.71 (p=3.1×10(-8)). Imputed SNPs at LIMK2 locus were also strongly associated with this toxicity (HR=2.78, p=2.0×10(-7)). CONCLUSIONS This study provides independent support of EPHA5-rs7349683 and XKR4-rs4737264 as the first markers of risk of paclitaxel induced neuropathy. In addition, it suggests that other EPHA genes also involved in axonal guidance and repair following neural injury, as well as LIMK2 locus, may play an important role in the development of this toxicity. The identified SNPs could form the basis for individualised paclitaxel chemotherapy.This work was supported by projects from the Spanish Ministry of Science and Innovation (grant numbers SAF2006-01139 and SAF2009-08307), the Spanish Ministry of Economy and Competiveness (grant number SAF2012-35779), the Swedish Cancer Society, the Swedish Research Council, Fondkistan, Stiftelsen Sigurd och Elsa Goljes Minne and Markus Borgstroms stiftelse, and The Cancer Research Funds of Radiumhemmet. Luis Javier Leandro-Garcia was supported by a FIS fellowship (grant number FI08/00375).S

Expression of CYP3A4 as a predictor of response to chemotherapy in peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) are aggressive tumors in which the current therapy based on multiagent chemotherapy is not successful. Since cytochrome P450 3A subfamily (CYP3A) enzymes are involved in the inactivation of chemotherapy drugs, we hypothesized that CYP3A and P-glycoprotein (MDR1) expression in these lymphomas could result in a poor clinical response. We measured tumoral CYP3A and MDR1 mRNA content in 44 T-cell lymphomas, finding a large variation in CYP3A expression. Multiplex polymerase chain reaction (PCR) analysis and fluorescence in situ hybridization (FISH) analysis showed genomic gains affecting CYP3A and MDR1 genes in T-cell lines and primary tumors, suggesting that this could be the mechanism underlying the tumoral expression variation. To test whether the tumoral expression of CYP3A and/or MDR1 could influence PTCL treatment outcome, their expression levels were compared with the clinical response and survival of the patients, finding that a high tumoral expression of CYP3A4 was significantly associated with a lower complete remission rate. This was further investigated with cell lines stably expressing CYP3A4 that exhibited an increased resistance to doxorubicin and etoposide. In conclusion, a high CYP3A4 tumoral expression could be useful to predict poor response to the standard PTCL chemotherapy; in these cases alternative chemotherapy combinations or doses should be explored.pre-print404 K