80 research outputs found
TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer
No full textTP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.
In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.
If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer
Gene-environment interactions involving functional variants: Results from the Breast Cancer Association Consortium
No full textInvestigating the most likely causal variants identified by fine-mapping analyses may improve the power to detect gene–environment interactions. We assessed the interplay between 70 single nucleotide polymorphisms identified by genetic fine-scale mapping of susceptibility loci and 11 epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind. Analyses were carried out separately for estrogen receptor (ER) positive (ER+) and ER negative (ER–) disease. The Bayesian False Discovery Probability (BFDP) was computed to assess the noteworthiness of the results. Four potential gene–environment interactions were identified as noteworthy (BFDP < 0.80) when assuming a true prior interaction probability of 0.01. The strongest interaction result in relation to overall breast cancer risk was found between CFLAR-rs7558475 and current smoking (ORint = 0.77, 95% CI: 0.67–0.88, pint = 1.8 × 10−4). The interaction with the strongest statistical evidence was found between 5q14-rs7707921 and alcohol consumption (ORint =1.36, 95% CI: 1.16–1.59, pint = 1.9 × 10−5) in relation to ER– disease risk. The remaining two gene–environment interactions were also identified in relation to ER– breast cancer risk and were found between 3p21-rs6796502 and age at menarche (ORint = 1.26, 95% CI: 1.12–1.43, pint =1.8 × 10−4) and between 8q23-rs13267382 and age at first full-term pregnancy (ORint = 0.89, 95% CI: 0.83–0.95, pint = 5.2 × 10−4). While these results do not suggest any strong gene–environment interactions, our results may still be useful to inform experimental studies. These may in turn, shed light on the potential interactions observed
Assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels
No full textInternational audienceCirculating insulin‐like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome‐wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts ( N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF‐I, IGF‐II, IGFBP‐2 and IGFBP‐3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs . high (≥ 7) Gleason grade, localised vs . advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF‐II and IGFBP‐3, less so for IGF‐I. Rs11977526 was associated with high ( vs . low) Gleason grade (OR per IGF‐II/IGFBP‐3 level‐raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF‐II (∼265 ng/mL) on risk of high vs . low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker
Common genetic variants associated with disease from genome-wide association studies are mutually exclusive in prostate cancer and rheumatoid arthritis
No full textObjectives: To investigate if potential common pathways exist for the pathogenesis of autoimmune disease and prostate cancer (PrCa). To ascertain if the single nucleotide polymorphisms (SNPs) reported by genome-wide association studies (GWAS) as being associated with susceptibility to PrCa are also associated with susceptibility to the autoimmune disease rheumatoid arthritis (RA).
Materials and Methods: The original Wellcome Trust Case Control Consortium (WTCCC) UK RA GWAS study was expanded to include a total of 3221 cases and 5272 controls.
In all, 37 germline autosomal SNPs at genome-wide significance associated with PrCa risk were identified from a UK/Australian PrCa GWAS. Allele frequencies were compared for these 37 SNPs between RA cases and controls using a chi-squared trend test and corrected for multiple testing (Bonferroni).
Results: In all, 33 SNPs were able to be analysed in the RA dataset. Proxies could not be located for the SNPs in 3q26, 5p15 and for two SNPs in 17q12. After applying a Bonferroni correction for the number of SNPs tested, the SNP mapping to CCHCR1 (rs130067) retained statistically significant evidence for association (P = 6 × 10–4; odds ratio [OR] = 1.15, 95% CI: 1.06–1.24); this has also been associated with psoriasis.
However, further analyses showed that the association of this allele was due to confounding by RA-associated HLA-DRB1 alleles.
Conclusions: There is currently no evidence that SNPs associated with PrCa at genome-wide significance are associated with the development of RA. Studies like this are important in determining if common genetic risk profiles might predispose individuals to many diseases, which could have implications for public health in terms of screening and chemoprevention
Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort
No full textInternational audienceBackgroundEpidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach.MethodsWe derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the PRACTICAL consortium (n = 43,737) as a replication sample.ResultsIn ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64–0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43–91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91–1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90–0.98), but not with disease grade.ConclusionsOlder age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease
Genomic risk model to implement precision prostate cancer screening in clinical care: the ProGRESS study
No full textInternational audiencePrecision healthcare aims to tailor disease prevention and early detection to individual risk. Prostate cancer screening may benefit from genomics-informed approaches. We developed and validated the P-CARE model, a prostate cancer risk prediction tool combining a polygenic score, family history and genetic ancestry, using data from over 585,000 male participants in the Million Veteran Program. The model was externally validated in diverse cohorts and implemented via a blended genome-exome assay for clinical use. Here we show that the P-CARE model identifies clinically meaningful gradients of prostate cancer risk among men, with higher scores associated with increased risk of any, metastatic and fatal prostate cancer. The model is now being used in a clinical trial of precision prostate cancer screening. This work demonstrates the potential for genomics-enabled health systems to improve prostate cancer screening and prevention in men. ClinicalTrials.gov registration: NCT0592610
Role of type I Interferons in the treatment of endocrine and non-endocrine cancers
No full textGli interferoni (IFNi) costituiscono una complessa famiglia di citochine, individuate inizialmente per la loro capacità di conferire uno stato anti-virale alle cellule. Successivamente, altri effetti biologici sono stati attribuiti agli IFNi, tra i quali una potente attività anti-tumorale. In relazione al tipo di recettore con cui interagiscono, gli IFNi sono stati classificati in due gruppi: IFNi di tipo I (IFN-, -, - and -) e IFNi di tipo II (IFN-).
L’attività di ricerca svolta dal candidato durante il corso di Dottorato ha avuto come obiettivo quello di valutare l’efficacia in vitro dell’IFN- e IFN- in linee cellulari umane di tumore neuroendocrino del pancreas (BON), adenocarcinoma del pancreas (BxPC-3, MiaPaCa-2, Panc-1) e carcinoma del surrene (SW-13, H-295), e di analizzare i meccanismi d’azione ed il ruolo delle relative subunità recettoriali.
Gli effetti dell’IFN-2b e IFN-1a sulla proliferazione cellulare sono stati valutati tramite la quantificazione del DNA, rappresentativa del numero delle cellule, mediante determinazione fluorimetrica con il colorante fluorescente HoechstTM 33258. In tutte le linee cellulari che abbiamo testato, l’effetto inibitorio dell’IFN- risulta essere dose-dipendente e maggiore dell’IFN-. L’attività antitumorale dell’IFN- è prevalentemente dovuta all’arresto del ciclo cellulare, con accumulo delle cellule in fase S, evidenziato mediante lo studio dell’incorporazione di ioduro di propidio con la citometria a flusso (FACS). Mentre, l’IFN-, oltre ad indurre un ritardo di transizione delle cellule dalla fase S a G2M, ha un potente effetto stimolatorio sull’apoptosi in quasi tutte le linee cellulari esaminate. L’espressione dell’mRNA e delle proteine per le subunità recettoriali attive degli IFNi di tipo I (IFNAR-1 e IFNAR-2c) e’ stata identificata rispettivamente mediante RT-PCR quantitativa ed immunoistochimica in tutte le cellule esaminate. E’ interessante notare nelle linee cellulari di adenocarcinoma pancreatico le relazioni riscontrate tra la responsività alla terapia, l’espressione e la distribuzione delle due subunita’ recettoriali. L’analisi quantitativa alla RT-PCR dell’mRNA per IFNAR-1 e IFNAR-2c rivela una maggiore espressione nelle BxPC-3, la linea cellulare più sensibile agli IFNi di tipo I. L’immunoistochimica, oltre a confermare la superiore espressione del recettore nelle BxPC-3, evidenzia anche differenze nella localizzazione e distribuzione cellulare. Mentre nelle BxPC-3 le subunità IFNAR-1 e IFNAR-2c sono principalmente localizzate a livello della membrana cellulare, nelle Panc-1 (le cellule maggiormente resistenti alla terapia con IFN-/IFN-) il segnale è prevalentemente citoplasmatico, con una lieve positività membranosa. Pertanto, la maggiore sensibilità alla terapia con IFN nelle BxPC-3 potrebbe essere legata all’elevata espressione recettoriale, evidenziata prevalentemente a livello della membrana cellulare. L’IFN- sembra anche essere in grado di modulare l’espressione di importanti fattori di crescita tumorali. Infatti, nelle BON e H-295, cellule in grado di produrre grandi quantità di IGF-2, l’IFN- inibisce la trascrizione di tale fattore di crescita.
Infine, l’attività di ricerca è stata finalizzata all’identificazione di nuove strategie volte alla sensibilizzazione delle cellule tumorali all’azione dell’IFN-. L’IFN- a concentrazioni citostatiche aumenta l'espressione e la funzione del recettore per l'epidermal growth factor nelle cellule KB di carcinoma umano epidermoide, costituendo una risposta protettiva all'apoptosi indotta dall'IFN-. Abbiamo evidenziato che le cellule KB antagonizzano l'effetto antiproliferativo ed apoptotico dell'IFN- attraverso l'iperattivazione della cascata delle chinasi attivate da mitogeni (MAPK) dipendente da ras. Pertanto, il targeting selettivo di tale via metabolica potrebbe essere un valido strumento per eludere i meccanismi di resistenza all’IFN- attivati dalla cellula. Infatti, l’inibizione selettiva di ras, attraverso la trasfezione del dominante negativo di ras RASN17 nelle cellule KB, potenzia l'apoptosi indotta da IFN come determinato con analisi al FACS e tecnica TUNEL. Analogo potenziamento dell’attività apoptotica dell’IFN- è stato evidenziato dall’associazione con un inibitore selettivo di MEK-1 (PD 98059), a sua volta attivatore selettivo di ERK-1/2
Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs).
No full textGenome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus
Promising digital solutions for medical management of patients with oncological diseases
No full textIntroduction. Malignant neoplasms remain a serious challenge for society, occupying the leading places next to cardiovascular pathology in the structure of causes of death in the vast majority of developed countries of the world. The wide popularization of innovative digital technologies in a professional clinical environment that does not have training in the relevant branches of physical and mathematical specialties is the key to the development and implementation of automated quality assessments. This fully meets the goals and objectives of the federal project “Fight against oncological diseases”, aimed at a drastically reduction in cancer mortality by 2024 among the population of the Russia. Purpose. Generalization of innovative individualized technological solutions to provide patients with high quality cancer care.Methods and materials. The scientific study was performed based on the results of a search using the PubMed / Medline database and the Google system. The search period covered about 6 years.Results. The article reflects examples of new digital solutions for medical management and the registration of multi-parametric indicators of oncological care at patient-oriented level. Among the actual solutions of mobile /remote e-health for cancer patients it is necessary to highlight: 1) portable (individual) medical gadgets; 2) “smart” piezoelectric necklaces; 3) implantable and internal sensors; 4) devices for performing blood tests at home in patients receiving chemotherapy; 5) mobile antitumor devices; 6) devices that implement neurotechnologies for pain relief; 7) integrated remote monitoring system.Findings. In the context of the spread of digital innovations a new environment is emerging, in which patient autonomy, collaborative medical decision making based on patient preferences, and ensuring wide access to the latest information technologies and resources are gradually becoming routine standards for providing oncological care
Time to revisit Geoffrey Rose: strategies for prevention in the genomic era?
No full textGeoffrey Rose, in his article “Sick individuals and sick populations” highlighted the need to distinguish between prevention for populations and prevention for high risk individuals. In this article we revisit some of these concepts in light of the burgeoning literature on “personalised medicine” and of findings from our investigations into personalised cancer prevention as part of an EU research gene-environment study on hormone related cancers, the Collaborative Oncological Gene- environment Study (COGS). We suggest that Rose’s high risk strategy may be modified by segmenting the population by risk (in our example genetic risk) into a number of individual strata, to each of which differential interventions may be applied. We call this “stratified prevention”, and argue that such an approach will lead to consequential advantages in efficiency, effectiveness and harm minimisation
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