| 1. |
- Campo, Chiara, et al.
(författare)
-
Bortezomib-induced peripheral neuropathy : A genome-wide association study on multiple myeloma patients
- 2018
-
Ingår i: Hematological Oncology. - : Wiley. - 0278-0232. ; 36:1, s. 232-237
-
Tidskriftsartikel (refereegranskat)abstract
- The proteasome-inhibitor bortezomib was introduced into the treatment of multiple myeloma more than a decade ago. It is clinically beneficial, but peripheral neuropathy (PNP) is a side effect that may limit its use in some patients. To examine the possible genetic predisposing factors to PNP, we performed a genome-wide association study on 646 bortezomib-treated German multiple myeloma patients. Our aim was to identify genetic risk variants associated with the development of PNP as a serious side effect of the treatment. We identified 4 new promising loci for bortezomib-induced PNP at 4q34.3 (rs6552496), 5q14.1 (rs12521798), 16q23.3 (rs8060632), and 18q21.2 (rs17748074). Even though the results did not reach genome-wide significance level, they support the idea of previous studies, suggesting a genetic basis for neurotoxicity. The identified single nucleotide polymorphisms map to genes or next to genes involved in the development and function of the nervous system (CDH13, DCC, and TENM3). As possible functional clues, 2 of the variants, rs12521798 and rs17748074, affect enhancer histone marks in the brain. The rs12521798 may also impact expression of THBS4, which affects specific signal trasduction pathways in the nervous system. Further research is needed to clarify the mechanism of action of the identified single nucleotide polymorphisms in the development of drug-induced PNP and to functionally validate our in silico predictions.
|
|
| 2. |
- Campo, Chiara, et al.
(författare)
-
Genetic Susceptibility to Bortezomib-Induced Peripheral Neuroropathy : Replication of the Reported Candidate Susceptibility Loci
- 2017
-
Ingår i: Neurochemical Research. - : Springer Science and Business Media LLC. - 0364-3190 .- 1573-6903. ; 42:3, s. 925-931
-
Tidskriftsartikel (refereegranskat)abstract
- The introduction of proteasome inhibitors in the treatment of multiple myeloma (MM) patients has been a therapeutic success. Peripheral neuropathy (PNP) remains one of the most frequent side-effects experienced by patients who receive these novel agents. Recent investigations on the mechanisms of PNP in patients treated with bortezomib have suggested genetic susceptibility to neurotoxicity. We used data from a genome-wide association study conducted on 646 bortezomib-treated German MM patients to replicate the previously reported associations between single-nucleotide polymorphisms (SNPs) in candidate genes and PNP in MM patients, including 298 SNPs with a nominal significance (p value <0.05). Twelve associations were confirmed at a significance level p value <0.05. The corresponding SNPs are located in genes involved in drug metabolism (ABCC1, ABCC6), development and function of the nervous system (POGZ, NFAT pathway, EDN1), modulation of immune responses (IL17RD, IL10RA) and the NF-κB signaling pathway (PSMB4, BTCR, F2). We systematically investigated functional consequences of those variants using several bioinformatics tools, such as HaploRegV4.1, RegulomeDB and UCSC Genome Browser. Expression quantitative trait loci (eQTL) data suggested that some of the identified SNPs might influence gene expression through a differential recruitment of transcription factors. In conclusion, we confirmed some of the recently reported associations between germline variation and PNP. Elucidating the mechanisms underlying these associations will contribute to the development of new strategies for the prevention or reduction of PNP.
|
|
| 3. |
- Campo, Chiara, et al.
(författare)
-
Inherited variants in genes somatically mutated in thyroid cancer
- 2017
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:4
-
Tidskriftsartikel (refereegranskat)abstract
- Background Tumour suppressor genes when mutated in the germline cause various cancers, but they can also be somatically mutated in sporadic tumours. We hypothesized that there may also be cancer-related germline variants in the genes commonly mutated in sporadic well-differentiated thyroid cancer (WDTC). Methods We performed a two-stage case-control association study with a total of 2214 cases and 2108 healthy controls from an Italian population. By genotyping 34 single nucleotide polymorphisms (SNPs), we covered a total of 59 missense SNPs and SNPs located in the 5' and 3' untranslated regions (UTRs) of 10 different genes. Results The Italian1 series showed a suggestive association for 8 SNPs, from which three were replicated in the Italian2 series. The meta-analysis revealed a study-wide significant association for rs459552 (OR: 0.84, 95%CI: 0.75-0.94) and rs1800900 (OR: 1.15, 95%CI: 1.05-1.27), located in the APC and GNAS genes, respectively. The APC rs459552 is a missense SNP, located in a conserved amino acid position, but without any functional consequences. The GNAS rs1800900 is located at a conserved 5'UTR and according to the experimental ENCODE data it may affect promoter and histone marks in different cell types. Conclusions The results of this study yield new insights on WDTC, showing that inherited variants in the APC and GNAS genes can play a role in the etiology of thyroid cancer. Further studies are necessary to better understand the role of the identified SNPs in the development of WDTC and to functionally validate our in silico predictions.
|
|
| 4. |
- Crowther-Swanepoel, Dalemari, et al.
(författare)
-
Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:2, s. 132-136
-
Tidskriftsartikel (refereegranskat)abstract
- To identify new risk variants for chronic lymphocytic leukemia (CLL), we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four new risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio (OR) = 1.39; P = 2.11 x 10(-9)), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 x 10(-10)), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 x 10(-7)) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 x 10(-7)). We also found evidence for risk loci at 15q25.2 (rs783540, CPEB1; OR = 1.18; P = 3.67 x 10(-6)) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 x 10(-6)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy.
|
|
| 5. |
- Engert, Andreas, et al.
(författare)
-
The European Hematology Association Roadmap for European Hematology Research : a consensus document
- 2016
-
Ingår i: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
-
Tidskriftsartikel (refereegranskat)abstract
- The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
|
|
| 6. |
- Figlioli, Gisella, et al.
(författare)
-
Novel genetic variants in differentiated thyroid cancer and assessment of the cumulative risk.
- 2015
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- A genome-wide association study (GWAS) performed on a high-incidence Italian population followed by replications on low-incidence cohorts suggested a strong association of differentiated thyroid cancer (DTC) with single nucleotide polymorphisms (SNPs) at 9q22.33, 2q35, 20q11.22-q12 and 14q24.3. Moreover, six additional susceptibility loci were associated with the disease only among Italians. The present study had two aims, first to identify loci involved in DTC risk and then to assess the cumulative effect of the SNPs identified so far in the Italian population. The combined analysis of the previous GWAS and the present Italian study provided evidence of association with rs7935113 (GALNTL4, OR = 1.36, 95%CI 1.20-1.53, p-value = 7.41 × 10(-7)) and rs1203952 (FOXA2, OR = 1.29, 95%CI 1.16-1.44, p-value = 4.42 × 10(-6)). Experimental ENCODE and eQTL data suggested that both SNPs may influence the closest genes expression through a differential recruitment of transcription factors. The assessment of the cumulative risk of eleven SNPs showed that DTC risk increases with an increasing number of risk alleles (p-trend = 3.13 × 10(-47)). Nonetheless, only a small fraction (about 4% on the disease liability scale) of DTC is explained by these SNPs. These data are consistent with a polygenic model of DTC predisposition and highlight the importance of association studies in the discovery of the disease hereditability.
|
|
| 7. |
- Hess, Timo, et al.
(författare)
-
Dissecting the genetic heterogeneity of gastric cancer
- 2023
-
Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 92
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.
|
|
| 8. |
- Mahmoudpour, Seyed Hamidreza, et al.
(författare)
-
Chemotherapy-induced peripheral neuropathy : Evidence from genome-wide association studies and replication within multiple myeloma patients
- 2018
-
Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 18:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Based on the possible shared mechanisms of chemotherapy-induced peripheral neuropathy (CIPN) for different drugs, we aimed to aggregate results of all previously published genome-wide association studies (GWAS) on CIPN, and to replicate them within a cohort of multiple myeloma (MM) patients. Methods: Following a systematic literature search, data for CIPN associated single nucleotide polymorphisms (SNPs) with P-values<10-5 were extracted; these associations were investigated within a cohort of 983 German MM patients treated with bortezomib, thalidomide or vincristine. Cases were subjects that developed CIPN grade 2-4 while controls developed no or sub-clinical CIPN. Logistic regression with additive model was used. Results: In total, 9 GWASs were identified from the literature on CIPN caused by different drugs (4 paclitaxel, 2 bortezomib, 1 vincristine, 1 docetaxel, and 1 oxaliplatin). Data were extracted for 526 SNPs in 109 loci. One hundred fourty-eight patients in our study population were CIPN cases (102/646 bortezomib, 17/63 thalidomide and 29/274 vincristine). In total, 13 SNPs in 9 loci were replicated in our population (p-value< 0.05). The four smallest P-values relevant to the nerve function were 0.0006 for rs8014839 (close to the FBXO33 gene), 0.004 for rs4618330 (close to the INTU gene), 0.006 for rs1903216 (close to the BCL6 gene) and 0.03 for rs4687753 (close to the IL17RB gene). Conclusions: Replicated SNPs provide clues of the molecular mechanism of CIPN and can be strong candidates for further research aiming to predict the risk of CIPN in clinical practice, particularly rs8014839, rs4618330, rs1903216, and rs4687753, which showed relevance to the function of nervous system.
|
|
| 9. |
|
|
| 10. |
- Mitchell, Jonathan S., et al.
(författare)
-
Genome-wide association study identifies multiple susceptibility loci for multiple myeloma
- 2016
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P = 1.31 x 10(-8)), 6q21 (rs9372120, P = 9.09 x 10(-15)), 7q36.1 (rs7781265, P = 9.71 x 10(-9)), 8q24.21 (rs1948915, P = 4.20 x 10(-11)), 9p21.3 (rs2811710, P = 1.72 x 10(-13)), 10p12.1 (rs2790457, P = 1.77 x 10(-8)), 16q23.1 (rs7193541, P = 5.00 x 10(-12)) and 20q13.13 (rs6066835, P = 1.36 x 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.
|
|
