| 1. |
- Cipollini, Monica, et al.
(författare)
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Polymorphisms within base and nucleotide excision repair pathways and risk of differentiated thyroid carcinoma
- 2016
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Ingår i: DNA Repair. - : Elsevier BV. - 1568-7864. ; 41, s. 27-31
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Tidskriftsartikel (refereegranskat)abstract
- The thyrocytes are exposed to high levels of oxidative stress which could induce DNA damages. Base excision repair (BER) is one of the principal mechanisms of defense against oxidative DNA damage, however recent evidences suggest that also nucleotide excision repair (NER) could be involved. The aim of present work was to identify novel differentiated thyroid cancer (DTC) risk variants in BER and NER genes. For this purpose, the most strongly associated SNPs within NER and BER genes found in our previous GWAS on DTC were selected and replicated in an independent series of samples for a new case-control study. Although a positive signal was detected at the nominal level of 0.05 for rs7689099 (encoding for an aminoacid change proline to arginine at codon 117 within NEIL3), none of the considered SNPs (i.e. rs7990340 and rs690860 within RFC3, rs3744767 and rs1131636 within RPA1, rs16962916 and rs3136166 in ERCC4, and rs17739370 and rs7689099 in NEIL3) was associated with the risk of DTC when the correction of multiple testing was applied. In conclusion, a role of NER and BER pathways was evoked in the susceptibility to DTC. However, this seemed to be limited to few polymorphic genes and the overall effect size appeared weak.
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| 2. |
- Zhang, Mingfeng, et al.
(författare)
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Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:41, s. 66328-66343
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10(-15)), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10(-9)) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10(-8)). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10(-8)). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10(-4)-2.0x10(-3)). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
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| 3. |
- Campo, Chiara, et al.
(författare)
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Inherited variants in genes somatically mutated in thyroid cancer
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:4
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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.
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| 4. |
- Figlioli, Gisella, et al.
(författare)
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A comprehensive meta-analysis of case-control association studies to evaluate polymorphisms associated with the risk of differentiated thyroid carcinoma
- 2016
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Ingår i: Cancer Epidemiology Biomarkers & Prevention. - 1055-9965. ; 25:4, s. 700-713
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Tidskriftsartikel (refereegranskat)abstract
- Background: Linkage analyses and association studies suggested that inherited genetic variations play a role in the development of differentiated thyroid carcinoma (DTC). Methods: We combined the results from a genome-wide association study (GWAS) performed by our group and frompublished studies onDTC. With a first approach, we evaluated whether a SNP published as associated with the risk of DTC could replicate in our GWAS (using FDR as adjustment for multiple comparisons). With the second approach, meta-analyses were performed between literature and GWAS when both sources suggested an association, increasing the statistical power of the analysis. Results: rs1799814 (CYP1A1), rs1121980 (FTO), and 3 SNPs within 9q22 (rs965513, rs7048394, and rs894673) replicated the associations described in the literature. In addition, the meta-analyses between literature and GWAS revealed 10 more SNPs within 9q22, six within FTO, two within SOD1, and single variations within HUS1, WDR3, UGT2B7, ALOX12, TICAM1, ATG16L1, HDAC4, PIK3CA, SULF1, IL11RA, VEGFA, and 1p31.3, 2q35, 8p12, and 14q13. Conclusion: This analysis confirmed several published risk loci that could be involved in DTC predisposition. Impact: These findings provide evidence for the role of germline variants in DTC etiology and are consistent with a polygenic model of the disease.
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| 5. |
- Figlioli, Gisella, et al.
(författare)
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Novel genetic variants in differentiated thyroid cancer and assessment of the cumulative risk.
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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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.
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| 6. |
- Figueroa, Jonine D., et al.
(författare)
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Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry
- 2016
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 25:6, s. 1203-1214
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Tidskriftsartikel (refereegranskat)abstract
- Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10−6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10−11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10−10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region—the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case–case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
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| 7. |
- Haycock, Philip C., et al.
(författare)
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Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study
- 2017
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Ingår i: JAMA Oncology. - : American Medical Association. - 2374-2437 .- 2374-2445. ; 3:5, s. 636-651
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [ 95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [ 95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [ 95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [ 95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [ 95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
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| 8. |
- Hung, Rayjean J., et al.
(författare)
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Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5(p)15.33 TERT-CLPTM1Ll Region
- 2019
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Ingår i: Journal of Thoracic Oncology. - : ELSEVIER SCIENCE INC. - 1556-0864 .- 1556-1380. ; 14:8, s. 1360-1369
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 x 10(-16)), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 x 10(-16)), and rs4975616 OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 x 10(-14)). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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| 9. |
- Klein, Alison P., et al.
(författare)
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Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer
- 2018
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 x 10(-8)). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PAN-DoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 x 10(-14)), rs2941471 at 8q21.11 (HNF4G, P = 6.60 x 10(-10)), rs4795218 at 17q12 (HNF1B, P = 1.32 x 10(-8)), and rs1517037 at 18q21.32 (GRP, P = 3.28 x 10(-8)). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.
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| 10. |
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