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1.
Int J Cancer ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33534179

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10-9 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism.

2.
J Am Board Fam Med ; 34(Suppl): S222-S224, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33622842

RESUMO

BACKGROUND: Since December 2019, the dramatic escalation in coronavirus (COVID-19) cases worldwide has had a significant impact on health care systems. Family physicians (FPs) have played a critical role in the coordination of care. MATERIALS AND METHODS: In April 2020, we performed an online prospective survey to assess the impact of the pandemic on FPs' practices. RESULTS: Three hundred FPs were included. Mean age was 53.6 ± 13.5 years. Before the pandemic, 60.2% reported >75 outpatient visits/week, which reduced down to an average of <20/week for 79.8% of FPs; 24.2% of FPs discontinued home visits, while for 94.7% of FPs there was a >50% increase in the number of telephone consultations. Concern related to the risk of contagion was elevated (≥3/5 in 74.6%) and even higher to the risk of infecting relatives and patients (≥3/5 in 93.3%). The majority of FPs (87%) supported the role of telemedicine in the near future. Satisfaction regarding the network with hospitals/COVID-19-dedicated wards received a score ≤2/5 in 46.9% of cases. CONCLUSIONS: The COVID-19 pandemic has had a significant impact on the working practices of FPs. A collaboration is needed with well-established networks between FPs and referral centers to provide new insights and opportunities to inform future working practices.

3.
Thyroid ; 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33308024

RESUMO

Background: Galectin-3 (LGALS3) is an important glycoprotein involved in the malignant transformation of thyrocytes acting in the extracellular matrix, cytoplasm, and nucleus where it regulates TTF-1 and TCF4 transcription factors. Within LGALS3 gene, a common single-nucleotide polymorphism (SNP) (c.191C>A, p.Pro64His; rs4644) encoding for the variant Proline to Histidine at codon 64 has been extensively studied. However, data on rs4644 in the context of thyroid cancer are lacking. Thus, the aim of the present work was to evaluate the role of the rs4644 SNP as risk factor for differentiated thyroid cancer (DTC) and to determine the effect on the transcriptome in thyrocytes. Methods: A case/control association study in 1223 controls and 1142 unrelated consecutive DTC patients was carried out to evaluate the association between rs4644-P64H and the risk of DTC. We used the nonmalignant cell line Nthy-Ori (rs4644-C/A) and the CRISPR/Cas9 technique to generate isogenic cells carrying either the rs4644-A/A or rs4644-C/C homozygosis. Then, the transcriptome of the derivative and unmodified parental cells was analyzed by RNA-seq. Genes differentially expressed were validated by quantitative reverse transcription PCR and further tested in the parental Nthy-Ori cells after LGALS3 gene silencing, to investigate whether the expression of target genes was dependent on galectin-3 levels. Results: rs4644 AA genotype was associated with a reduced risk of DTC (compared with CC, ORadj = 0.66; 95% confidence interval = 0.46-0.93; Pass = 0.02). We found that rs4644 affects galectin-3 as a transcriptional coregulator. Among 34 genes affected by rs4644, HES1, HSPA6, SPC24, and NHS were of particular interest since their expression was rs4644-dependent (CC>AA for the first and AA>CC for the others), also in 574 thyroid tissues of Genotype-Tissue Expression (GTEx) biobank. Moreover, the expression of these genes was regulated by LGALS3-silencing. Using the proximity ligation assay in Nthy-Ori cells, we found that the TTF-1 interaction was genotype dependent. Conclusions: Our data show that in thyroid, rs4644 is a trans-expression quantitative trait locus that can modify the transcriptional expression of downstream genes, through the modulation of TTF-1.

4.
Invest New Drugs ; 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33300108

RESUMO

Objectives Malignant pleural mesothelioma (MPM) is an occupational disease mainly due to asbestos exposure. Effective therapies for MPM are lacking, making this tumour type a fatal disease. Materials and Methods In order to meet this need and in view of a future "drug repositioning" approach, here we screened five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model, with a library of 1170 FDA-approved drugs. Results Among several potential compounds, we found that fludarabine (F-araA) and, to a lesser extent, risedronic acid (RIS) were cytotoxic in MPM cells, in comparison to the non-malignant Met-5A cells. In particular, F-araA reduced the proliferation and the colony formation ability of the MPM malignant cells, in comparison to the non-malignant control cells, as demonstrated by proliferation and colony formation assays, in addition to measurement of the phospho-ERK/total-ERK ratio. We have shown that the response to F-araA was not dependent upon the expression of DCK and NT5E enzymes, nor upon their functional polymorphisms (rs11544786 and rs2295890, respectively). Conclusion This drug repositioning screening approach has identified that F-araA could be therapeutically active against MPM cells, in addition to other tumour types, by inhibiting STAT1 expression and nucleic acids synthesis. Further experiments are required to fully investigate this.

5.
Carcinogenesis ; 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33319241

RESUMO

One of the principal mechanisms of chemotherapy resistance in highly frequent solid tumors like colorectal cancer (CRC) is the decreased activity of drug transport into tumor cells due to low expression of important membrane proteins, such as solute carrier (SLC) transporters. Sequence complementarity is a major determinant for target gene recognition by microRNAs (miRNAs). Single nucleotide polymorphisms (SNPs) in target sequences transcribed into messenger RNA may therefore alter miRNA binding to these regions by either creating a new site or destroying an existing one. miRSNPs may explain the modulation of expression levels in association with increased/decreased susceptibility to common diseases as well as in chemoresistance and the consequent interindividual variability in drug response. In the present study, we investigated whether miRSNPs in SLC transporter genes may modulate CRC susceptibility and patient's survival. Using an in silico approach for functional predictions, we analyzed twenty-six miRSNPs in nine SLC genes in a cohort of 1368 CRC cases and 698 controls from the Czech Republic. After correcting for multiple tests, we found several miRSNPs significantly associated with patient's survival. SNPs in SLCO3A1, SLC22A2, and SLC22A3 genes were defined as prognostic factors in the classification and regression tree analysis. In contrast, we did not observe any significant association between miRSNPs and CRC risk. To the best of our knowledge, this is the first study investigating miRSNPs potentially affecting miRNA binding to SLC transporter genes and their impact on CRC susceptibility or patient's prognosis.

6.
Front Genet ; 11: 975, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33014022

RESUMO

Soluble mesothelin-related peptide (SMRP) is a promising biomarker for malignant pleural mesothelioma (MPM), but several confounding factors can reduce SMRP-based test's accuracy. The identification of these confounders could improve the diagnostic performance of SMRP. In this study, we evaluated the sequence of 1,000 base pairs encompassing the minimal promoter region of the MSLN gene to identify expression quantitative trait loci (eQTL) that can affect SMRP. We assessed the association between four MSLN promoter variants and SMRP levels in a cohort of 72 MPM and 677 non-MPM subjects, and we carried out in vitro assays to investigate their functional role. Our results show that rs2235503 is an eQTL for MSLN associated with increased levels of SMRP in non-MPM subjects. Furthermore, we show that this polymorphic site affects the accuracy of SMRP, highlighting the importance of evaluating the individual's genetic background and giving novel insights to refine SMRP specificity as a diagnostic biomarker.

7.
J Transl Med ; 18(1): 341, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887638

RESUMO

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the pleura, mainly related to asbestos exposure. As in other solid tumors, malignant cells exhibit high glucose uptake and glycolytic rates with increased lactic acid efflux into the interstitial space. Lactate transport into and out of cells, crucial to maintaining intracellular pH homeostasis and glycolysis, is carried out by monocarboxylate transporters (MCTs) and the chaperone basigin (CD147). We set out to examine the clinical significance of basigin, MCT1 and MCT4 in the context of MPM and to evaluate their expression in relation to the evolution of the disease. METHODS: We used immunohistochemistry to measure the expression of basigin, MCT1 and MCT4 in a cohort of 135 individuals with MPM compared to a series of 15 non-MPM pleura specimens. Moreover, by Kaplan-Meier and Cox analyses we evaluated whether an expression over the average of these markers could be associated with the patients' overall survival (OS). RESULTS: We detected positive staining of basigin, MCT1, and MCT4 in most MPM specimens. In particular, MCT4 was always positive in malignant tissues but undetectable in the 4 normal pleural specimens incorporated within the tissue microarray. This was confirmed in the additional series of 15 normal pleural samples. Moreover, MCT4 expression was significantly associated with reduced OS. CONCLUSION: In this study, the tissue expression of basigin did not prove to be exploitable as a diagnostic or prognostic marker for MPM patients. The expression of MCT1 was not informative either, being tightly correlated with that of basigin. However, the expression of MCT4 showed promise as a diagnostic/therapeutic and prognostic biomarker.

8.
Semin Cancer Biol ; 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32818625

RESUMO

Pancreatic cancer (PC), particularly its most common form, pancreatic ductal adenocarcinoma (PDAC), is relatively rare but highly lethal. Knowledge about PC risk factors could in the long term contribute to early diagnosis and mortality reduction. We review the current status of research on germline genetic factors for PC risk. Genome-wide association studies (GWAS) successfully identified common loci convincingly associated with PC risk, an endeavor that is still ongoing. The function of only a handful of risk loci has being thoroughly characterized so far. Secondary analyses of existing GWAS data are being used to discover novel loci. GWAS data have also been used to study additional risk factors with a Mendelian randomization approach. Polygenic/multifactorial risk scores show much larger risks than individual variants, but their use for risk stratification in the population is not warranted yet. At the other end of the spectrum of inherited PC risk factors, rare high-penetrance variants co-segregating with the disease have been observed in familial cancer syndromes that include PC, or in families with multiple recurrence of PC alone. Rare variants predicted to have a deleterious effect on function are studied also with a case-control approach, by resequencing candidate genes or whole-exomes/whole-genomes. Telomere length and mitochondrial DNA copy number are useful additional DNA-based markers of PC susceptibility. The role of common variants in prognosis of PC patients has also been explored, albeit with more limited success than risk. Finally, genetics of pancreatic neuroendocrine tumors (PNET), a rarer and heterogeneous form of PC, is still understudied.

9.
Int J Mol Sci ; 21(14)2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32659970

RESUMO

For malignant pleural mesothelioma (MPM) novel therapeutic strategies are urgently needed. In a previous study, we identified 51 putative cancer genes over-expressed in MPM tissues and cell lines. Here, we deepened the study on nine of them (ASS1, EIF4G1, GALNT7, GLUT1, IGF2BP3 (IMP3), ITGA4, RAN, SOD1, and THBS2) to ascertain whether they are truly mesothelial cancer driver genes (CDGs) or genes overexpressed in an adaptive response to the tumoral progression ("passenger genes"). Through a fast siRNA-based screening, we evaluated the consequences of gene depletion on migration, proliferation, colony formation capabilities, and caspase activities of four MPM (Mero-14, Mero-25, IST-Mes2, and NCI-H28) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model. The depletion of EIF4G1 and RAN significantly reduced cell proliferation and colony formation and increased caspase activity. In particular, the findings for RAN resemble those observed for other types of cancer. Thus, we evaluated the in vitro effects of importazole (IPZ), a small molecule inhibitor of the interaction between RAN and importin-ß. We showed that IPZ could have effects similar to those observed following RAN gene silencing. We also found that primary cell lines from one out of three MPM patients were sensitive to IPZ. As EIF4G1 and RAN deserve further investigation with additional in vitro and in vivo studies, they emerged as promising CDGs, suggesting that their upregulation could play a role in mesothelial tumorigenesis and aggressiveness. Furthermore, present data propose the molecular pathways dependent on RAN as a putative pharmacological target for MPM patients in the view of a future personalized medicine.

10.
Health Serv Manage Res ; : 951484820928302, 2020 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-32475173

RESUMO

Inequalities in effective access to healthcare are present among countries and within the same country. Despite in Italy exist the principle of equity in access to health system, there are evidence of different access rates in the form of unequal waiting time within the country. Waiting times are an instruments to ration healthcare services dealing with resource scarsity. Theoretically, it is a fair tool because waiting times should depend only on health needs and not on the ability to pay. However, a growing literature has pointed out that belonging to a particular socioeconomic status leads to waiting times inequalities for healthcare services. Many countries have socioeconomic disparities among regions, and healthcare organizations need to take into account these differences. The increasing power of Regional Health Authorities in decentralized health systems, as in the case of Italy, has generated different organizational ways to provide health care, possibly leading to different access rates in the form of unequal waiting time within the country. This paper aims to understand if the administrative area (Regional Health Authorities) in charge of health services affects waiting times lowering or strengthening health care access inequalities. Using a series of logistic regression models, this work suggests the presence of two vectors: socioeconomic inequalities and regional inequalities. Health organizations need to implement different kinds of answers for each vectors of inequalities.

11.
Dig Liver Dis ; 52(10): 1178-1187, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32425734

RESUMO

The pandemic diffusion of the SARS-CoV-2 infection throughout the world required measures to prevent and strategies to control the infection, as well as the reallocation of the hospital structures in order to take care of an increased number of infected patients. Endoscopy Units should be able to perform endoscopic procedures on COVID-19 infected as well as on noninfected patients. The aim of this manuscript is to propose a model for a fast reorganization of the endoscopy department environment in order to safely perform endoscopic procedures in this Pandemic COVID-19 scenario, according to the current advices given by the Scientific Societies.


Assuntos
Infecções por Coronavirus , Endoscopia do Sistema Digestório/métodos , Planejamento Ambiental , Gastroenterologia/organização & administração , Unidades Hospitalares/organização & administração , Controle de Infecções/métodos , Pandemias , Pneumonia Viral , Betacoronavirus , Humanos , Equipamento de Proteção Individual
12.
Thyroid ; 30(11): 1579-1588, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32228166

RESUMO

Background: Sporadic medullary thyroid carcinoma (sMTC) is an uncommon neoplasia arising from the calcitonin-producing parafollicular cells of the thyroid. Previous studies evaluated whether single nucleotide polymorphisms (SNPs) within RET (a pivotal proto-oncogene for this disease) are associated with the risk for developing sMTC, but the results are inconclusive. Methods: In this work, we evaluated the association of RET-SNPs c.74-126G>T (rs2565206), p.Gly691Ser (rs1799939, G>A), p.Leu769 = (rs1800861, G>T), p.Ser836 = (rs1800862, C>T), and p.Ser904 = (rs1800863, C>G) (listed in the order of their chromosomal location) with sMTC. This is one of the largest case-control association studies carried out on sMTC, including 585 sMTC cases (negative for germline mutations within RET), 1529 patients affected by sporadic nonmedullary thyroid carcinoma (sNMTC), and 989 healthy controls, from central and southern Italy and collected in the period 2000-2017. Results: sNMTC patients showed similar genotype and allele frequencies compared with healthy controls. On the other hand, among sMTC patients, the T-allele of p.Leu769 = was less frequent (OR = 0.70 [CI 0.58-0.84], p = 1.9 × 10-4) and rare homozygotes TT showed an OR = 0.32 ([CI 0.17-0.60], p = 2.3 × 10-4). Moreover, a statistically significant excess of the haplotype 2 (characterized by the alleles T-G-G-C-C of the listed SNPs) was observed (p = 3.9 × 10-3). The SNPs were not associated with the expression of RET mRNA, that is, they did not exert an effect in cis as quantitative trait locus (cis-eQTL). However, a strong eQTL association was found for p.Leu769 = and the neighboring gene CSGALNACT2 (p = 9.3 × 10-50; effect-size = -0.65), whose function in cancer is unknown. Conclusions: This study shows that specific RET haplotypes, in particular haplotype 2 and the T-allele of p.Leu769 = , are associated with a reduced risk of sMTC in Italians.

13.
Int J Cancer ; 147(8): 2065-2074, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32270874

RESUMO

Early onset pancreatic cancer (EOPC) is a rare disease with a very high mortality rate. Almost nothing is known on the genetic susceptibility of EOPC, therefore, we performed a genome-wide association study (GWAS) to identify novel genetic variants specific for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) at younger ages. In the first phase, conducted on 821 cases with age of onset ≤60 years, of whom 198 with age of onset ≤50, and 3227 controls from PanScan I-II, we observed four SNPs (rs7155613, rs2328991, rs4891017 and rs12610094) showing an association with EOPC risk (P < 1 × 10-4 ). We replicated these SNPs in the PANcreatic Disease ReseArch (PANDoRA) consortium and used additional in silico data from PanScan III and PanC4. Among these four variants rs2328991 was significant in an independent set of 855 cases with age of onset ≤60 years, of whom 265 with age of onset ≤50, and 4142 controls from the PANDoRA consortium while in the in silico data, we observed no statistically significant association. However, the resulting meta-analysis supported the association (P = 1.15 × 10-4 ). In conclusion, we propose a novel variant rs2328991 to be involved in EOPC risk. Even though it was not possible to find a mechanistic link between the variant and the function, the association is supported by a solid statistical significance obtained in the largest study on EOPC genetics present so far in the literature.

15.
Neurosci Lett ; 720: 134754, 2020 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-31945448

RESUMO

BACKGROUND: Recent evidence suggests that psychiatric symptoms share a common genetic liability across diagnostic categories. The present study investigated the effects of variants within previously identified relevant genes on specific symptom clusters, independently from the diagnosis. METHODS: 1550 subjects affected by Schizophrenia (SCZ), Major Depressive Disorder or Bipolar Disorder were included. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Hamilton Depression Rating Scale (HDRS). Principal component analysis and a further clinical refinement were used to define symptom clusters. Clusters scores were tested for association with 46 genetic variants within nine genes previously linked to one or more major psychiatric disorders by large genome wide association studies (ANK3, CACNA1C, CACNB2, FKBP5, FZD3, GRM7, ITIH3, SYNE1, TCF4). Exploratory analyses were performed in each disorder separately to further elucidate the SNPs effects. RESULTS: five PANSS clusters (Negative; Impulsiveness; Cognitive; Psychotic; Depressive) and four HDRS clusters (Core Depressive; Somatic; Psychotic-like; Insomnia) were identified. CACNA1C rs11615998 was associated with HDRS Psychotic cluster in the whole sample. In the SCZ sample, CACNA1C rs11062296 was associated with PANSS Impulsiveness cluster and CACNA1C rs2238062 was associated with PANSS negative cluster. DISCUSSION: CACNA1C rs11615998 was associated with psychotic symptoms (C-allele carriers have decreased psychotic-risk) independently from the diagnosis, in line with the evidence of a cross disorder effect of many risk variants. This gene was previously associated with SCZ and cross-disorder liability to psychiatric disorders. Our findings confirmed that deep phenotyping is pivotal to clarify the role of genetic variants on symptoms patterns.

17.
Mol Biol Rep ; 47(1): 191-200, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31595439

RESUMO

Serotoninergic system is one of the most important neurotransmission systems investigated in the field of psychiatry. Extensive evidence reveals how alterations of this system, and especially of the SLC6A4 gene, may be associated with psychiatric disorders. In this study we aimed to evaluate the pleiotropic nature of SLC6A4 alterations and their association with the overall risk of brain diseases rather than disorder-specific. SLC6A4 variants, namely 5HTTLPR, STin2, rs2066713, rs25531, rs4251417, rs6354 and rs7224199 were investigated in 4 independent cohorts of subjects with specific psychiatric disorders, including Alcohol dependence disorder (ALC), Alzheimer disease (ALZ), Schizophrenia (SCZ) and Bipolar disorder (BPD). Other variables (biochemical parameters and Psychiatric scales scores) were also tested for association. SLC6A4 polymorphisms are not associated with the risk of developing major psychiatric disorders (SCZ and BPD); however some signals were detected in ALC (HTTLPR pd = 9.25 × 10-03, pr = 7.24 × 10-03; rs2066713 pd = 6.35 × 10-08; rs25531 pd = 2.95 × 10-02; rs4251417 pd = 2.46 × 10-03), and ALZ (rs6354 pr = 1.22 × 10-02; rs7224199 pd = 1.00 × 10-08, pr = 2.65 × 10-02) cohorts. Some associations were also observed on exploratory analyses. Our findings did not reveal any major influence on SCZ and BPD development; On the other hand, some alteration of the SLC6A4 sequence were associated with an increased risk of ALC and ALZ disorders, suggesting common pathways. The results of this study should be carefully interpreted since it suffers of some inherent limitations (e.g. cohort size, slight ethnic heterogeneity). Further analyses may provide better detail on the molecular processes behind SLC6A4 alterations.


Assuntos
Alcoolismo/genética , Doença de Alzheimer/genética , Transtornos Mentais/genética , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alcoolismo/complicações , Alcoolismo/epidemiologia , Doença de Alzheimer/complicações , Doença de Alzheimer/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Comorbidade , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Grécia/epidemiologia , Humanos , Itália/epidemiologia , Desequilíbrio de Ligação , Transtornos Mentais/epidemiologia , Pessoa de Meia-Idade , Adulto Jovem
19.
Eur J Health Econ ; 21(3): 381-396, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31811513

RESUMO

Health inequalities exist between nations, regions, and even smaller units. In societies where social and economic structures change rapidly and continuously, analysis of health socioeconomic determinants plays a fundamental role to provide proper policy answers. This study aims to measure accurately two different conceptions of deprivation by developing two different indexes using non-compensatory among sub-indicators aggregation methods. The proposed indicators are compared with premature mortality to verify deprivation's effect on health status. The results show that materially deprived areas are not necessarily socially deprived and vice versa. Material deprivation has a positive statistical co-graduation with premature mortality, while social deprivation has no association with premature mortality.

20.
Int J Cancer ; 146(2): 363-372, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31209889

RESUMO

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.


Assuntos
Neoplasias do Colo/genética , Reparo do DNA/genética , Predisposição Genética para Doença , Neoplasias Retais/genética , Adulto , Idoso , Variação Biológica da População/genética , Carcinogênese/genética , Estudos de Casos e Controles , Colo/patologia , Neoplasias do Colo/patologia , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Retais/patologia , Reto/patologia , Sistema de Registros/estatística & dados numéricos , Medição de Risco , Proteínas Supressoras de Tumor/genética , Adulto Jovem
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