Recognized clinical risk factors for progression (emergency presentation, poorly differentiated tumor, depth of tumor invasion, and adjacent organ involvement) are insufficient to identify those ...patients with stage II CRC at higher risk of disease progression 4,5. ...a meta-analysis aimed to assess the predictive ability of these signatures revealed that although gene expression signatures may be associated with prognosis, their ability to accurately predict patients’ risk of progression was limited, probably due to the molecular heterogeneity of tumors 7. ...the identification of new biomarkers to inform clinical decision-making for adjuvant chemotherapy is needed 8. Methods Patients and samples The discovery dataset (named ICO/CLX) included a previously described set of 100 patients with colon cancer diagnosed at stage II and MSS paired normal-tumor samples (Colonomics study, “CLX”: www.colonomics.org; NCBI BioProject PRJNA188510). Raw sequence data were filtered based on the TCRβ V, D, and J gene definitions provided by the international ImMunoGeneTics information system (IMGT) database and binned using a modified nearest-neighbor algorithm to merge closely related sequences and remove both PCR and sequencing errors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Somatic copy number aberrations (CNAs) are common acquired changes in cancer cells having an important role in the progression of colon cancer (colorectal cancer, CRC). This study aimed to perform a ...characterisation of CNA and their impact in gene expression.
Copy number aberrations were inferred from SNP array data in a series of 99 CRC. Copy number aberration events were calculated and used to assess the association between copy number dosage, clinical and molecular characteristics of the tumours, and gene expression changes. All analyses were adjusted for the quantity of stroma in each sample, which was inferred from gene expression data.
High heterogeneity among samples was observed; the proportion of altered genome ranged between 0.04 and 26.6%. Recurrent CNA regions with gains were frequent in chromosomes 7p, 8q, 13q, and 20, whereas 8p, 17p, and 18 cumulated losses. A significant positive correlation was observed between the number of somatic mutations and total CNA (Spearman's r=0.42, P=0.006). Approximately 37% of genes located in CNA regions changed their level of expression and the average partial correlation (adjusted for stromal content) with copy number was 0.54 (interquartile range 0.20 to 0.81). Altered genes showed enrichment in pathways relevant for CRC. Tumours classified as CMS2 and CMS4 by the consensus molecular subtyping showed higher frequency of CNA. Losses of one small region in 1p36.33, with gene CDK11B, were associated with poor prognosis. More than 66% of the recurrent CNA were validated in the The Cancer Genome Atlas (TCGA) data when analysed with the same procedure. Furthermore, 79% of the genes with altered expression in our data were validated in the TCGA.
Although CNA are frequent events in microsatellite stable CRC, few focal recurrent regions were found. These aberrations have strong effects on gene expression and contribute to deregulate relevant cancer pathways. Owing to the diploid nature of stromal cells, it is important to consider the purity of tumour samples to accurately calculate CNA events in CRC.
The cancer-predisposing syndrome caused by biallelic mutations in NTHL1 may not be a solely colorectal cancer (CRC) and polyposis syndrome but rather a multi-tumor recessive disease. The presence of ...≤10 adenomas in several mutation carriers suggests a possible causal role of NTHL1 in hereditary or early-onset nonpolyposis CRC. The involvement of NTHL1 in serrated/hyperplastic polyposis remains unexplored. The aim of our study is to elucidate the role of NTHL1 in the predisposition to personal or familial history of multiple tumor types, familial/early-onset nonpolyposis CRC, and serrated polyposis. NTHL1 mutational screening was performed in 312 cancer patients with personal or family history of multiple tumor types, 488 with hereditary nonpolyposis CRC, and 96 with serrated/hyperplastic polyposis. While no biallelic mutation carriers were identified in patients with personal and/or family history of multiple tumor types or with serrated polyposis, one was identified among the 488 nonpolyposis CRC patients. The carrier of c.268C>T (p.Q90*) and 550-1G>A was diagnosed with CRC and meningioma at ages 37 and 45 respectively, being reclassified as attenuated adenomatous polyposis after the cumulative detection of 26 adenomas. Our findings suggest that biallelic mutations in NTHL1 rarely cause CRC, a personal/familial multi-tumor history, or serrated polyposis, in absence of adenomas.
Genome-wide association studies on colorectal cancer have identified more than 60 susceptibility loci, but for most of them there is no clear knowledge of functionality or the underlying gene ...responsible for the risk modification. Expression quantitative trail loci (eQTL) may provide functional information for such single nucleotide polymorphisms (SNPs).
We have performed detailed eQTL analysis specific for colon tissue on a series of 97 colon tumours, their paired adjacent normal mucosa and 47 colon mucosa samples donated by healthy individuals. R package MatrixEQTL was used to search for genome-wide cis-eQTL and trans-eQTL fitting linear models adjusted for age, gender and tissue type to rank transformed expression data.
The cis-eQTL analyses has revealed 29,073 SNP-gene associations with permutation-adjusted P-values < 0.01. These correspond to 363 unique genes. The trans-eQTL analysis identified 10,665 significant SNP-gene associations, most of them in the same chromosome, further than 1 Mb of the gene. We provide a web tool to search for specific SNPs or genes. The tool calculates Pearson or Spearman correlation, and allows to select tissue type for analysis. Data and plots can be exported.
This resource should be useful to prioritise SNPs for further functional studies and to identify relevant genes behind identified loci.
Gain insight about the role of DNA methylation in the malignant growth of colon cancer.
Methylation and gene expression from 90 adjacent-tumor paired tissues and 48 healthy tissues were analyzed. ...Tumor genes whose change in expression was explained by changes in methylation were identified using linear models adjusted for tumor stromal content.
No differences in methylation were found between adjacent and healthy tissues, but clear differences were found between adjacent and tumor samples. We identified hypermethylated CpG islands located in promoter regions that drive differential gene expression of transcription factors and their target genes.
Changes in methylation of a few genes provoke important changes in gene expression, by expanding the signal through transcription activation/repression.
Colorectal cancer (CRC) screening of the average risk population is only indicated according to age. We aim to elaborate a model to stratify the risk of CRC by incorporating environmental data and ...single nucleotide polymorphisms (SNP). The MCC-Spain case-control study included 1336 CRC cases and 2744 controls. Subjects were interviewed on lifestyle factors, family and medical history. Twenty-one CRC susceptibility SNPs were genotyped. The environmental risk model, which included alcohol consumption, obesity, physical activity, red meat and vegetable consumption, and nonsteroidal anti-inflammatory drug use, contributed to CRC with an average per factor OR of 1.36 (95% CI 1.27 to 1.45). Family history of CRC contributed an OR of 2.25 (95% CI 1.87 to 2.72), and each additional SNP contributed an OR of 1.07 (95% CI 1.04 to 1.10). The risk of subjects with more than 25 risk alleles (5
quintile) was 82% higher (OR 1.82, 95% CI 1.11 to 2.98) than subjects with less than 19 alleles (1
quintile). This risk model, with an AUROC curve of 0.63 (95% CI 0.60 to 0.66), could be useful to stratify individuals. Environmental factors had more weight than the genetic score, which should be considered to encourage patients to achieve a healthier lifestyle.
To explore the association of colorectal cancer with environmental solar radiation and sun exposure behavior, considering phenotypic variables (eye color, hair color and skin phenotype), dietary ...intake of vitamin D and calcium, and socio-demographic factors.
Multicenter population-based frequency matched case-control study in Spain (MCC-Spain), with 2140 CRC cases and 3950 controls.
Data were obtained through personal interviews using a structured epidemiological questionnaire that included socio-demographic data, residential history, environmental exposures, behavior, phenotypic and dietary information. An environmental-lifetime sun exposure score was constructed combining residential history and average daily solar radiation, direct and diffuse. Logistic regression was used to explore the association between different variables. A structural equation model was used to verify the associations of the conceptual model.
We found a lower risk of CRC in subjects frequently exposed to sunlight during the previous summer and skin burning due to sun exposure. No association was observed in relation to the residential solar radiation scores. Subjects with light eye or light hair colors had a lower risk of CRC that those with darker colors. Dietary calcium and vitamin D were also protective factors, but not in the multivariate model. The structural equation model analysis suggested that higher sun exposure was associated with a decreased risk of CRC, as well as dietary intake of calcium and vitamin D, and these factors are correlated among themselves and with environmental solar radiation and skin phenotypes.
The results agree with previous observations that sun exposure, dietary vitamin D and calcium intake, and serum 25(OH)D concentration reduce the risk of CRC and indicate that these factors may be relevant for cancer prevention.
•Sunlight, dietary intake of vitamin D and calcium were associated with a reduced risk of colorectal cancer•Risk of CRC was higher for individuals with dark hair or eyes, though these effects could be related to sun exposure habits•Our model indicates that vitamin D and calcium, sun exposure and skin phenotype, coordinately contribute to CRC prevention•Weaker associations were observed in women, possible related to differential adiposity that influence vitamin D availability
The evidence on the relationship between breast cancer and different types of antihypertensive drugs taken for at least 5 years is limited and inconsistent. Furthermore, the debate has recently been ...fueled again with new data reporting an increased risk of breast cancer among women with a long history of use of antihypertensive drugs compared with nonusers.
In this case-control study, we report the antihypertensive drugs-breast cancer relationship in 1,736 breast cancer cases and 1,895 healthy controls; results are reported stratifying by the women's characteristics (i.e., menopausal status or body mass index category) tumor characteristics and length of use of antihypertensive drugs.
The relationship among breast cancer and use of calcium channel blockers (CCB) for 5 or more years had odds ratio (OR) = 1.77 (95% CI, 0.99 to 3.17). Stratifying by BMI, the OR increased significantly in the group with BMI ≥ 25 (OR 2.54, 95% CI, 1.24 to 5.22). CCBs were even more strongly associated with more aggressive tumors, (OR for invasive tumors = 1.96, 95% CI = 1.09 to 3.53; OR for non ductal cancers = 3.97, 95% CI = 1.73 to 9.05; OR for Erbb2+ cancer = 2.97, 95% CI: 1.20 to 7.32). On the other hand, premenopausal women were the only group in which angiotensin II receptor blockers may be associated with breast cancer (OR = 4.27, 95% CI = 1.32 to 13.84) but this could not be identified with any type or stage. Use of angiotensin-converting-enzyme inhibitors, beta blockers and diuretics were not associated with risk.
In this large population-based study we found that long term use of calcium channel blockers is associated with some subtypes of breast cancer (and with breast cancer in overweight women).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BackgroundOnly certain disseminated cells are able to grow in secondary organs to create a metastatic tumor. Under the hypothesis that the immune microenvironment of the host tissue may play an ...important role in this process, we have categorized metastatic samples based on their immune features.MethodsGene expression data of metastatic samples (n=374) from four secondary sites (brain, bone, liver and lung) were used to characterize samples based on their immune and stromal infiltration using gene signatures and cell quantification tools. A clustering analysis was done that separated metastatic samples into three different immune categories: high, medium and low.ResultsSignificant differences were found between the immune profiles of samples metastasizing in distinct organs. Metastases in lung showed a higher immunogenic score than metastases in brain, liver or bone, regardless of their primary site of origin. Also, they preferentially clustered in the high immune group. Samples in this cluster exhibited a clear inflammatory phenotype, higher levels of immune infiltrate, overexpression of programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) pathways and upregulation of genes predicting clinical response to programmed cell death protein 1 (PD-1) blockade (T-cell inflammatory signature). A decision tree algorithm was used to select CD74 as a biomarker that identify samples belonging to this high-immune subtype of metastases, having specificity of 0.96 and sensitivity of 1.ConclusionsWe have found a group of lung-enriched metastases showing an inflammatory phenotype susceptible to be treated with immunotherapy.
Chronic inflammation is an important factor in colorectal carcinogenesis. However, evidence on the effect of pro-inflammatory and anti-inflammatory foods and nutrients is scarce. Moreover, there are ...few studies focusing on diet-gene interactions on inflammation and colorectal cancer (CRC). This study was designed to investigate the association between the novel dietary inflammatory index (DII) and CRC and its potential interaction with polymorphisms in inflammatory genes. Data from the Bellvitge Colorectal Cancer Study, a case-control study (424 cases with incident colorectal cancer and 401 hospital-based controls), were used. The DII score for each participant was obtained by multiplying intakes of dietary components from a validated dietary history questionnaire by literature-based dietary inflammatory weights that reflected the inflammatory potential of components. Data from four important single nucleotide polymorphisms located in genes thought to be important in inflammation-associated CRC: i.e., interleukin (IL)-4, IL-6, IL-8, and peroxisome proliferator-activated receptor-γ (PPARG) were analyzed. A direct association was observed between DII score and CRC risk (ORQ4 vs. Q1 1.65, 95 % CI 1.05-2.60, and P trend 0.011). A stronger association was found with colon cancer risk (ORQ4 vs. Q1 2.24, 95 % CI 1.33-3.77, and P trend 0.002) than rectal cancer risk (ORQ4 vs. Q1 1.12, 95 % CI 0.61-2.06, and P trend 0.37). DII score was inversely correlated with SNP rs2243250 in IL-4 among controls, and an interaction was observed with CRC risk. Neither correlation nor interaction was detected for other inflammatory genes. Overall, high-DII diets are associated with increased risk of CRC, particularly for colon cancer, suggesting that dietary-mediated inflammation plays an important role in colorectal carcinogenesis.
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