The molecular basis of colorectal cancer (CRC) can guide patient prognosis and therapy. In Brazil, knowledge on the CRC mutation landscape is limited. Here, we investigated the mutation profile of ...150 cancer-related genes by next-generation sequencing and associated with microsatellite instability (MSI) and genetic ancestry in a series of 91 Brazilian CRC patients. Driver mutations were found in the APC (71.4%), TP53 (56.0%), KRAS (52.7%), PIK3CA (15.4%) and FBXW7 (10.9%) genes. Overall, genes in the MAPK/ERK, PIK3/AKT, NOTCH and receptor tyrosine kinase signaling pathways were mutated in 68.0%, 23.1%, 16.5%, and 15.3% of patients, respectively. MSI was found in 13.3% of tumors, most of which were proximal (52.4%, P< 0.001) and had a high mutation burden. European genetic ancestry was predominant (median of 83.1%), followed by Native American (4.1%), Asian (3.4%) and African (3.2%). NF1 and BRAF mutations were associated with African ancestry, while TP53 and PIK3CA mutations were inversely correlated with Native American ancestry. Our study suggests that Brazilian CRC patients exhibit a mutation profile similar to other populations and identify the most frequently mutated genes, which could be useful in future target therapies and molecular cancer screening strategies.
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Fecal immunochemical tests (FITs) are sensitive and specific for detecting colorectal cancer (CRC), but their diagnostic accuracy (DA) in bleed-positive (CRAb+) and bleed-negative colorectal adenomas ...(CRAb-) has been rarely tested.
A total of n=506 patients were included in the study, each collecting 3 consecutive stool samples for analysis. The stool samples were analyzed by the ColonView FIT (CV) and Hemoccult SENSA tests. A total of 484/5,090 (9.5%) patients returned all 3 samples and were subjected to final analysis. Hierarchical summary receiver operating characteristic (HSROC) analysis with different cut-offs for hemoglobin/haptoglobin (Hb and Hb/Hp) complex was performed to assess the DA of CV.
In the HSROC analysis, the AUC values were as follows: i) bleed-positive adenoma patients by visual analysis mode (VA), AUC=0.566, ii) bleed-positive adenoma patients by automatic analysis mode (AA), AUC=0.546, iii) bleed-negative adenoma patients by VA, AUC=0.534 and iv) bleed-negative adenoma patients by AA, AUC=0.589: In roccomp analysis, there were significant differences in AUC values between iii) and iv) p=0.045.
When stratified by the 'blood in stool' (as b+ or b- endpoint), the DA of the CV test is quite similar for CRAb+ and CRAb-. However, of the two modes (VA/AA) of the CV test, the AA reading gives a slightly higher DA both CRAb+ and CRAb-.
The present study compared the accuracy of ColonView (CV) quick test in detecting proximal versus distal colorectal cancer (CRC). A traditional guaiac-based fecal occult blood test (gFOBT) (Hemoccult ...SENSA) was used as a reference.
A cohort of 368 colonoscopy-referral patients were asked to collect 3 consecutive fecal samples, to be analyzed by both assays (CV, SENSA). Receiver operating characteristic (ROC) analysis was used to find the optimal cut-off values for both Hb and Hb/Hp of the CV test. Summary hierarchical ROC (HSROC) curves were used to visualize the pooled overall accuracy of visually analysed (VA) and automatically analyzed (AA) reading modes in proximal and distal CRC detection.
The overall specificity (Sp) of the AA reading mode for the proximal CRC and distal CRC endpoint was 73% and 76%, respectively. For proximal CRC, the two most sensitive AA tests showed 90% sensitivity (Se), while for distal CRC, the two most sensitive AA tests showed 100% Se. In the HSROC analysis, the AUC values were as follows: i) VA in proximal CRC: 0.765, ii) AA in proximal CRC: 0.878, iii) VA in distal CRC: 0.955 and iv) AA in distal CRC: 0.961. In roccomp analysis, AUC values were significantly different in: VA vs. AA in proximal CRC p=0.009; VA in proximal vs. VA in distal CRC p<0.0001; VA in proximal vs. AA in distal CRC p<0.0001; AA in proximal vs. VA in distal CRC p=0.021; AA in proximal CRC vs. AA in distal CRC p=0.006.
The applicability of the CV test (a new-generation FIT) in CRC screening was confirmed. The AA reading was superior to VA (or SENSA) in its diagnostic accuracy in detecting proximal CRC patients. Distal CRCs were more accurately detected than proximal CRCs by both reading modes.
Colorectal cancer (CRC) is one of the most frequent and deadly neoplasms worldwide. Genetic factors, lifestyle habits, and inflammation are important risk factors associated with CRC development. In ...recent years, growing evidence has supporting the significant role of the intestinal microbiome in CRC carcinogenesis. Disturbances in the healthy microbial balance, known as dysbiosis, are frequently observed in these patients. Pathogenic microorganisms that induce intestinal dysbiosis have become an important target to determine the role of bacterial infection in tumorigenesis. Interestingly, the presence of different bacterial strains, such as Fusobacterium nucleatum, has been detected in tissue and stool from patients with CRC and associated with substantial clinical and molecular features, as well as with patient therapy response. Therefore, understanding how the presence and levels of F. nucleatumstrains in the gut affect the risk of CRC onset and progression may inform suitable candidates for interventions focused on modulation of this bacteria. Here we review new insights into the role of gut microbiota in CRC carcinogenesis and the clinical utility of using the detection of F. nucleatum in different settings such as screening, prognosis, and microbiota modulation as a means to prevent cancer, augment therapies, and reduce adverse effects of treatment.
Serrated pathway in colorectal carcinogenesis Yamane, Letícia; Scapulatempo-Neto, Cristovam; Reis, Rui Manuel ...
World journal of gastroenterology,
03/2014, Volume:
20, Issue:
10
Journal Article
Open access
Serrated adenocarcinoma is a recently described subset of colorectal cancer(CRC),which account for about10%of all CRCs and follows an alternative pathway in which serrated polyps replace the ...traditional adenoma as the precursor lesion to CRC.Serrated polyps form a heterogeneous group of colorectal lesions that includes hyperplastic polyps(HPs),sessile serrated adenoma(SSA),traditional serrated adenoma(TSA)and mixed polyps.HPs are the most common serrated polyp followed by SSA and TSA.This distinct histogenesis is believed to have a major influence in prevention strategies,patient prognosis and therapeutic impact.Genetically,serrated polyps exhibited also a distinct pattern,with KRAS and BRAF having an important contribution to its development.Two other molecular changes that have been implicated in the serrated pathway include microsatellite instability and the CpG island methylator phenotype.In the present review we will address the current knowledge of serrated polyps,clinical pathological features and will update the most recent findings of its molecular pathways.The understanding of their biology and malignancy potential is imperative to implement a surveillance approach in order to prevent colorectal cancer development.
Microbial diversity has been pointed out as a major factor in the development and progression of colorectal cancer (CRC). We sought to explore the richness and abundance of the microbial community of ...a series of colorectal tumor samples treated at Barretos Cancer Hospital, Brazil, through 16S rRNA sequencing. The presence and the impact of
Fusobacterium nucleatum
(
Fn
) DNA in CRC prognosis was further evaluated by qPCR in a series of 152 CRC cases. An enrichment for potentially oncogenic bacteria in CRC was observed, with
Fusobacterium
being the most abundant genus in the tumor tissue. In the validation dataset,
Fn
was detected in 35/152 (23.0%) of fresh-frozen tumor samples and in 6/57 (10.5%) of paired normal adjacent tissue, with higher levels in the tumor (
p
= 0.0033).
Fn
DNA in the tumor tissue was significantly associated with proximal tumors (
p
= 0.001), higher depth of invasion (
p
= 0.014), higher clinical stages (
p
= 0.033), poor differentiation (
p
= 0.011), MSI-positive status (
p
< 0.0001), BRAF mutated tumors (
p
< 0.0001), and the loss of expression of mismatch-repair proteins MLH1 (
p
< 0.0001), MSH2 (
p
= 0.003), and PMS2 (
p
< 0.0001). Moreover, the presence of
Fn
DNA in CRC tissue was also associated with a worse patient cancer-specific survival (69.9 vs. 82.2% in 5 years;
p
= 0.028) and overall survival (63.5 vs. 76.5%;
p
= 0.037). Here we report, for the first time, the association of
F. nucleatum
presence with important clinical and molecular features in a Brazilian cohort of CRC patients. Tumor detection and classification based on the gut microbiome might provide a promising approach to improve the prediction of patient outcome.
Colorectal cancer (CRC) is the third most frequent and the second deadliest cancer worldwide. The ethnic structure of the population has been gaining prominence as a cancer player. The purpose of ...this study was to determine the genetic ancestry of Brazilian CRC patients. Moreover, we intended to interrogate its impact on patients' clinicopathological features.
Retrospective observational cohort study with 1,002 patients with CRC admitted from 2000 to 2014 at Barretos Cancer Hospital. Following tumor DNA isolation, genetic ancestry was assessed using a specific panel of 46 ancestry informative markers. Survival rates were obtained by the Kaplan-Meier method, and the log-rank test was used to compare the survival curves. Multivariable Cox proportional regression models were used to estimate hazard ratios (HRs).
We observed considerable admixture in the genetic composition, with the following average proportions: European 74.2%, African 12.7%, Asian 6.5%, and Amerindian 6.6%. The multivariate analysis for cancer-specific survival showed that clinical stage, lymphovascular invasion, and the presence of recurrence were associated with an increased relative risk of death from cancer (
< 0.05). High African proportion was associated with younger age at diagnosis, while high Amerindian proportion was associated with the mucinous histological subtype.
This represents the larger assessment of genetic ancestry in a population of Brazilian patients with CRC. Brazilian CRC patients exhibited similar clinicopathological features as described in Western countries.
Genetic ancestry components corroborated the significant admixture, and importantly, patients with high African proportion develop cancer at a younger age.
Esophageal cancer is an aggressive tumor that has a high rate of incidence and mortality worldwide. It is the 10th most frequent type in Brazil, being squamous cell carcinoma (ESCC) the predominant ...subtype. There is currently an incessant search to identify the frequently altered genes associated with esophageal squamous cell carcinoma biology that could be druggable. This study aimed to analyze the somatic mutation profile of a large panel of cancer-related genes in Brazilian ESCC. In a series of 46 ESCC diagnoses at Barretos Cancer Hospital, DNA isolated from paired fresh-frozen and blood tissue, a panel of 150 cancer-related genes was analyzed by next-generation sequencing. The genes with the highest frequency of mutations were TP53 (39/46, 84.8%), followed by NOTCH1 (7/46, 15.2%), NFE2L2 (5/46, 10.8%), RB1 (3/46, 6.5%), PTEN (3/46, 6.5%), CDKN2A (3/46, 6.5%), PTCH1 (2/46, 4.3%) and PIK3CA (2/46, 4.3%). There was no significant association between molecular and patients' clinicopathological features. Applying an evolutionary action score of p53 (EAp53), we observed that 14 (35.9%) TP53 mutations were classified as high-risk, yet no association with overall survival was observed. Concluding, this the largest mutation profile of Brazilian ESCC patients, which helps in the elucidation of the major cancer-related genes in this population.
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Colorectal cancer (CRC) has a high incidence and mortality worldwide. Microsatellite instability (MSI) is crucial in CRC, with distinct molecular and clinicopathological features in patients. ...Nowadays, it is a predictive marker for immunotherapy. We proposed to evaluate the 5-year outcome of MSI status in 1002 Brazilian CRC, and associate it with genetic ancestry, molecular and clinicopathological features. MSI evaluation was performed using molecular markers. MSI+ tumors were analyzed for alterations in 23 MSI-targeted genes. Genetic ancestry was evaluated using an Ancestry-Informative markers panel. MSI status was analyzed in relation to CRC specific survival and other clinical and genetic variables. MSI+ status was observed in 10.5% of cases. MSI+ status was significantly associated with the anatomic site right colon, mucinous histological type, clinical stage II, histological grade III/undifferentiated, no recurrence of disease, and live cases without cancer. No association of MSI status with genetic ancestry components was observed. MSI-targeted genes analyses showed the most frequently altered genes: ATM, EGFR, MRE11, ROCK1, and TGFBRII. There was a statistically significant difference in cancer-specific survival between cases according to MSI status. This study constitutes the most comprehensive analyses of the MSI impact on the Brazilian CRC. MSI+ frequency in Brazilian CRC agreed with the literature and was associated with several clinicopathological features related with less aggressive tumors, independently of their genetic ancestry.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Most colorectal cancers (CRC) arise from precursor lesions. This study aimed to characterize the mutation profile of colorectal cancer precursor lesions in a Brazilian population. In total, 90 ...formalin-fixed paraffin-embedded colorectal precursor lesions, including 67 adenomas, 7 sessile serrated lesions, and 16 hyperplastic polyps, were analyzed by next-generation sequencing using a panel of 50 oncogenes and tumor suppressor genes. The genetic ancestry of the patients was estimated. Somatic driver mutations were identified in 66.7% of cases, including alterations in APC (32.2%), TP53 (20.0%), KRAS (18.9%), BRAF (13.3%) and EGFR (7.8%). Adenomas displayed a higher number of mutations, mainly in APC, compared to serrated polyps (73.1% vs. 47.8%, p = 0.026). Advanced adenomas had a significantly higher frequency of mutation in KRAS and a high overall mutation rate than early adenomas (92.9% vs. 59%, p = 0.006). A high degree of ancestry admixture was observed in the population studied, with a predominance of European components (mean of 73%) followed by African (mean of 11.3%). No association between genetic ancestry and type of lesions was found. The mutation profile of Brazilian colorectal precursor lesions exhibits alteration in APC, KRAS, TP53, and BRAF at different frequencies according to lesion type. These results bestow the knowledge of CRC's biologic history and support the potential of these biomarkers for precursor lesions detection in CRC screening of the Brazilian population.
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