ABSTRACT
Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Genome-Wide Association Study , Genetic Predisposition to Disease , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/pathology , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Regulatory Sequences, Nucleic Acid , Polymorphism, Single Nucleotide/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Binding Sites/geneticsABSTRACT
Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10-5). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association.
Subject(s)
Antigens, Neoplasm , Carcinoma, Pancreatic Ductal , DNA Methylation , GPI-Linked Proteins , Genetic Predisposition to Disease , Linkage Disequilibrium , Neoplasm Proteins , Pancreatic Neoplasms , Polymorphism, Single Nucleotide , Humans , Pancreatic Neoplasms/genetics , Carcinoma, Pancreatic Ductal/genetics , Male , GPI-Linked Proteins/genetics , Antigens, Neoplasm/genetics , Neoplasm Proteins/genetics , Case-Control Studies , White People/genetics , Female , Quantitative Trait Loci , Alleles , Asian People/genetics , Middle AgedABSTRACT
INTRODUCTION: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. MATERIALS AND METHODS: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. RESULTS: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1. CONCLUSION: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Genome-Wide Association Study , Pancreatic Neoplasms/genetics , Carcinoma, Pancreatic Ductal/genetics , DNA Methylation/genetics , Pancreatic NeoplasmsABSTRACT
OBJECTIVES: In recent years, the local excision of benign rectal lesions or early-stage rectal cancers using minimally invasive surgical techniques has replaced radical interventions that caused impairment in patients' quality of life. The aim of the present study was to investigate the feasibility of transanal minimally invasive surgery (TAMIS), as well as its excision quality, its oncologic outcomes, and its impact on anorectal function. METHODS: Patients who underwent TAMIS at a single colorectal unit of a tertiary university hospital from 2015 until 2020 for benign rectal lesions or early-stage malignant rectal lesions, along with unsuitable patients for radical interventions, were included in the present study. RESULTS: Twenty-five patients underwent TAMIS for rectal lesions. Their median distance from the anal verge was 7 cm (range 4-12 cm) and their median size was 3.8 cm (range 2-6 cm). The median operative duration was 75 minutes (range 30-150 minutes) and the median hospitalization interval was 2 days (range 1-6 days). In addition, the negative resection rate was 100% and the recurrence rate was 4% during an average follow-up period of 30 months (range 3-36 months). Two patients (8%) presented short-term complications, and in 1 patient (4%) a hybrid technique was required. Seventeen patients (68%) reported moderate incontinence symptoms 6 weeks postoperatively that subsided in all patients 3 months postoperatively. CONCLUSIONS: TAMIS seemed to be a feasible technique with adequate oncologic outcomes and high excision quality, which preserved patients' quality of life. The impact of TAMIS on anorectal function after neoadjuvant chemoradiotherapy for rectal cancer should be further investigated, however.
Subject(s)
Rectal Neoplasms , Transanal Endoscopic Surgery , Humans , Patient Selection , Quality of Life , Treatment Outcome , Rectal Neoplasms/surgery , Rectal Neoplasms/pathology , Transanal Endoscopic Surgery/methods , Anal Canal/surgeryABSTRACT
BACKGROUND: Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection. OBJECTIVE: We generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score. METHODS: We tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes. RESULTS: The scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10-10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10-8, highest vs lowest quintile of the weighted multifactorial score). CONCLUSION: We found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.
Subject(s)
Multifactorial Inheritance , ABO Blood-Group System/genetics , Alleles , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/genetics , Early Detection of Cancer , Female , Gene Frequency , Humans , Male , Pancreatic Neoplasms/genetics , Polymorphism, Single Nucleotide , Risk AssessmentABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10-10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10-6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.
Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Pancreatic Neoplasms/genetics , Quantitative Trait Loci , Aged , Alleles , Case-Control Studies , Female , GTPase-Activating Proteins/genetics , Humans , Male , Middle Aged , Polymorphism, Single NucleotideABSTRACT
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.
Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Cyclin-Dependent Kinase Inhibitor p15/genetics , MicroRNAs/genetics , Pancreatic Neoplasms/genetics , Polymorphism, Single Nucleotide , RNA, Long Noncoding/genetics , Aged , Case-Control Studies , Computational Biology/methods , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Middle AgedABSTRACT
A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80-0.90, p = 8.3 × 10(-8)). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r(2) = 0.07, D' = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10(-5) ), rs4583925 (p = 4.0 × 10(-5) ) and rs2735948 (p = 5.0 × 10(-5) ). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.
Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Pancreatic Neoplasms/genetics , Telomerase/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Genetic Predisposition to Disease , Humans , Linkage Disequilibrium , Male , Middle Aged , Mutation , Polymorphism, Single Nucleotide , Young AdultABSTRACT
OBJECTIVES: Crohn disease (CD) and ulcerative colitis (UC), known collectively as inflammatory bowel diseases (IBDs), are chronic immunoinflammatory pathologies of unknown aetiology. Despite the frequent use of biomarkers in medical practice, there is a relative lack of information regarding validated paediatric biomarkers for IBD. Furthermore, biomarkers proved to be efficacious in adults are frequently extrapolated to the paediatric clinical setting without considering that the pathogenesis of many diseases is distinctly different in children. In the present study, proteomics technology was used to monitor differences in protein expression among adult and young patients with CD, identify a panel of candidate protein biomarkers that may be used to improve prognostic-diagnostic accuracy, and advance paediatric medical care. METHODS: Male and female serum samples from 12 adults and 12 children with active CD were subjected to 2-dimensional gel electrophoresis. Following the relative quantitation of protein spots exhibiting a differential expression between the 2 groups by densitometry, the spots were further characterized by matrix-assisted laser desorption tandem time-of-flight mass spectrometer. The results were confirmed by Western blot analysis. RESULTS: Clusterin was found to be significantly overexpressed in adults with CD, whereas ceruloplasmin and apolipoprotein B-100 were found to be significantly overexpressed in children, indicating that the expression of these proteins may be implicated in the onset or progression of CD in these 2 subgroups of patients. CONCLUSIONS: Interestingly, we found a differential expression of several proteins in adults versus paediatric patients with CD. Undoubtedly, future experiments using a larger cohort of patients with CD are needed to evaluate the relevance of our preliminary findings.
Subject(s)
Apolipoprotein B-100/blood , Ceruloplasmin/analysis , Clusterin/blood , Crohn Disease/blood , Adult , Age of Onset , Apolipoprotein B-100/chemistry , Apolipoprotein B-100/metabolism , Biomarkers/blood , Biomarkers/chemistry , Biomarkers/metabolism , Blood Proteins/analysis , Blood Proteins/chemistry , Blood Proteins/metabolism , Blotting, Western , Ceruloplasmin/chemistry , Ceruloplasmin/metabolism , Child , Clusterin/chemistry , Clusterin/metabolism , Crohn Disease/epidemiology , Crohn Disease/physiopathology , Female , Greece/epidemiology , Humans , Male , Peptide Mapping , Proteomics/methods , Severity of Illness Index , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Two-Dimensional Difference Gel ElectrophoresisABSTRACT
BACKGROUND: Anastomotic leaks after colorectal resections for cancer are a leading cause of postoperative morbidity, mortality, and long hospital stay. Few data exist on the potentially deleterious effect of the anastomotic leaks after proctectomy for cancer on patient health-related quality of life. OBJECTIVE: The aim of this study was to explore the effect of clinically evident anastomotic leaks on health-related quality of life after rectal cancer excision. DESIGN: This is a case-matched study. SETTINGS: This study was conducted in a Greek academic surgical department. PATIENTS: Included were 25 patients undergoing low anterior resection complicated by an anastomotic leak (Clavien classification II, n = 14, and III, n = 11) and 50 patients undergoing low anterior resection with an uncomplicated course. MAIN OUTCOME MEASURES: Health-related quality-of-life data were prospectively collected at fixed assessment time points (baseline, 3, 6, and 12 months postoperatively) by the use of validated questionnaires (Medical Outcomes Study Short Form 36, Gastrointestinal Quality of Life Index, European Organization of Research and Treatment of Cancer Quality of Life Questionnaire-C30, and European Organization of Research and Treatment of Cancer Quality of Life Questionnaire-CR29). RESULTS: "Leak" patients required a longer hospitalization. Although the numbers of initially constructed defunctioning loop ileostomies were not significantly different between cases and controls, "leak" patients were required to remain with a stoma significantly more often at all postoperative assessment time points. No differences were observed in the baseline scores between the 2 groups. Physical function of "leak" patients was significantly worse at all postoperative assessment time points. At 6 and 12 months, their emotional and social function and overall quality-of-life scores were significantly decreased in comparison with the patients with an uncomplicated course. "Leak" patients experienced significantly more "stoma-related problems" and "sore skin" around the stoma site. LIMITATIONS: Limited number of patients, restriction of follow-up to the end of the first year, and heterogeneity in terms of the presentation, severity, and management of anastomotic leaks were the limitations of this study. CONCLUSIONS: Anastomotic leaks have an adverse effect on postoperative health-related quality of life.
Subject(s)
Anastomotic Leak/physiopathology , Anastomotic Leak/psychology , Health Status , Quality of Life , Rectal Neoplasms/surgery , Aged , Aged, 80 and over , Anastomotic Leak/etiology , Colectomy/adverse effects , Colectomy/psychology , Female , Hospitalization , Humans , Ileostomy/adverse effects , Ileostomy/psychology , Male , Middle Aged , Outcome Assessment, Health Care , Recovery of Function , Rectal Neoplasms/physiopathology , Rectal Neoplasms/psychology , Retrospective Studies , Time FactorsABSTRACT
BACKGROUND: Malignant bowel obstruction (MBO) is a serious clinical entity that requires surgical intervention in almost 50% of cases. However, overall survival remains low even for operable cases. The aim of the present study was to investigate the correlation between patients' characteristics, perioperative details, histopathological results and postoperative outcomes of patients who were operated on due to MBO. METHODS: A retrospective search of patients who were operated on due to MBO in a university and a rural hospital was conducted. Patients' characteristics, perioperative details, histopathological results and postoperative outcomes were reported. Univariable and multivariable analysis was performed. RESULTS: Seventy patients were included with a mean age of 76.1 ± 10.6 years. The 30-day mortality rate was 18.6%, the Intensive Care Unit (ICU) admission rate was 17.1% and the mean length of stay (LOS) was 12.4 ± 5.7 days. Postoperative 30-day mortality was associated with increased age, known malignant recurrence, microscopically visible metastatic foci and defunctioning stoma creation. Colorectal malignancy type, sigmoid obstruction and primary anastomosis were correlated with decreased 30-day mortality. In addition, operation at the university hospital led to increased LOS, while stoma creation led to decreased LOS. Finally, ICU admission rates were increased for operations at university hospitals, at least one comorbidity, known malignant recurrence and longer preoperative waiting interval, whereas they were decreased for colorectal primary malignancy type. CONCLUSIONS: Surgery due to MBO leads to increased morbidity and mortality. Therefore, prospective studies are needed to highlight inter-patient differences regarding the best individualized therapeutic strategy.
ABSTRACT
Malnutrition is a major issue in gastrointestinal perioperative situations, as only 40% of malnourished patients are finally treated. This literature review investigates the inconsistencies regarding the diagnostic approach to both preoperative and postoperative patients and the various underlying causes, as well as the efficiency of the various therapeutic regimens. A literature search was conducted until August 2023 in MEDLINE and Scopus. Clinical studies involving perioperative nutritional assessment in adult gastrointestinal surgery patients during the last 10 years were included in the present review. Finally, 19 articles were included in the study. Preoperative nutritional therapy is increasingly recognized as a key component of surgical care. Malnourished patients who are hospitalized and operated on, have significantly worse clinical results. Gastrointestinal postoperative malnutrition coexists with metabolic stress, as patients usually suffer from minor chronic inflammations; therefore, postoperative malnutrition is the result of a combination of the effects of inflammation and a lack of food intake. Postoperative malnutrition leads to prolonged hospitalizations and hospital complications and therefore the need to treat it is essential. There are many recognized tools for detecting malnutrition. However, all tools showed inconsistent results regarding their validity. Per os feeding after surgery, and dietary supplements when necessary, have been recommended. Therefore, it is very important to reduce malnutrition and define clear strategies towards that direction.
ABSTRACT
Background: Colorectal cancer surgery has been associated with surgical site infections (SSIs), leading to an increase in postoperative morbidity, length of stay and total cost. The aim of the present randomized study was to investigate the relationship between the preoperative administration of oral antibiotic therapy and SSI rate, as well as other postoperative outcomes in patients undergoing colorectal cancer surgery. Material and Methods: Patients who underwent colorectal cancer surgery in a university surgical department were included in the present study. Patients were randomized into two groups using the "block randomization" method. The intervention group received three doses of 400 mg rifaximin and one dose of 500 mg metronidazole per os, as well as mechanical bowel preparation the day before surgery. The control group underwent only mechanical bowel preparation the day before surgery. The study has been registered in ClinicalTrials.gov (NCT03563586). Results: Two hundred and five patients were finally included in the present study, 97 of whom received preoperative antibiotic therapy per os (intervention group). Patients of this group demonstrated a significantly lower SSI rate compared with patients who did not receive preoperative antibiotic therapy (7% vs. 16%, p = 0.049). However, preoperative antibiotic administration was not correlated with any other postoperative outcome (anastomotic leak, overall complications, readmissions, length of stay). Conclusions: Preoperative antibiotic therapy in combination with mechanical bowel preparation seemed to be correlated with a lower SSI rate after colorectal cancer surgery.
ABSTRACT
OCT4, a POU-domain transcription factor is considered to be a key factor in maintaining the pluripotency of stem cells. Several OCT4 isoforms are differentially expressed in human pluripotent and non-pluripotent cells. Reactivation of OCT4 expression is postulated to occur in differentiated cells that have undergone tumorigenesis. To examine OCT4 expression in colorectal cancer (CRC) tissues, and to assess the efficacy of OCT4 as a potential biomarker for CRC, in this study, we investigated its expression in CRC tissues, evaluated its relationship to various clinicopathological parameters and defined the isoform of OCT4 that was found to be expressed in CRC cases. Primary tumor tissues and matching adjacent non-cancerous tissues were obtained from 84 CRC patients. OCT4 expression and isoform determination were documented by reverse transcription-PCR and real-time PCR. OCT4, Sox-2, and NANOG localization were performed using immunohistochemistry. The isoforms expressed in the studied cases were confirmed by sequencing. Twenty biopsy specimens representing healthy tissues, retrieved from colonoscopy were studied in parallel as controls. OCT4 expression levels were higher in CRC tissues compared to matching, adjacent non-cancerous tissues, and healthy controls. Additionally, the levels of OCT4 expression in CRC tissues correlated with tumor stage. OCT4 and Sox-2 were localized in the nuclei and the cytoplasm of CRC cells. In all CRC cases, we found that the OCT4B1 isoform is expressed. Over-expression of OCT4B1 was found in poorly and moderately differentiated CRC tissues. In conclusion, the data imply that OCT4B1 isoform may represent a potential biomarker for the initiation, progression, and differentiation of CRC.
Subject(s)
Colorectal Neoplasms/genetics , Octamer Transcription Factor-3/genetics , RNA Splicing , Adult , Aged , Aged, 80 and over , Base Sequence , DNA Primers , Female , Humans , Male , Middle Aged , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
BACKGROUND/AIMS: Pro-/pre-/synbiotics supplementation seems to provide beneficial effects in various aspects of abdominal pathology. Skepticism exists with respect to their effects on colorectal cancer (CRC) patients. This review presents the potential clinical applications of pro-/pre-/synbiotics in CRC surgery. METHODS: A literature search of electronic databases was conducted and all studies published on 'probiotics', 'prebiotics' and 'synbiotics' were collected. Among them, the ones referring to CRC and which had any clinical relevance offering information on perioperative parameters were used. RESULTS: Incorporation of pre-/pro-/synbiotic formulations in the preoperative mechanical bowel preparation cannot be supported by the current evidence. Limited clinical studies may be promising in supporting their potentially protective role against postoperative infectious complications. Encouraging are the results on their protective role against adjuvant (chemo)radiation-induced diarrhea. Such supplementation may also hold promise to improve postcolectomy gastrointestinal related quality of life. CONCLUSIONS: Despite the positive results and plethora of agents, bacterial combinations and concentrations, the inconsistency in administration, the inhomogeneity of comparison groups and lack of stringent clinical endpoints remain obstacles in the effort to establish a definitive clinical strategy at this time. Further work is warranted to gain a keen understanding of their clinical value in CRC patients.
Subject(s)
Colorectal Neoplasms/therapy , Dietary Supplements , Preoperative Care , Antineoplastic Agents/adverse effects , Colectomy/adverse effects , Diarrhea/etiology , Diarrhea/prevention & control , Humans , Prebiotics , Probiotics/therapeutic use , Radiotherapy/adverse effects , Surgical Wound Infection/etiology , Surgical Wound Infection/prevention & control , SynbioticsABSTRACT
Background: There is a relative shortage of studies directly addressing the postoperative rectal cancer patients' evacuatory dysfunction, as estimated by the low anterior resection syndrome (LARS) score at repeated assessment time-points. The aim of the present study was to prospectively evaluate the incidence of LARS at predefined time intervals during the first 3 years after sphincter preserving rectal cancer surgery and to enlighten the effect of identified risk factors.Materials and methods: Seventy-eight patients, who remained alive and recurrence-free 2 years after (ultra-) low anterior resection were prospectively assessed at 6, 12, 18, 24, 30 and 36 months postoperatively, using the LARS score as bowel dysfunction outcome measure. All patients have completed the 2-year follow-up functional assessment, while 56 and 37 of them have been evaluated up to the 30th and the 36th postoperative month, respectively.Results: The proportion of patients with "major and minor" LARS significantly decreased during the first 3 evaluations (up to 18 months) (74% vs 62% vs 35%, p = 0.0001). The tumor distance from the anal verge and the neoadjuvant radiotherapy were identified as risk factors for high LARS score at 6 months (p < 0.03). The tumor distance remained as risk factor throughout the entire follow-up. All patients with high tumors were alleviated from symptoms reflecting "major" or "minor" LARS at 18 months. Most patients (90%) after radiotherapy showed a high LARS score in the first semester, but improved afterwards.Conclusion: Overall, the LARS score improves in the majority of patients after 18 months, with low tumor height and radiation adversely affecting them. Our results may be useful in more accurately define the postoperative "functional course" of rectal cancer patients and in aiding their consultation on expected functional outcome.
Subject(s)
Proctectomy , Rectal Neoplasms , Humans , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Prospective Studies , Quality of Life , Rectal Neoplasms/epidemiology , Rectal Neoplasms/surgery , SyndromeABSTRACT
Background - Objective: Primary colorectal squamous cell carcinoma is an extremely rare neoplasm with an incidence of 0.1 to 0.25 per 1,000 diagnosed colorectal carcinomas.The objective of this study was to evaluate its biological behavior and highlight the role of a surgical approach for its management.MethodsPubMed and Cohrane databases were independently searched (last search: April 10th, 2020) for articles concerning colorectal squamous cell carcinoma in adult population.Results: Seventy-one studies met predefined inclusion criteria and involved 99 patients (54.5% females) with an age of 56.98 ± 12.19 years (mean ± SD). The most frequent site of occurrence was the rectum (63.5%). Open surgery was conducted at 95% of patients, while 21.4% and 30.3% received neoadjuvant and adjuvant therapy respectively.Postoperative complications were developed in 31.3% of patients, while 6.1% died withing the first month following operation. Five-years survival rate was 49.5% (95% CI: 33.7%-63.4%). Female sex (HR: 0.24; 95% CI: 0.11-0.54; p-value: 0.001) and presence of postoperative complications (HR: 4.10; 95%CI: 1.47-1.46; p-value: 0.007) significantly affected the survival.Conclusions Colorectal Squamous Cell Carcinoma is a rare tumor with an aggressive behavior. Surgery is the standard of treatment for the colontumors, while the role of chemoradiotherapy is promising especially for rectal tumors. Further clinical trials are necessary to determine the preferred treatment approach.
Subject(s)
Carcinoma, Squamous Cell , Rectal Neoplasms , Adult , Aged , Carcinoma, Squamous Cell/epidemiology , Carcinoma, Squamous Cell/surgery , Colon , Female , Humans , Male , Middle Aged , Neoadjuvant Therapy , Rectal Neoplasms/epidemiology , Rectal Neoplasms/surgery , Rectum/surgeryABSTRACT
PURPOSE: Caspase-8 (CASP8) and caspase-9 (CASP9) play crucial roles in regulating apoptosis, and their functional polymorphisms may alter cancer risk. Our aim was to investigate the association between CASP8 and CASP9 gene polymorphisms and colorectal cancer (CRC) susceptibility. METHODS: A case-control study at 402 CRC patients and 480 healthy controls was undertaken in order to investigate the association between the genotype and allelic frequencies of CASP8 -652 6N ins/del and CASP9 -1263 A>G polymorphisms and the CRC susceptibility. The polymerase chain reaction (PCR) restriction fragment length polymorphism method was used and the incidence of polymorphisms on messenger RNA (mRNA) expression levels was detected by quantitative reverse-transcriptase PCR in CRC tissues. RESULTS: No statistical significant association was observed between CASP8 -652 6N ins/del polymorphism frequencies and CRC susceptibility. CASP9 -1263 G allele was observed to be significant associated with reduced risk of CRC. Homozygotes for the -1263 GG CASP9 genotype, and hetrozygotes for the -1263 AG genotype expressed 6.64- and 3.69-fold higher mRNA levels of Caspase-9, respectively compared to the -1263 AA genotype cases. No significant association was observed between CASP9 -1263 A>G polymorphism and tumor characteristics. The CASP9 -1263 GG genotype was associated with increased overall survival in CRC patients. CONCLUSION: The CASP9 -1263 A>G polymorphism was observed to play a protective role in CRC predisposition, while the CASP9 -1263 GG genotype may confer a better prognosis at CRC patients.
Subject(s)
Caspase 8/genetics , Caspase 9/genetics , Colorectal Neoplasms/enzymology , Colorectal Neoplasms/genetics , Genetic Predisposition to Disease , Polymorphism, Genetic , Adult , Aged , Aged, 80 and over , Caspase 9/metabolism , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/pathology , Female , Gene Expression Regulation, Enzymologic , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Prognosis , Proportional Hazards Models , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched in silico the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case-Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of p in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07-1.17, p = 3.03 × 10-6 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of UCHL3, a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.
ABSTRACT
Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10-5) compared with the additive effects (p>10-3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10-8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.