Case-control study of the PERIOD3 clock gene length polymorphism and colorectal adenoma formation (original) (raw)
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Association of the clock genes polymorphisms with colorectal cancer susceptibility
Journal of Surgical Oncology, 2013
Background and Objectives: The circadian rhythm regulates the cell cycle progression and DNA damage response. The aim of our study was to investigate the association between polymorphisms in the CLOCK1, PER2, and PER3 genes with the colorectal cancer (CRC) susceptibility and clinicopathological variables. Methods: Four hundred two CRC patients and 480 healthy controls were included in a case-control study. Genotype and allelic frequencies of 311T>C (rs1801260) in CLOCK1 gene, G3853A (rs934945) in PER2 gene and 4/5 repeats polymorphisms in PER3 gene were evaluated by the polymerase chain reaction (PCR) restriction fragment length polymorphism method in the DNA extracted from the peripheral blood of patients and controls. Results: The frequencies of the 311T>C CLOCK1 gene, CC genotype and C allele were significantly higher among CRC patients compared to controls (P < 0.0001) elevating the CRC risk by 2.78-and 1.78-fold respectively. No correlation was found between G3853A and 4/5 repeats polymorphisms and CRC risk. The C/G/5 and C/G/4 repeats haplotypes were higher in CRC patients (P ¼ 0.0009 and P ¼ 0.038) elevating the CRC risk by 60% and 89% respectively. No correlation was found between any polymorphism and clinicopathological characteristics of CRC patients. Conclusion: The 311T>C polymorphism in the CLOCK1 gene significantly increases the risk for CRC development while it does not affect the outcome of CRC patients.
Data from Mutations in the Circadian Gene <i>CLOCK</i> in Colorectal Cancer
2023
The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53% of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G 2-M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis. Mol Cancer Res; 8(7); 952-60. ©2010 AACR.
Cancer genetics: colorectal cancer as a model
Journal of Human Genetics, 2006
Cancer is essentially a somatic evolutionary process and is, therefore, effectively defined by the genetic and epigenetic changes underlying this process. An understanding of the function of these changes is fundamental to devising new approaches to prevention and treatment. Colorectal cancer (CRC), apart from its obvious importance as one of the most frequent cancers, provides an excellent model for such studies because of the availability of precursor adenoma lesions and the existence of several clear-cut familial inherited susceptibilities. These include familial adenomatous polyposis (FAP), which led to the identification of the APC gene and the importance of the Wnt pathway, and hereditary non-polyposis CRC (HNPCC), which identified the role of the mismatch repair genes in colorectal and other cancers. The presently known range of genetic and epigenetic changes in CRCs and adenomas is reviewed in this paper and the evidence against a requirement for genomic instability presented, together with a discussion of patterns of gene methylation, including especially our work on the homeobox gene, CDX1. Clearly, familial cancers, such as FAP and HNPCC, cannot account for more than perhaps 5% of the incidence of CRC. There is, however, evidence that approximately a further 25-30% have some inherited susceptibility. Based on the association of APC missense variants with multiple adenomas, we proposed that much of this may be due to the cumulative effects of low frequency, low penetrance variants, and the "rare variant hypothesis". The evidence for this from our work on multiple adenoma cases, and certain other examples, is discussed.
Mutations in the Circadian Gene CLOCK in Colorectal Cancer
Molecular Cancer Research, 2010
The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53% of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G 2-M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis. Mol Cancer Res; 8(7); 952-60. ©2010 AACR.
Gut, 2001
Introduction-As large scale genetic analysis becomes increasingly eYcient, attention is turning to problems arising from inaccurate measurement of the phenotype. We have investigated the underlying basis of variation in disease severity in the large intestine of familial adenomatous polyposis (FAP) patients. The development of objective and reproducible measures may have future use in genetic studies, such as analysis of modifier genes. Methods-We examined the ratio of adenomas to crypts from microscopic slides taken from all parts of the colon of 44 resected FAP specimens. These findings were compared with a carefully reported macroscopic polyp count. Age dependency of adenoma counts (in the period around colectomy) was also analysed. Results-The adenoma:crypt ratio strongly correlated with reported macroscopic polyp count (r=0.82, p<0.001) with no significant residual variation. Polyp density measured using the adenoma: crypt ratio did not vary significantly within an individual colon. Apparent visible variation in polyp density within any colon was not found at the microscopic level. There was no detectable age related increase in macroscopic adenoma count between siblings over the age range at which colectomies were performed. Discussion-The severity of colonic polyposis in FAP can be determined accurately by counting the adenoma:crypt ratio in sections derived from stored tissue blocks. Variation between patients-dependent on APC genotype and, probably, modifier genes-is manifest at both the microscopic and macroscopic levels. Thus variation in disease severity is more likely to result from diVerent rates of tumour initiation than from diVerences in progression of microadenomas to macroscopic tumours. The absence of a detectable relationship between adenoma number and age (over the range studied) suggests that most tumours may be initiated relatively early in the patient's life, perhaps at a time of particular susceptibility.
Chronobiology International, 2011
The clock gene machinery controls cellular metabolism, proliferation, and key functions, such as DNA damage recognition and repair. Dysfunction of the circadian clock is involved in tumorigenesis, and altered expression of some clock genes has been found in cancer patients. The aim of this study was to evaluate the expression levels of core clock genes in colorectal cancer (CRC). Quantitative real-time polymerase chain reaction (qPCR) was used to examine ARNTL1, CLOCK, PER1, PER2, PER3, CRY1, CRY2, Timeless (TIM), TIPIN, and CSNK1Ε expression levels in the tumor tissue and matched apparently healthy mucosa of CRC patients. In the tumor tissue of CRC patients, compared to their matched healthy mucosa, expression levels of ARNTL1 (p = .002), PER1 (p = .002), PER2 (p = .011), PER3 (p = .003), and CRY2 (p = .012) were lower, whereas the expression level of TIM (p = .044) was higher. No significant difference was observed in the expression levels of CLOCK (p = .778), CRY1 (p = .600), CSNK1Ε (p = .903), and TIPIN (p = .136). As to the clinical and pathological features, a significant association was found between low CRY1 expression levels in tumor mucosa and age (p = .026), and female sex (p = .005), whereas high CRY1 expression levels in tumor mucosa were associated with cancer location in the distal colon (p = .015). Moreover, high TIM mRNA levels in the tumor mucosa were prevalent whenever proximal lymph nodes were involved (p = .013) and associated with TNM stages III-IV (p = .005) and microsatellite instability (p = .015). Significantly poorer survival rates were evidenced for CRC patients with lower expression in the tumor tissue of PER1 (p = .010), PER3 (p = .010), and CSNKIE (p = .024). In conclusion, abnormal expression levels of core clock genes in CRC tissue may be related to the process of tumorigenesis and exert an influence on host/tumor interactions.
Phenotypic expression in familial adenomatous polyposis: partial prediction by mutation analysis
Gut, 1994
The phenotypic expression in familial adenomatous polyposis (FAP) is variable. This study compares the phenotype of 27 patients with an identical 5 base pair (bp) deletion at codon 1309 with a group of 61 matched patients with FAP where knowledge of specific mutations is not available and with seven other different mutations in 24 subjects. Patients with the codon 1309 deletion have significantly more colorectal polyps at the time of colectomy than age and sex matched FAP controls (p=0 0001). The median number of polyps in colectomy specimens of patients with the deletion at codon 1309 was 4000 (interquartile (IQ) range 3000-4875), compared with 600 (IQ range 488-1400) in the matched controls. Mutations at codon 1323, 1407, and 233 were also associated with large numbers of polyps. Desmoid disease and extracolonic cancers were more common with the mutation at codon 1309 (p=0.003). In conclusion, there may be a correlation between a specific germline mutation and the number of large bowel polyps. There is residual heterogeneity in phenotypic expression, however, and this may result from the influence of other genes, specific environmental factors or chance.
Association between adenoma location and risk of recurrence
Gastrointestinal Endoscopy, 2016
Background and Aims-The biological environment varies across the colorectum and may therefore differently affect neoplastic growth in the proximal and distal colon. The aim of the study was to evaluate the risk for recurrent adenomas and their anatomic location based on adenoma location at baseline colonoscopy. Methods-Data were extracted from three adenoma prevention trials (n= 2430). Participants had at least one adenoma at baseline colonoscopy and underwent subsequent surveillance colonoscopy, at which time metachronous adenomas could be detected. We calculated the risk ratio (RR) and the 95% confidence interval (CI) for metachronous adenomas by location of the baseline lesion and considered the impact of advanced neoplasia and multiplicity. Results-At baseline 522 subjects (21.5%) had adenomas only in the proximal colon, 1266 subjects (52.1%) had adenomas only in the distal colorectum and 642 (26.4%) had adenomas in both regions. Overall 877 subjects (36.5%) had metachronous adenomas during the follow-up period. Those with only proximal adenomas at baseline had a higher risk of metachronous adenomas compared to subjects with only distal adenomas (RR 1.17, 95% CI 1.01-1.35). A greater proximal risk was found after restricting the analysis to subjects with multiple proximal adenomas versus multiple distal adenomas (RR 1.35, 95%
943 Beyond the Adenoma Carcinoma Sequence
British Journal of Surgery, 2021
Introduction Looking beyond the adenoma carcinoma sequence researchers have discovered alternate morpho-genetic routes, and tumour biomarkers in colorectal cancer. This has caused a paradigm shift in the management, resulting in improved diagnosis, prevention, and delivery of tailored treatment aiming at specific molecular pathways. Aim This review summarises Method PubMed, Google Scholar, NLM searches based on aims and key words were conducted. Further, academically, and clinically relevant searches were made if more information was required. When required, references of articles were also retrieved. Results The two main theories regarding the morphological origins of colorectal cancer are the adenoma carcinoma sequence and the De-novo origins. The underlying genetic models are the (i) chromosomal instability pathway (CIN), (ii) the microsatellite instability pathway (MSI) and (iii) the CpG Island methylator phenotype (CIMP) pathways. Though unique, the pathways communicate with ea...