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Approximately one-third of individuals diagnosed with colorectal cancer have a family history of cancer, suggesting that CRCs may result from a heritable component. Despite the availability of current gene-identification techniques, only 5% of all CRCs emerge from well-identifiable inherited causes for predisposition, including polyposis and nonpol...
Citations
... The majority are associated with Lynch Syndrome (LS), which has an autosomal dominant inheritance pattern caused by germline pathogenic variants (PV) in DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, and PMS2. Although not considered an MMR gene, a genomic rearrangement in EPCAM can lead to epigenetic silencing of MSH2, resulting in a similar phenotype [3,4]. ...
... Finally, androstenedione and testosterone undergo extra-glandular aromatization to produce estrone and estradiol, respectively [37] . SHBG is a hepatically produced glycoprotein that serves as the primary transport protein for testosterone, making it a crucial regulator of their bioactivity shows in Figure 3, and its altered level also determines the CRC risk [20,38,39] . One such site is the colon epithelial cells, once the SHBG complex with testosterone reached the site, testosterone is released and due to its lipophilic nature, it passes into the cell through the cell membrane [12,40,41] . ...
Background: Colorectal cancer (CRC) is known to be a very life-threatening disease that causes a significant loss of lives. What factors are responsible for the susceptibility to such devastating conditions? One such example is the level of testosterone, which is known to affect both males and females physiologically and is principally in charge of the maturation of the male reproductive system. Aim: In the present study we aimed to examine testosterone levels of expression in CRC patients among the South Indian population. Method: The experimental samples were selected from hospitals in Tamil Nadu, South India and for comparative analysis, healthy controls were also collected. Around 7mL of blood samples were collected and prepared for radioimmunoassay. SPSS was used to analyze the significant difference between discrete and continuous data variables, and chi-square and t-tests were used. Result: In the present study, a total of 130 subjects, which includes 65 experimental subjects and an equal number of physically healthy. The experimental subjects depicted a significant (p <0.0001) decreased mean levels of testosterone of 06.68±2.15 in comparison to controls of 22.54±8.85. In the non-smoker group, testosterone levels of experimental subjects were 06.81±2.21 as well controls were 10.15±2.48 and the difference was found statically significant (p <0.0001). The experimental subjects adjusted for alcohol consumption showed a decreased mean level of testosterone 06.31±2.30 in contrast to controls 07.96±2.45 and the difference was found significant (p <0.022) Conclusion: The present study supports the notion that decreased level of testosterone is a critical risk biomarker for the CRC pathogenesis.
... The development of CRC is characterized by a sequence of events driven by an accumulation of molecular genetic alterations during which normal colonic epithelium gradually transforms to carcinoma tissue, in most cases via the development of colorectal adenomas [15][16][17][18]. Hereditary predisposition is considered an important factor in colorectal carcinogenesis, although 80% of colorectal neoplasms occur in the absence of a family history of CRC [19][20][21]. Up to 15% of all CRC are of heredity pattern, and family history is a major risk factor for CRC predisposition [22]. Moreover, common genetic variants leading to tumorigenesis is one of the major causes for development of CRC [23][24][25][26]. ...
Background
Genetic polymorphisms play an important role in the development of colorectal cancer (CRC). Functional variants in the epidermal growth factor (EGF), survivin, and Ephrin A1 (EFNA1) genes have been previously reported to play a potential role in susceptibility to CRC, but these polymorphisms have not been well replicated. The aim of this study was to assess the association of the EGF 61A>G, Survivin -31G>C, and EFNA1 -1732G>A polymorphisms with the susceptibility to CRC in an Iranian population.
Methods
A total of 148 cases diagnosed with CRC and 160 healthy subjects were recruited. The EGF 61A>G, survivin -31G>C, and EFNA1 -1732G>A polymorphisms were genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay.
Results
Our data revealed that the homozygous mutant genotype (CC: OR = 2.895, 95% CI = 1.092–7.673, p = 0.033) and mutant allele (C: OR = 1.629, 95% CI = 1.152–2.303, p = 0.006) of the survivin -31G>C were associated with an increased risk of CRC in the Iranian population. However, our results failed to show an association between the EGF 61A>G and EFNA1 -1732G>A polymorphisms and CRC risk.
Conclusion
Our results revealed that the survivin -31G>C polymorphism might play an important role in development of CRC in Iranian population. However, no association of EGF 61A>G and EFNA1 -1732G>A polymorphisms with CRC risk was found.
... The primary risk is found in patients with familial adenomatosis, wherein they have a high probability of developing CRC at early age. Overall, heritable forms of polyposis and nonpolyposis syndromes are responsible for approximately 5% of all colonic cancers [40,41]. ...
Colorectal cancer (CRC) has an important bearing (top five) on cancer incidence and mortality in the world. The etiology of sporadic CRC is related to the accumulation of genetic and epigenetic alterations that result in the appearance of cancer hallmarks such as abnormal proliferation, evasion of immune destruction, resistance to apoptosis, replicative immortality, and others, contributing to cancer promotion, invasion, and metastasis. It is estimated that, each year, at least four million people are diagnosed with CRC in the world. Depending on CRC staging at diagnosis, many of these patients die, as CRC is in the top four causes of cancer death in the world. New and improved screening tests for CRC are needed to detect the disease at an early stage and adopt patient management strategies to decrease the death toll. The three pillars of CRC screening are endoscopy, radiological imaging, and molecular assays. Endoscopic procedures comprise traditional colonoscopy, and more recently, capsule-based endoscopy. The main imaging modality remains Computed Tomography (CT) of the colon. Molecular approaches continue to grow in the diversity of biomarkers and the sophistication of the technologies deployed to detect them. What started with simple fecal occult blood tests has expanded to an armamentarium, including mutation detection and identification of aberrant epigenetic signatures known to be oncogenic. Biomarker-based screening methods have critical advantages and are likely to eclipse the classical modalities of imaging and endoscopy in the future. For example, imaging methods are costly and require highly specialized medical personnel. In the case of endoscopy, their invasiveness limits compliance from large swaths of the population, especially those with average CRC risk. Beyond mere discomfort and fear, there are legitimate iatrogenic concerns associated with endoscopy. The risks of perforation and infection make endoscopy best suited for a confirmatory role in cases where there are positive results from other diagnostic tests. Biomarker-based screening methods are largely non-invasive and are growing in scope. Epigenetic biomarkers, in particular, can be detected in feces and blood, are less invasive to the average-risk patient, detect early-stage CRC, and have a demonstrably superior patient follow-up. Given the heterogeneity of CRC as it evolves, optimal screening may require a battery of blood and stool tests, where each can leverage different pathways perturbed during carcinogenesis. What follows is a comprehensive, systematic review of the literature pertaining to the screening and diagnostic protocols used in CRC. Relevant articles were retrieved from the PubMed database using keywords including: “Screening”, “Diagnosis”, and “Biomarkers for CRC”. American and European clinical trials in progress were included as well
... 7,12 The different clinical aspects and molecular features of these three groups have been summarised elsewhere. 13 Recently, we compared the risks of different tumour types between LS, LLS and FCCX using prospective cohort data. 14 It is assumed that LS associated CRC develop mainly via the classical adenoma-carcinoma sequence, although other pathways of CRC development have recently been proposed. ...
Lynch syndrome (LS), Lynch‐like syndrome (LLS) and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer (CRC). The aim of this prospective study was to characterise and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. Our study may support the development of risk‐adapted surveillance policies in LS, LLS and FCCX.
... LS is also known as hereditary non-polyposis colorectal cancer (HNPCC), with an approximate prevalence of one in 600 to one in 3,000 individuals (17,18). HNPCC is a heterogeneous group of disorders with overlapping features that are clinically evaluated using Amsterdam (I or II) or Bethesda guidelines (19)(20)(21)(22). Clinical guidelines are based on family and personal history of cancer, and their use as diagnostic tools for LS is restricted due to their low sensitivity. ...
... By the poor clinical diagnostic approaches, it is difficult to differentiate Lynch CRC tumors from non-hereditary ones due to the high frequency of MSI occurrence in sporadic tumors. This situation becomes more complicated when there is a positive family history of developing CRC or different related cancer types (19). In the present study, a CRC-affected individual from a fulfilled Amsterdam II criteria pedigree, showing Lynch-associated MSI and IHC phenotypes, underwent whole-exome sequencing (WES). ...
Background
Familial cancers comprise a considerable distribution of colorectal cancers (CRCs), of which only about 5% occurs through well-established hereditary syndromes. It has been demonstrated that deleterious variants at the newly identified cancer-predisposing genes could describe the etiology of undefined familial cancers.
Methods
The present study aimed to identify the genetic etiology in a 32-year-old man with early onset familial CRC employing several molecular diagnostic techniques. DNA was extracted from tumoral and normal formalin-fixed-paraffin-embedded (FFPE) blocks, and microsatellite instability (MSI) was evaluated. Immunohistochemistry staining of MMR proteins was performed on tumoral FFPE blocks. Next-generation sequencing (NGS), multiplex ligation-dependent amplification (MLPA) assay, and Sanger sequencing were applied on the genomic DNA extracted from peripheral blood. Data analysis was performed using bioinformatics tools. Genetic variants interpretation was based on ACMG.
Results
MSI analysis indicated MSI-H phenotype, and IHC staining proved no expressions of MSH2 and MSH6 proteins. MLPA and NGS data showed no pathogenic variants in MMR genes. Further analysis of NGS data revealed a candidate WRN frameshift variant (p.R389Efs*3), which was validated with Sanger sequencing. The variant was interpreted as pathogenic since it met the criteria based on the ACMG guideline including very strong (PVS1), strong (PS3), and moderate (PM2).
Conclusion
WRN is a DNA helicase participating in DNA repair pathways to sustain genomic stability. WRN deficient function may contribute to CRC development that is valuable for further investigation as a candidate gene in hereditary cancer syndrome diagnosis.
... The Amsterdam and the Bethesda criteria can be used to identify individuals at risk for LS. The Amsterdam criteria include at least three relatives with HNPCC-related malignancies (colon, endometrium, small bowel, renal pelvis, or ureter), one affected person is a first-degree relative of the other two affected family members, at least two successive generations are affected, one affected person is diagnosed at younger than age 50, familial adenomatous polyposis is excluded, and tumors are verified by a pathologist [12]. The Bethesda guidelines include CC diagnosed in a patient before age 50; the presence of synchronous, metachronous colorectal, or other HNPCC associated tumors (colorectal, endometrial, stomach, ovarian, pancreatic, ureter, renal pelvis, biliary tract, brain, or small bowel); CC with MSIhigh-like histology in a patient younger than 60 years; CC in a patient with one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed before age 50; and CC in a patient with two or more first-degree relatives with HNPCC-related tumors, regardless of age [13]. ...
Endometrial cancer (EC) is the fifth most common cancer in women from developed countries, accounting for 4.8% of new cases and 2.1% of deaths. The genetic basis for the familial risk of endometrial cancer has not been completely defined. Mostly, hereditary EC is part of two syndromes as Lynch syndrome (LS) and Hereditary Breast and Ovarian Cancer syndrome (HBOC). LS is the prototypical hereditary cancer syndrome in EC and accounts for 2–6% of all endometrial cancers. This disease is caused by autosomal dominant mutations in DNA mismatch repair (MMR) genes. Patients carrying a germline mutation in one of the MMR genes have a cumulative lifetime risk to develop EC of 20–70%. HBOC is an autosomal dominantly inherited disease, which mostly predisposes to breast and ovarian cancers, but it can be also associated with other malignancies. HBOC results from germline mutations in BRCA1/2 genes. The aim of this study was to determine the mutational status of a cohort of 40 EC patients, 19 belonging to families with LS and 21 to HBOC. Mutation analysis of MLH1 , MSH2 , BRCA1 and BRCA2 genes showed pathogenic variants in 17/40 (42.5%) patients. Out of 19 patients belonging to LS families, 8 (42.1%) showed a pathogenic variant. Out of 21 patients belonging to HBOC families, 9 (42.8%) showed a pathogenic variant. 1/21 (4.8%) patient report 1 variant of unknown significance (UV), c.599 C > T (p.T200I), in BRCA2 . Moreover, in 1/21 (4.8%) patient we identified a novel missense variant in BRCA2 , c.9541A > T (p.Met3181Leu). Mutational analysis was extended to family members, both healthy and cancer affected, of mutated patients; all the tested relatives affected with cancer displayed the pathogenic variant. Our data suggest that patients with hereditary EC have a high percentage of mutations in the LS and HBOC main susceptibility genes; therefore, the surveillance for EC, already indicated in LS patients, should also be recommended for patients with HBOC.
... The major part of the cancer is sporadic; thus, no major hereditary genetic cause can be found, although chromosomal instability (CIN) is detected in a vast number of sporadic CRC [5]. A clear genetic trait can only be seen in less than five per cent (Fig. 2) and a large number of new insights in this field after the genetic recognition of mutations in the APC gene in patients with familial adenomatous polyposis in 1991 [6], followed by the discovery of the microsatellite instability pathway and the CPG island methylation (CIMP) pathway, seen in Lynch syndrome [7]. ...
Colorectal cancer (CRC) is besides breast, prostate, lung and skin cancers the most common cancers worldwide, and CRC is suitable for screening. The incidence of CRC varies considerably in different parts of the world; in well‐developed countries, the incidence is between 30 and 70 per 100 000 inhabitants. In less developed countries such as Sub‐Saharan Africa, the incidence is 10–20/100 000. Women have a lower incidence of CRC, and usually they have a 1/3 lower incidence. Several studies have shown that it is possible to decrease mortality in CRC with about 20%, and data from countries with screening indicate that mortality is decreasing. The method of choice is under debate but the most feasible method is to test for blood in faeces, and if blood is present, a colonoscopy is performed. Other methods are more advanced faecal analyses, testing for mutations from CRC cancer, sigmoidoscopy, CT colonoscopy or optical colonoscopy. Colonoscopy is in most countries not available in sufficient amount and has to be carried out with big accuracy; otherwise, lesions will be missed or lead to complications. Gender is an issue in CRC screening, women have about 20% fewer colorectal adenomas and CRCs but they also have more right‐sided lesions, more difficult to detect with tests for faecal blood less blood in faeces which leads to that other strategies may have to be developed for women in order to have the same effect of screening. Colorectal cancer screening is important to introduce in all countries together with other preventive measures such as information to stop smoking, obesity, exercise and smoking in order to reduce one of the most dangerous cancers.
Abstract
... The CRC develops (70%) via a serious transformation of specific morphological traits, denoted as adenoma to a carcinoma sequence [2]. About 30% of CRC cases are caused due to hereditary disorder, often connected with familial adenomatous polyposis and/or hereditary nonpolyposis [3]. Chronic inflammatory bowel diseases (IBD) or family history of CRC are the primary causes of CRC [4]. ...
Colorectal cancer (CRC) is a fatal disease caused by the uncontrolled propagation and endurance of atypical colon cells. A person's lifestyle and eating pattern have significant impacts on the CRC in a positive and/or negative way. Diet-derived phytochemicals modulate the microbiome as well as targeting colon cancer stem cells (CSCs) that are found to offer significant protective effects against CRC, which were organized in an appropriate spot on the paper. All information on dietary phytochemicals, gut microbiome, CSCs, and their influence on CRC were accessed from the various databases and electronic search engines. The effectiveness of CRC can be reduced using various dietary phytochemicals or modulating microbiome that reduces or inverses the progression of a tumor as well as CSCs, which could be a promising and efficient way to reduce the burden of CRC. Phytochemicals with modulation of gut microbiome continue to be auspicious investigations in CRC through noticeable anti-tumorigenic effects and goals to CSCs, which provides new openings for cancer inhibition and treatment.
... Individuals from Amsterdam-positive families without any signs of dMMR were characterised as a distinct risk group, the so-called "familial colorectal cancer type X" (FCCTX or FCCX) [18,20]. The different clinical aspects and molecular features of LS, LLS, and FCCX are summarized elsewhere [21]. ...
... A comprehensive characterisation of cancer risks is an important prerequisite for developing appropriate cancer surveillance and prevention programmes. To date, many studies have characterised cancer risks in LS, also using prospective data, but fewer studies have characterised cancer risks in LLS and FCCX [7][8][9][10][11][12][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. The aim of the present analysis was therefore to estimate and compare the risk for different types of cancers in individuals with LS, LLS, and FCCX based on data from a prospective surveillance study of the German Consortium for Familial Intestinal Cancer. ...
Background:
Individuals with pathogenic germline variants in DNA mismatch repair (MMR) genes are at increased risk of developing colorectal, endometrial and other cancers (Lynch syndrome, LS). While previous studies have extensively described cancer risks in LS, cancer risks in individuals from families without detectable MMR gene defects despite MMR deficiency (Lynch-like syndrome, LLS), and in individuals from families fulfilling the Amsterdam-II criteria without any signs of MMR deficiency (familial colorectal cancer type X, FCCX) are less well studied. The aim of this prospective study was to characterise the risk for different cancer types in LS, LLS, and FCCX, and to compare these with the cancer risks in the general population.
Methods:
Data was taken from the registry of the German Consortium for Familial Intestinal Cancer, where individuals were followed up prospectively within the framework of an intensified surveillance programme at recommended annual examination intervals. A total of 1120 LS, 594 LLS, and 116 FCCX individuals were analysed. From this total sample, eight different cohorts were defined, in which age-dependent cumulative risks and standardised incidence ratios were calculated regarding the first incident occurrence of any, colorectal, stomach, small bowel, urothelial, female breast, ovarian, and endometrial cancer, separately for LS, LLS, and FCCX.
Results:
The number of individuals at risk for first incident cancer ranged from 322 to 1102 in LS, 120 to 586 in LLS, and 40 to 116 in FCCX, depending on the cancer type of interest. For most cancer types, higher risks were observed in LS compared to LLS, FCCX, and the general population. Risks for any, colorectal, stomach, urothelial, and endometrial cancer were significantly higher in LLS compared to the general population. No significantly increased risks could be detected in FCCX compared to LLS patients, and the general population. Colorectal and endometrial cancer risks tended to be higher in LLS than in FCCX.
Conclusions:
The characterisation of cancer risks in patients with LLS and FCCX is important to develop appropriate surveillance programmes for these specific intermediate risk groups. Larger prospective studies are needed to obtain more precise risk estimates.
