Microsatellite Instability Pathway Research Articles

Effect of ctDNA whole-exome sequencing in pancreatic adenocarcinoma on prognostic value, actionable alterations, and organ tropisms in metastatic disease.

4149 Background: The dismal prognosis associated with pancreatic ductal adenocarcinoma (PDAC) needs a deeper understanding of progression mechanisms and personalized treatment. While the prognostic value of ctDNA has already been established, this study purposes to apply plasma whole-exome sequencing (WES) to identify molecular alterations beyond KRAS. This approach aims to predict survival, uncover progression mechanisms, and identify therapeutic targets. Methods: Eighty metastatic PDAC patients were prospectively recruited and divided into two consecutive cohorts: discovery (n=37) and validation (n=43). Tumor and plasma obtained at diagnosis were analyzed using WES. The variant allele frequency (VAF) of KRASmutations was quantified by ddPCR in plasma at baseline and at response from all patients (n=80). Results: Plasma WES identified at least one pathogenic variant across all individuals, which can be categorized into four pathways: oncogenic mechanisms, DNA repair, microsatellite instability and TGFb pathway alterations. 7 unique druggable mutations were detected in tissue and 11 in plasma. Other targetable mutations ( CDK12, NF1, BRCA2, and TSC2), were prevalent in plasma but absent in tissue. Patients with survival less than 11 months showed enrichment in cellular organization pathways and exclusive targetable CDK12 mutations. Longer survival cases exhibited exclusive mutations in DNA regulation and repair genes. Patients with liver metastasis displayed unique mutations not just in KRAS but also in the adaptive immune response pathway genes. Baseline plasma KRAS mutations detected by ddPCR was associated with worse progression-free survival. (HR=2.315, CI 95%= 1.027-5.217, p = 0.038; and HR= 3.022, CI 95% = 1.299 - 7.030, p= 0.007 in the discovery and validation cohort, respectively). A significant risk of progression (p = 0.006) was observed if KRAS VAF at response assessment did not decrease, at least, 84.75% in both cohorts. Conclusions: ctDNA WES unveils molecular signatures of rapid progression, potential actionable alterations, and liver metastasis-specific mutations in the adaptive immune response pathway. KRAS detection at baseline and its evolution during treatment emerge as prognostic biomarkers. [Table: see text]

Association of Microsatellite Instability and Gene Expression Profile in Colorectal Carcinoma and Potential Implications for Therapy.

Background and Objective: In sporadic colorectal carcinomas (CRC), microsatellite instability (MSI) pathways play important roles. Previously, we showed differences in DNA methylation patterns in microsatellite stable (MSS) colorectal carcinomas and MSI-CRC. In the current study, we explore the similarities and differences in gene expression profiles in MSS and MSI at the gene level and at the pathway level to better understand CRC pathogenesis and/or the potential for therapeutic opportunities. Material and Methods: Seventy-one CRC patients (MSI = 18, MSS = 53) were studied. Paired tumor and adjacent normal tissues were used for genome-wide gene expression assays. Result: At the gene level, we compared the list of differentially expressed genes (fold change (FC) ≥ 3 and FDR < 0.05) in tumor tissues compared to corresponding normal tissue in CRC patients with MSI tumors (190 genes) and MSS tumors (129 genes). Of these, 107 genes overlapped. The list of genes that were differentially expressed in MSI tumors only showed enrichment predominantly in two broad categories of pathways-(a) Inflammation-related pathways including the interleukin-17 (IL-17) signaling pathway, tumor necrosis factor (TNF) signaling pathway, chemokine signaling, nuclear factor kappa B (NFκB) signaling, and cytokine-cytokine interactions, and (b) metabolism-related pathways, including retinol metabolism, steroid hormone biosynthesis, drug metabolism, pentose and glucoronate interconversions, and ascorbate and aldarate metabolism. The genes in inflammation-related pathways were up-regulated whereas genes in metabolism-related pathways were down-regulated in MSI tumor tissue. Pathway-level analysis also revealed similar results confirming the gene enrichment findings. For example, the 150 genes involved in the IL-17 signaling pathway were on average up-regulated by 1.19 fold (CI 1.16-1.21) in MSI compared to 1.14 fold (CI 1.13-1.16) in MSS patients (interaction p = 0.0009). Conclusions: We document an association between MSI status and differential gene expression that broadens our understanding of CRC pathogenesis. Furthermore, targeting one or more of these dysregulated pathways could provide the basis for improved therapies for MSI and MSS CRC.

An integrative pan-cancer analysis of WWC family genes and functional validation in lung cancer

The WW and C2 domain containing (WWC) protein family functions as scaffolds regulating cell proliferation and organ growth control through the Hippo signaling pathway. However, their pan-cancer dysregulation and mechanistic roles in signaling transduction have remained unclear. We performed integrated pan-cancer analyses of WWC family gene expression using data from The Cancer Genome Atlas (TCGA) across 33 different cancer types. Prognostic relevance was evaluated by survival analyses. WWC genetic alterations, DNA methylation, pathway activities, drug response, and tumor immunology were analyzed using online databases. Furthermore, we examined the functional roles of WWCs in lung cancer cells. We observed aberrant WWC expression in various cancers, which associated with patient prognosis. WWC hypermethylation occurred in many cancers and exhibited negative correlation with expression, alongside mutations linked to poor outcomes. Pathway analysis implicated WWCs as Hippo pathway scaffolds, while drug sensitivity analysis suggested associations with diverse chemotherapies. Additionally, pan-cancer analyses elucidated vital immunomodulatory roles for WWC through heterogeneous correlations with immune cell infiltrates, checkpoint molecules, tumor mutation burden, microsatellite instability, and chemokine pathways across cancers. Experimentally, WWCs suppressed lung cancer cell proliferation, migration, and invasion while enhancing apoptosis and paclitaxel chemosensitivity. Mechanistically, WWCs bound large tumor suppressor 1 and 2 (LATS1/2) kinases to stimulate phosphorylation cascades, thereby inhibiting nuclear translocation of the Yes-associated protein (YAP) oncoprotein. Taken together, our multi-omics characterization provides comprehensive evidence for WWCs as putative tumor suppressors across cancers via Hippo pathway modulation. WWCs may serve as prognostic markers and therapeutic targets in lung cancer.

Focusing on colorectal cancer in young adults (Review).

Colorectal cancer (CRC) ranks as the third leading cause of cancer-related mortality worldwide. Recent years have witnessed an increase in the incidence of CRC among adults <50 years old on a global scale. The increased incidence is associated with several modifiable risk factors, including obesity, type II diabetes, physical inactivity and frequent antibiotic use. In younger individuals, haematochezia and abdominal pain are the most common symptoms, predominantly affecting the left-side colon. While certain cases of early-onset CRC (eoCRC) are associated with a genetic predisposition, the majority result from sporadic mutations in the genes APC, KRAS, BRAF and TP53, which trigger uncontrolled cell proliferation and tumour formation. Colorectal carcinogenesis involves three major pathways: The chromosomal instability (CIN), microsatellite instability and CpG island methylator phenotype pathways. Dysregulation of the CIN pathway accounts for 85% of sporadic cases of eoCRC. Notably, eoCRC exhibits a distinctive molecular profile, characterized by a decreased prevalence of BRAF mutations, an increased prevalence of KRAS mutations and LINE-1 hypomethylation, and involvement of the Microsatellite and Chromosomal Stable pathway. Prevention strategies for eoCRC primarily centre on lifestyle modifications and the development of screening programs targeting younger populations. Further exploration into the molecular mechanisms involved in the identification of novel risk factors associated with eoCRC is imperative. These efforts, in conjunction with the development of specific screening strategies, hold the potential to reduce morbidity and mortality in the future.

Genomic and transcriptomic analysis of cutaneous squamous cell carcinoma arising in immunocompetent and immunosuppressed patients

BackgroundCutaneous squamous cell carcinoma (cSCC) is the most common skin malignancy arising in immunocompromised patients such as solid organ transplant recipients. In addition to an abundance in number, the morbidity and mortality of these tumors in this patient population exceeds that of immune competent individuals. Here, we used whole exome and bulk RNA sequencing to analyze mutation profiles between tumors arising in immunocompetent and immunosuppressed patients. MethodsDNA and RNA extracted from twenty formalin-fixed, paraffin embedded tumors and adjacent skin was sequenced. Bioinformatic analysis revealed tumor mutational burden, mutational signatures, microsatellite instability, and aberrant signaling pathways. ResultsSimilar median tumor mutational burden was found in both the tumors from the immunocompetent and the immunosuppressed cohorts. Mutation signature analysis revealed UVR signatures and evidence of azathioprine exposure. 50% of tumors from the immunosuppressed patients have mutations consistent with microsatellite instability, yet mismatch repair protein expression was preserved in the samples analyzed. Additionally, frequently mutated genes in this cohort belong to the extracellular matrix receptor interaction and calcium signaling pathways, suggesting these may be targets for future treatments of this disease. ConclusionsThis study utilizes whole exome and bulk RNA sequencing to identify difference between cSCC arising in immunosuppressed and immunocompetent patients using the patient’s photo exposed, but histologically normal appearing skin as the “germline” comparison. We demonstrate an enrichment in microsatellite instability in the tumors from immunosuppressed patients and differences in oxidative phosphorylation and epithelial-mesenchymal transition which may be targets for therapeutic intervention based on identification of mutations.

Role of Mismatch Repair Deficiency Status and Microsatellite Instability in Relation to the Expression of Immune Checkpoint Proteins in Colorectal Cancer.

Introduction Colorectal cancer (CRC) is the third most common cancer in the world among men and second among women worldwide. One of the major molecular pathways responsible for the development of colorectal cancer (CRC) is the microsatellite instability (MSI) pathway. During carcinogenesis, the tumor cellsexpress programmed death ligand-1 (PD-L1), which reduces the immunogenicity leading to the escape of immune attack. Anti-PD-L1 interactionis an upcoming line of research for the treatment of colorectal carcinoma patients. Materials and methods The present study was an ambispective study where the mismatch repair deficiency status (MMR) and programmed death ligand-1 (PD-L1) expression were studied using immunohistochemistry and then later analyzed and compared with the clinicopathological parameters and MSI status in relation to the expression of programmed death ligand-1 (PD-L1) in neoplastic and immune cells in a total of 55 biopsy specimen. MMR expression was reported as retained or loss of nuclear staining, and PD-L1 expression was taken as positive with a cut-off of more than or equal to 5% membranous positivity in both tumor cells and immune cells. Results The analysis showed a significant correlation of microsatellite instability (MSI) status with two of the clinicopathological parameters, which were the site of the tumor (p-value<0.001) and M stage (p-value<0.001). PD-L1 expression in neoplastic cells showed no significant correlation with the clinicopathological parameters, whereas PD-L1 expression in immune cells showed a significant association with gender (p-value=0.043). Also, MSI status showed a significant association with PD-L1 expression in tumor cells (p-value <0.001).

Pattern of mismatch repair proteins in colorectal cancer patients in tertiary cancer center.

40 Background: Prevalence of MSI high in colorectal cancer patients in India has been debated in previous literature. Microsatellite instability pathway is one of the major pathways in carcinogenesis of colorectal carcinoma. MSI status has paramount significance in therapeutic and prognostic aspects of colorectal cancer management. MSI status can be evaluated by presence or absence of mismatch repair proteins. Aims &amp; objectives: we aimed to determine the prevalence of MSI high in colorectal carcinoma and pattern of mismatch repair proteins. Methods: This was retrospective study which included consecutively operated colorectal carcinoma patients from 01 may 2022 to 31 December 2022 in our institute. Immunohistochemistry with four mismatch repair (MMR) proteins; MLH1, MSH2, MSH6, and PMS2 was performed. Correlation with various clinical and histopathological features was done. Results: total 296 colorectal carcinoma patients were included in our study. Fourty one (13.85%) patients were MSI high. Most common pattern of MMR protein expression loss was dual loss of MLH1 and PMS2 (n=18). Most common single protein loss was PMS2 (n=22). Most common location of tumor in MSI high patients was the right colon. (n=20). Out of 153 carcinoma rectum patients only five patients were MSI high. Conclusions: The study shows that prevalence of MSI high is more common in right colon cancer. Prevalence of MSI high is very low in carcinoma rectum. We discuss and compare our results with previous studies.

Biomarkers and Immunotherapy for Colorectal Cancer

Colorectal cancer (CRC) is the second major cause of mortality from cancer globally. Most CRCs are sporadic and may be classified into three main genetic pathways: the chromosomal instability (CIN) pathway, the microsatellite instability (MSI) pathway and the CpG island methylator phenotype (CIMP) pathway, which are associated with genetic mutations or epigenetic alterations and have the possibility to intersect, thus making the treatment of CRC challenging. Immunotherapy has offered some promising insights by inducing antitumor immune responses, but its effectiveness is restricted to certain groups of CRC patients with specific characteristics. Several biomarkers have demonstrated their potentials to predict the outcomes of immunotherapy in individual patients. Some of them include the extent of tumor mutations (MMR/MSI, POLE/POLD1, KRAS), PDL-1 expression, pre-existing immunity and gut microbial compositions. Immune checkpoint inhibitors (ICIs-)-based immunotherapy is considered to be the relatively traditional immunotherapeutic strategy in the treatment of CRC. However, it mainly targets CRCs with defective mismatch repair (dMMR) mechanisms. The more recently developed immunotherapies include cancer vaccines (molecular-based, cell-based and vector-based vaccines) and adoptive cell therapy (ACT), which have the potential to further enhance the stimulation of antitumor immune responses. This review summarizes the predictive biomarkers that have the potential application in CRC treatment, and discusses the immunotherapeutic strategies targeting CRCs that have been developed or are currently under investigation.

Sex Difference of Colon Adenoma Pathway and Colorectal Carcinogenesis.

Colorectal cancer (CRC) is one of the most common causes of cancer morbidity in both sexes but shows sex differences. First, sex-specific differences in tumor recurrence and survival rates have been reported. For example, the development of CRC is found about 1.5 times higher and 4-8 years earlier in males compared to females, suggesting the protective role of estrogen in the disease. Furthermore, female patients have a higher risk of developing right-sided (proximal) colon cancer than male patients, which is known to have more aggressive clinical character compared to left-sided (distal) colon cancer. That is, left and right CRCs show differences in carcinogenic mechanism, that the chromosomal instability pathway is more common in left colon cancer while the microsatellite instability and serrated pathways are more common in right colon cancer. It is thought that there are sex-based differences on the background of carcinogenesis of CRC. Sex differences of CRC have two aspects, sexual dimorphism (biological differences in hormones and genes) and gender differences (non-biological differences in societal attitudes and behavior). Recently, sex difference of colon adenoma pathway and sexual dimorphism in the biology of gene and protein expression, and in endocrine cellular signaling in the CRC carcinogenesis have been accumulated. In addition, behavioral patterns can lead to differences in exposure to risk factors such as drinking or smoking, diet and physical activity. Therefore, understanding sex/gender-related biological and sociocultural differences in CRC risk will help in providing strategies for screening, treatment and prevention protocols to reduce the mortality and improve the quality of life. In this review, sex/gender differences in colon adenoma pathway and various aspects such as clinicopathological, biological, molecular, and socio-cultural aspects of CRC were described.

Identification and Validation of a Novel Multiomics Signature for Prognosis and Immunotherapy Response of Endometrial Carcinoma.

Purpose Cancer development and immune escape involve DNA methylation, copy number variation, and other molecular events. However, there are remarkably few studies integrating multiomics genetic profiles into endometrial cancer (EC). This study aimed to develop a multiomics signature for the prognosis and immunotherapy response of endometrial carcinoma. Methods The gene expression, somatic mutation, copy number alteration, and DNA methylation data of EC were analyzed from the UCSC Xena database. Then, a multiomics signature was constructed by a machine learning model, with the ROC curve comparing its prognostic power with traditional clinical features. Two computational strategies were utilized to estimate the signature's performance in predicting immunotherapy response in EC. Further validation focused on the most frequently mutant molecule, ARID1A, in the signature. The association of ARID1A with survival, MSI (Microsatellite-instability), immune checkpoints, TIL (tumor-infiltrating lymphocyte), and downstream immune pathways was explored. Results The signature consisted of 22 multiomics molecules, showing excellent prognostic performance in predicting the overall survival of patients with EC (AUC = 0.788). After stratifying patients into a high and low-risk group according to the signature's median value, low-risk patients displayed a greater possibility of respond to immunotherapy. Further validation on ARID1A suggested it could induce immune checkpoints upregulation, promote interferon response pathway, and interact with Treg (regulatory T cell) to facilitate immune activation in EC. Conclusion A novel multiomics prognostic signature of EC was identified and validated in this study, which could guide clinical management of EC and benefit personalized immunotherapy.

The Molecular Associations of Signet-Ring Cell Carcinoma in Colorectum: Meta-Analysis and System Review.

Background: Signet ring cell carcinoma (SC) accounts for 1% of total colorectal cancer (CRC) cases and is associated with aggressive behaviors, such as lymphatic invasion and distant metastases, resulting in poor prognosis. To date, there is still a lack of consensus on the genetic etiology underpinning this cancer subtype. This study aimed to clarify the molecular associations of SC by using meta-analysis and a systematic review. Methods: PubMed, Embase, and Cochrane Library were searched for studies evaluating the KRAS, BRAF, P53 statuses, and microsatellite instability (MSI) in CRC patients with different histological subtypes, including SC. The diagnosis of SC is defined as the signet ring cells comprising ≥50 percent of the tumor mass. By dividing the studies into subgroups based on the composition of control groups, such as classic adenocarcinoma (AC; no SC components) and non-SC (including those with SC components < 50%), the relative risk (RR) of molecular alterations for SC in each study were pooled using a random-effects model. Two reviewers identified trials for inclusion, assessed quality, and extracted data independently. Results: Data from 29 studies consisting of 9366 patients were included in this analysis. SC was associated positively with MSI (RR 1.78, 95% CI 1.34 to 2.37; 95% CI 0.77 to 4.15; p = 0.0005), BRAF mutation (RR 1.99, 95% CI 1.21 to 3.26; 95%CI 0.68 to 5.82; p = 0.0146), and negatively with KRAS mutation (RR 0.48, 95% CI 0.29 to 0.78; 95% CI 0.09 to 2.49; p = 0.0062). No association was found between SC and P53 expression (RR 0.92, 95% CI 0.76 to 1.13; 95%CI 0.61 to 1.39; p = 0.3790). Moreover, it was associated negatively with P53 gene mutations (RR 0.92, 95% CI 0.77 to 1.09; 95% CI 0.46 to 1.82; p = 0.1568), and P53 protein (RR 0.93, 95% CI 0.58 to 1.49; 95% CI 0.40 to 2.17; p = 0.6885). Conclusions: The molecular etiology of SC may be associated with the BRAF and MSI pathways. Its features, such as the high frequency of BRAF mutation, could partly explain its less favorable outcomes and limited effects of traditional chemotherapy.

EP.FRI.181 Beyond the adenoma- carcinoma sequence. A review of the morphogenetic basis of colorectal cancer

Abstract 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. Aims, Methods This review summarises Methods 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 each other. The genetic fingerprinting of colorectal cancers has an impact on their tailored management and consequently a through grounding in the basics are essential for those in gastrointestinal subspecialties. Conclusions Two morphologically distinct pathways and three unique genetic mechanisms have been described. There are significant interactions between them. Behaviours of sporadic and inherited colorectal cancer, their treatment and prognosis depend on our understanding of these mechanisms and the availability of targeted therapies to assist surgical resection.

943 Beyond the Adenoma Carcinoma Sequence

Abstract 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 each other. The genetic fingerprinting of colorectal cancers has an impact on their tailored management and consequently a through grounding in the basics are essential for those in gastrointestinal subspecialties. Conclusions Two morphologically distinct pathways and three unique genetic mechanisms have been described. There are significant interactions between them. Behaviours of sporadic and inherited colorectal cancer, their treatment and prognosis depend on our understanding of these mechanisms and the availability of targeted therapies to assist surgical resection.

Mismatch Repair Protein Expressions in Cohort of Colorectal Carcinoma Patients in Lagos.

Colorectal carcinoma (CRC) is a major cause of morbidity and mortality worldwide. Microsatellite instability pathway is important in the pathogenesis of CRC. Immunohistochemistry expression of mismatch repair (MMR) proteins serves as surrogate marker for MMR gene mutation. This study aimed to determine MSI status of a cohort of CRC cases using immunohistochemistry. Surgical pathology blocks of resected colonic carcinoma (CC) between 2011 and 2015 were extracted from our departmental archives and The Specialist Laboratories in Lagos. Immunohistochemical expression profile of 4 MMR proteins was assessed in the representative blocks and this was correlated with the demographic and pathological characteristics. There were 19 males and 16 females with CC, mean age of 51.6 years, and 40% of them were below 50 years of age. Twenty (57.1%) out of the 35 CC cases seen were mismatch repair proficient (pMMR) while the remaining 15 (42.9%) were mismatch repair deficient (dMMR). Seven dMMR cases were seen equally on the right and left colonic tumors respectively. Five (71.4%) out of the 7 mucinous tumors in this study were dMMR, right sided with 3 of them in patients who were below 50 years of age. The frequency of mismatch repair deficiency in CC among Nigerians is high, and presence of right-sided mucinous colon cancer in patients below 50 years is highly suggestive of dMMR status. Mutation studies of larger patient samples to determine the percentage with germline mutation will further our knowledge, and influence therapeutic options for CC.

Evaluating morphological features for predicting microsatellite instability status in colorectal cancer

BackgroundColorectal cancer (CRC) is one of the commonest cancers worldwide, with incidence rates in India being around 4%. It is a heterogeneous disease with multiple established prognostic factors. Ten to fifteen percent originate from microsatellite instability (MSI) pathway, characterized by defect in mismatch repair (MMR) gene. Identification of MMR defective protein is relevant for diagnosis, prognosis, and prediction. Certain clinical and histological features are known to be associated with defective MMR genes. The objectives of this study are to find the prevalence of MSI in CRC to identify features associated with MSI and assess the value of histopathology in predicting MSI. MethodsWe evaluated various clinical and histological parameters for identifying prognostically favorable colon cancers in a tertiary hospital. One hundred fifty colon cancers were evaluated, and MSI status was correlated with clinicopathologic variables. ResultsThe prevalence of MSI in CRC was found to be 11.3%. The factors associated with MSI were tumor differentiation, stage, tumor site, tumor size, tumor-infiltrating lymphocytes, Crohn’s-like lymphoid reaction, and dirty necrosis. We have defined a “P” score for prediction of MSI using the clinicohistological parameters, which could be used to select patients who are to be tested for MSI. ConclusionAssessment of clinical and histopathological features will help in patient stratification and selection of patients for MSI testing. The evaluation is economical, reproducible, and easy to apply.

Machine learning analysis of TCGA cancer data.

In recent years, machine learning (ML) researchers have changed their focus towards biological problems that are difficult to analyse with standard approaches. Large initiatives such as The Cancer Genome Atlas (TCGA) have allowed the use of omic data for the training of these algorithms. In order to study the state of the art, this review is provided to cover the main works that have used ML with TCGA data. Firstly, the principal discoveries made by the TCGA consortium are presented. Once these bases have been established, we begin with the main objective of this study, the identification and discussion of those works that have used the TCGA data for the training of different ML approaches. After a review of more than 100 different papers, it has been possible to make a classification according to following three pillars: the type of tumour, the type of algorithm and the predicted biological problem. One of the conclusions drawn in this work shows a high density of studies based on two major algorithms: Random Forest and Support Vector Machines. We also observe the rise in the use of deep artificial neural networks. It is worth emphasizing, the increase of integrative models of multi-omic data analysis. The different biological conditions are a consequence of molecular homeostasis, driven by both protein coding regions, regulatory elements and the surrounding environment. It is notable that a large number of works make use of genetic expression data, which has been found to be the preferred method by researchers when training the different models. The biological problems addressed have been classified into five types: prognosis prediction, tumour subtypes, microsatellite instability (MSI), immunological aspects and certain pathways of interest. A clear trend was detected in the prediction of these conditions according to the type of tumour. That is the reason for which a greater number of works have focused on the BRCA cohort, while specific works for survival, for example, were centred on the GBM cohort, due to its large number of events. Throughout this review, it will be possible to go in depth into the works and the methodologies used to study TCGA cancer data. Finally, it is intended that this work will serve as a basis for future research in this field of study.

Phenotype-Genotype Correlation in Colorectal Cancer: A Real-Life Study

Background and Aims: Colorectal cancer (CRC) is a heterogeneous disease with distinctive genetic pathways, such as chromosomal instability, microsatellite instability and methylator pathway. Our aim was to correlate clinical and genetic characteristics of CRC patients in order to understand clinical implications of tumour genotype. Methods: Single-institution retrospective cohort of patients who underwent curative surgery for CRC, from 2012 to 2014. RAS and BRAF mutations were evaluated with the real-time PCR technique Idylla®. Mismatch repair deficiency (dMMR) was characterized by absence of MLH1, MSH6, MSH2 and/or PMS2 expression, evaluated by tissue microarrays. Overall survival (OS) and disease-free survival (DFS) were assessed using survival analysis. Results: Overall, 242 patients were included (males 57.4%, age 69.3 ± 12.9 years; median follow-up 49 months). RAS-mutated tumours were associated with reduced DFS (p = 0.02) and OS (p = 0.045) in stage I–III CRC. BRAF-mutated tumours were more predominant in females and in the right colon, similarly to dMMR tumours. BRAF status did not influence OS (4 years)/DFS (3.5 years) in stage I–III disease. However, after relapse, length of survival was 3.5 months in BRAF-mutated tumours in contrast to 18.6 months in BRAF wild-type tumours (p = NS). No germline mutations in mismatch repair genes were so far identified in the patients with dMMR tumours. Molecular phenotype (RAS, BRAF and MMR) did not influence OS in metastatic patients. Our small sample size may be a limitation of the study. Conclusion: In our cohort, RAS-mutated tumours were associated with worse DFS and OS in early-stage CRC, whereas the remaining molecular variables had no prognostic influence.

Molecular profiling of the colon cancer in South-Eastern Romania: Results from the MERCUR study.

Colorectal cancer is a heterogeneous disease with multiple epigenetic alterations and different molecular features. The molecular classification is based on 2 major distinct pathways: microsatellite stable pathway and the microsatellite instability pathway. Molecular profiling of colorectal cancer provides important information regarding treatment and prognosis. Aim of the study was to assess the frequency of microsatellite instability in colon cancer and the clinicopathological characteristics of the tumors with high level of microsatellite instability (MSI-H) in our region. The secondary outcome was to assess the frequency of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in colon cancer.The study included 129 patients with colon cancer fit for surgery. Demographic data, clinical and pathological data, immunohistochemistry staining pattern (4 mismatch repair proteins were investigated), and BRAF gene mutations were assessed. According to microsatellite instability status by polymerase chain reaction, patients were divided into 3 groups: microsatellite stable (MSS) = 108 patients, high level of microsatellite instability (MSI-H) = 15 patients and low level of microsatellite instability (MSI-L) = 6 patients. Different clinicopathological comparisons between MSS and MSI-H patients, and between MSS and MSI-L patients were performed.Microsatellite instability was found in 16.3% patients: 11.6% had MSI-H and 4.7% had MSI-L. Significantly more patients in the MSI-H group than in the MSS group were female (P = .01) and had a family history of colon cancer (P < .001). MSI-H and MSI-L groups were associated with the ascending colon location of the tumors, were mostly type G3, T2, and stage I whereas MSS tumors were mostly G2, pT3, and stage III. Overall, BRAF mutations were identified in 18/129 patients (13.9%). BRAF mutant tumors were predominantly associated with MSI-H and MSI-L tumors. Immunohistochemistry had a sensitivity of 76% and a specificity of 89% in detecting MSI tumors and an accuracy of 87.6%.The frequency of microsatellite instability in our study was 16.3%. MSI-H is a distinct molecular phenotype of colon cancer with particular features: female gender, family history of colorectal cancer, a predilection for the ascending colon, poorly differentiated, predominantly T2, and stage I. The frequency of BRAF mutations was 13.9% and mutations were more often present in the MSI tumors.

Relationship between Microsatellite Status and Other Prognostic Factors in Patients with Colon Cancer

It is reported that 0.5-13 % of all colorectal cancers are hereditary. Many mutations that cause genomic instability have been described lately in this cancers; the most famous one is yet microsatellite instability pathway. Investigating the presence of these mutations is important in tailoring patients' treatment and predicting prognosis.&#x0D; Aims: We evaluated the association between micro satellite status and other pathologic prognostic factors like grade, tumor size, lymph node metastasis, lymphovascular invasion and perineural invasion in patients who underwent curative colon resection for colorectal cancers (CRC) in our clinic in the past five years.&#x0D; Study Design: A total of 205 sequential patients who were older than 18 and had curative colon resection for CRC in Ankara University Surgical Oncology Unit and been tested for microsatellite instability (MSI) were analyzed on behalf of the facultys’ database.&#x0D; Methodology: Pathology results had been determined and tumor localizations, lymph node metastasis status, grade, lymphovascular and perineural invasion status were evaluated. Information about MSI status and defected genes were obtained from detailed pathology reports. Patients were divided into two groups as MSI and MSS.&#x0D; Results: No significant difference was found between two the groups in the context of microsatellite instability status. Lymphovascular invasion had been seen higher in high frequency microsatellite instability (MSH-H) compared to low frequency microsatellite instability (MSH-L) group (76.4% vs 53.1%, P =.02). There was no statistical difference in perineural invasion between the two groups (P = 0.102). Signet ring cell status between the groups we found a higher rate of signet ring cells and consequently a higher grade in MSH-H group (17.6% vs 10.6%, P = 0.042).&#x0D; Conclusion: In conclusion, although many important points have been identified in our study, more studies are needed to compare the evaluation of MSI in colon cancer with other prognostic factors and to investigate its effect on the course of the disease.

Smoking and Colorectal Cancer Risk, Overall and by Molecular Subtypes: A Meta-Analysis.

The aim of this study was to provide the most comprehensive and up-to-date evidence on the association between cigarette smoking and colorectal cancer (CRC) risk. We conducted a systematic review and meta-analysis of epidemiological studies on the association between cigarette smoking and CRC risk published up to September 2018. We calculated relative risk (RR) of CRC according to smoking status, intensity, duration, pack-years, and time since quitting, with a focus on molecular subtypes of CRC. The meta-analysis summarizes the evidence from 188 original studies. Compared with never smokers, the pooled RR for CRC was 1.14 (95% confidence interval [CI] 1.10-1.18) for current smokers and 1.17 (95% CI 1.15-1.20) for former smokers. CRC risk increased linearly with smoking intensity and duration. Former smokers who had quit smoking for more than 25 years had significantly decreased risk of CRC compared with current smokers. Smoking was strongly associated with the risk of CRC, characterized by high CpG island methylator phenotype (RR 1.42; 95% CI 1.20-1.67; number of studies [n] = 4), BRAF mutation (RR 1.63; 95% CI 1.23-2.16; n = 4), or high microsatellite instability (RR 1.56; 95% CI 1.32-1.85; n = 8), but not characterized by KRAS (RR 1.04; 95% CI 0.90-1.20; n = 5) or TP53 (RR 1.13; 95% CI 0.99-1.29; n = 5) mutations. Cigarette smoking increases the risk of CRC in a dose-dependent manner with intensity and duration, and quitting smoking reduces CRC risk. Smoking greatly increases the risk of CRC that develops through the microsatellite instability pathway, characterized by microsatellite instability-high, CpG island methylator phenotype positive, and BRAF mutation.