18q loss of heterozygosity in microsatellite stable colorectal cancer is correlated with CpG island methylator phenotype-negative (CIMP-0) and inversely with CIMP-low and CIMP-high

<p>Abstract</p> <p>Background:</p> <p>The CpG island methylator phenotype (CIMP) with widespread promoter methylation is a distinct epigenetic phenotype in colorectal cancer, associated with microsatellite instability-high (MSI-high) and <it>BRAF </it>mutations. 18q loss of heterozygosity (LOH) commonly present in colorectal cancer with chromosomal instability (CIN) is associated with global hypomethylation in tumor cell. A recent study has shown an inverse correlation between CIN and CIMP (determined by MINTs, p16, p14 and <it>MLH1 </it>methylation) in colorectal cancer. However, no study has examined 18q LOH in relation to CIMP-high, CIMP-low (less extensive promoter methylation) and CIMP-0 (CIMP-negative), determined by quantitative DNA methylation analysis.</p> <p>Methods:</p> <p>Utilizing MethyLight technology (real-time PCR), we quantified DNA methylation in 8 CIMP-specific promoters {<it>CACNA1G</it>, <it>CDKN2A </it>(p16), <it>CRABP1, IGF2</it>, <it>MLH1, NEUROG1, RUNX3 </it>and <it>SOCS1</it>} in 758 non-MSI-high colorectal cancers obtained from two large prospective cohorts. Using four 18q microsatellite markers (D18S55, D18S56, D18S67 and D18S487) and stringent criteria for 18q LOH, we selected 374 tumors (236 LOH-positive tumors with ≥ 2 markers showing LOH; and 138 LOH-negative tumors with ≥ 3 informative markers and no LOH).</p> <p>Results:</p> <p>CIMP-0 (0/8 methylated promoters) was significantly more common in 18q LOH-positive tumors (59% = 139/236, p = 0.002) than 18q LOH-negative tumors (44% = 61/138), while CIMP-low/high (1/8–8/8 methylated promoters) was significantly more common (56%) in 18q LOH-negative tumors than 18q LOH-positive tumors (41%). These relations persisted after stratification by sex, location, or the status of MSI, p53 expression (by immunohistochemistry), or <it>KRAS/BRAF </it>mutation.</p> <p>Conclusion:</p> <p>18q LOH is correlated positively with CIMP-0 and inversely with CIMP-low and CIMP-high. Our findings provide supporting evidence for relationship between CIMP-0 and 18q LOH as well as a molecular difference between CIMP-0 and CIMP-low in colorectal cancer.</p

Comprehensive Biostatistical Analysis of CpG Island Methylator Phenotype in Colorectal Cancer Using a Large Population-Based Sample

The CpG island methylator phenotype (CIMP) is a distinct phenotype associated with microsatellite instability (MSI) and BRAF mutation in colon cancer. Recent investigations have selected 5 promoters (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1) as surrogate markers for CIMP-high. However, no study has comprehensively evaluated an expanded set of methylation markers (including these 5 markers) using a large number of tumors, or deciphered the complex clinical and molecular associations with CIMP-high determined by the validated marker panel. METHOLODOLOGY/PRINCIPAL FINDINGS: DNA methylation at 16 CpG islands [the above 5 plus CDKN2A (p16), CHFR, CRABP1, HIC1, IGFBP3, MGMT, MINT1, MINT31, MLH1, p14 (CDKN2A/ARF) and WRN] was quantified in 904 colorectal cancers by real-time PCR (MethyLight). In unsupervised hierarchical clustering analysis, the 5 markers (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1), CDKN2A, CRABP1, MINT31, MLH1, p14 and WRN were generally clustered with each other and with MSI and BRAF mutation. KRAS mutation was not clustered with any methylation marker, suggesting its association with a random methylation pattern in CIMP-low tumors. Utilizing the validated CIMP marker panel (including the 5 markers), multivariate logistic regression demonstrated that CIMP-high was independently associated with older age, proximal location, poor differentiation, MSI-high, BRAF mutation, and inversely with LINE-1 hypomethylation and beta-catenin (CTNNB1) activation. Mucinous feature, signet ring cells, and p53-negativity were associated with CIMP-high in only univariate analysis. In stratified analyses, the relations of CIMP-high with poor differentiation, KRAS mutation and LINE-1 hypomethylation significantly differed according to MSI status.Our study provides valuable data for standardization of the use of CIMP-high-specific methylation markers. CIMP-high is independently associated with clinical and key molecular features in colorectal cancer. Our data also suggest that KRAS mutation is related with a random CpG island methylation pattern which may lead to CIMP-low tumors

Supporting Communities of Practice by Enterprise Social Platforms: The Case of an Engineering Company

Information and communication technology (ICT) is a key pillar of supporting CoPs. Virtual CoPs (i.e.: CoPs applying technology enabling asynchronous and distant communications), are growing in numbers. The increase is supported by the availability of new ICT, like for example Enterprise Social Platforms (ESP). ESPs support CoP however empirical based studies investigating ESP application in the context of intentionally developed CoPs are still scarce. This study contributes to filling this gap by exploring CoP participants\u2019 behaviour which includes use of an ESP. In particular, we investigate the case of a global engineering company specialized in pharmacy, that has an explicit strategy of developing global CoPs to improve internal knowledge exchange and collaboration processes. At present, 20 active communities involve about 1400 employees. The ESP \u2018Connect\u2019 supports the CoPs. The case company is explored through an online survey comprising 22 questions that was distributed via \u2018Connect\u2019 between September and October 2018. 262 responses were collected (Response rate app. 19%) from employees located in 8 different countries. According to the CoP participants can be divided into two groups that have distinctly different behaviour; active and passive. The \u2018Active\u2019 group rely significantly more on external sources and especially on Connect than passive users. Also, the \u2018active\u2019 group is more satisfied with 'Connect\u2019 and participate in collaborations. The \u2018passive\u2019 group relies on information from nearest colleagues and rarely contribute to conversations on \u2018Connect\u2019. The paper contributes with knowledge about how participants in CoPs supported by ESPs behave differently and thus might be motivated differently

Enterprise Social Media Users\u2019 Typology: a Bi-dimensional Classification

The use of Enterprise Social Media (ESM) platforms is rapidly diffusing in the business context, as they are increasingly considered crucial for the future competition. In particular, as commonly underlined by scholars, ESM can bring substantial benefits to companies and especially to their knowledge management (KM) processes. However, such benefits can materialize only if the active use and contribution by individual employees to ESM are ensured. Therefore, it is crucial to better understand how and how much an ESM platform is used by a company\u2019s employees. This explains why the literature is devoting particular attention to the analysis of the level of participation and the type of activity performed by the users of such platforms. While \u201cfrequency of use\u201d is the most considered dimension to classify different users\u2019 groups, scholars also resort to other dimensions, as the distinction between passive and active users, sometimes called as \u201cposters\u201d and \u201clurkers\u201d. The paper proposes a new typology of ESM users based on the results of a survey, which involved 262 employees of an international engineering project-based service company that has adopted an ESM platform. What emerged from the analysis of the survey data confirmed the existence of different types of ESM users and provided the empirical basis to develop a users\u2019 typology based on two dimensions: frequency (high vs. low) of use and kind (active vs. passive) of use. This allowed identifying four different users\u2019 groups (of different size but all populated), that were denoted as: \u201cfrequent contributors\u201d, \u201csporadic contributors\u201d, \u201cfrequent lurkers\u201d and \u201csporadic lurkers\u201d. Furthermore, applying descriptive statistics and variance analysis on the survey data allowed to verify the reasonableness of the proposed new typology and identify the main aspects that characterise the different users\u2019 groups such as: position in the company, role inside the community, specific types of relevant knowledge sources, perceived usefulness, information novelty and satisfaction with the platform and the Community of Practice. The findings of the study have both academic and managerial implications. As regards the latter, managers should consider that different employees might behave differently with respect to new media, so that an undifferentiated approach to different behaviours may be ineffective. The main limitation of the study is that only one company was analysed belonging to a particular sector with specific knowledge needs and capabilities

Social Media use in Communities of Practice: insights from an Engineering Service Company

The use of Communities of Practice (CoPs) to support knowledge sharing and collaboration within organisations has been increasing over the years. Today, many different companies from various sectors are deliberately resorting to CoPs to better managing cognitive assets and improving business performance. In particular, the availability of the new web-based technologies, like for example Enterprise Social Media platforms, are promoting the widespread utilisation of virtual CoPs, i.e. CoPs that make use of ICTs to enable distant and asynchronous communications among members. Even though the \u201cmarriage\u201d of Social Media with CoPs seems to be perfect, studies that investigate the use of the new social applications in the context of CoPs are still scarce. To contribute to fill this gap, the present paper analyses the factors that influence the frequency of CoP access by means of a Social Media platform. Specifically, the paper illustrates and discusses the results of a survey which involved 262 employees of an international engineering project-based service company that eight years ago established several global CoPs in order to improve internal knowledge exchange and collaboration processes. At present, inside the company there are 20 active communities, involving about 1,400 project execution employees, whose functioning is supported by a Social Media platform dubbed Connect. The survey, that included 22 questions, was administered online between September and October 2018. The findings of the survey have allowed to identify some factors that result to be strictly correlated with the frequency of use of the Social Media platform to interact with the others community members. Among others these are: position in the company, role inside the community, individual motivation, kind of use, perceived technical and organizational obstacles. The paper contributes to advance the research about the adoption of Social Media technologies as knowledge management tools by identifying some factors that influence their use inside a CoP. It also provides useful suggestions to managers who intend to promote the development of Social Media enabled virtual Communities of Practices. The main limitation of the study is that it bases on the experience of only one company working in a specific industry with specific knowledge needs and capabilities. In spite of this, the findings provide interesting insights that can be a basis for future investigations as well as suggestions to managers willing to create and sustain virtual CoPs