Prognostic analysis of Yes-associated protein 1 in patients with colorectal cancer. A systematic review and meta-analysis

Background: colorectal cancer (CRC) is the most common carcinoma worldwide, but a lack of effective prognostic markers limits clinical diagnosis and treatment. Yes-associated protein 1 (YAP1) is an effector of the HIPPO-pathway, which plays a critical role in cancer development and prognosis, including CRC. However, previous reports have suggested that it plays a dual role in CRC. Methods: a meta-analysis using RevMan 5.4 and Stata 14.0 was performed to evaluate the relationship between YAP1 and clinical outcomes of CRC, after searching for eligible studies in the PubMed, Web of Science and Embase databases. Online datasets GEPIA and LOGpc were also used to calculate survival results and for comparison with the meta-analysis results. Besides, “DESeq” packages were used for the expression analysis of YAP1 from the TCGA dataset. Results: YAP1 was overexpressed in the cancer tissues when compared to normal tissues in patients with CRC from the TCGA database (p = 0.000164) and GEPIA database. A total of 10 studies involving 2305 patients from the literature were selected. Pooled HR indicated that overexpression of YAP1 was associated with poor clinical outcomes (HR = 1.70, 95 % CI: 1.28-2.26, p = 0.0003). Subgroup analysis showed a clear correlation between overexpression of YAP1 and worse survival rate in Chinese patients (HR = 1.94, 95 % CI: 1.40-2.69, p = 0.0001), nuclear YAP1 overexpression (HR = 2.07, 95 % CI: 1.29-3.31, p = 0.003), 60 months of follow-up (HR = 1.89, 95 % CI: 1.30-2.73, p = 0.0008), IHC test (HR = 1.65, 95 % CI: 1.17-2.33, p = 0.005), IHC combined with other tests (HR = 1.77, 95 % CI: 1.13-2.77, p = 0.01) and multivariate analysis (HR = 1.70, 95 % CI: 1.24-2.31, p = 0.0009). Nevertheless, disease-free survival (DFS) showed no significant results in the patients with CRC in our meta-analysis (HR = 1.38, 95 % CI: 0.51-3.75, p = 0.52) as well as in the GEPIA and LOGpc databases. ... (AU)

Difference between right-sided and left-sided colorectal cancers: from embryology to molecular subtype.

INTRODUCTION: Colorectal cancer is one of the most common malignancies in the world, and it exhibits differences in incidence, pathogenesis, molecular pathways, and outcome depending on the location of the tumor. Differences in the microbiome, clinical characteristics, and chromosomal and molecular characteristics have been reported between the right and left side of the colon. Areas covered: This review focuses on the latest developments in epidemiological and chromosomal and molecular studies, which have enhanced our understanding on the underlying genetic and immunological differences between the right-sided colon and the left-sided colorectum in metastatic colorectal cancer. Expert commentary: The numerous findings regarding differences between right- and left-sided colon cancers should have an impact on colorectal cancer screening and therapy. The location of the colorectal cancer should be considered before group stratification into genetic, clinical, and especially chemotherapy trials. A more tailored approach to colon cancer treatment would be highly desirable if future trials further support the hypothesis of two distinct tumor entities.

Embryonic Origin of Primary Colon Cancer Predicts Pathologic Response and Survival in Patients Undergoing Resection for Colon Cancer Liver Metastases.

BACKGROUND: The aim of this study was to determine the prognostic value of embryonic origin in patients undergoing resection after chemotherapy for colon cancer liver metastases (CCLM). METHODS: We identified 725 patients with primary colon cancer and known RAS mutation status who underwent hepatic resection after preoperative chemotherapy for CCLM (1990 to 2015). Survival after resection of CCLM from midgut origin (n = 238) and hindgut origin (n = 487) was analyzed. Predictors of pathologic response and survival were determined. Prognostic value of embryonic origin was validated with a separate cohort of 252 patients with primary colon cancer who underwent resection of CCLM without preoperative chemotherapy. RESULTS: Recurrence-free survival (RFS) and overall survival (OS) after hepatic resection were worse in patients with midgut origin tumors (RFS rate at 3 years: 15% vs 27%, P < 0.001; OS rate at 3 years: 46% vs 68%, P < 0.001). Independent factors associated with minor pathologic response were midgut embryonic origin [odds ratio (OR) 1.55, P = 0.010], absence of bevacizumab (OR 1.42, P = 0.034), and mutant RAS (OR 1.41, P = 0.043). Independent factors associated with worse OS were midgut embryonic origin [hazard ratio (HR) 2.04, P < 0.001], carcinoembryonic antigen value ≥5 ng/mL at hepatic resection (HR 1.46, P = 0.0021), synchronous CCLM (HR 1.45, P = 0.012), and mutant RAS (HR 1.43, P = 0.0040). In the validation cohort, patients with CCLM of midgut origin had a worse 3-year OS rate (55% vs 78%, P = 0.003). CONCLUSIONS: Compared with CCLM from hindgut origin, CCLM from midgut origin are associated with worse pathologic response to chemotherapy and worse survival after resection. This effect appears to be independent of RAS mutation status.

Incidence of colorectal cancer in new users and non-users of low-dose aspirin without existing cardiovascular disease: A cohort study using The Health Improvement Network.

BACKGROUND: Evidence regarding the chemo-protective effects of aspirin has influenced expert opinion in favour of low-dose aspirin use in certain patient populations without cardiovascular disease (CVD). The effects of aspirin in reducing the incidence of colorectal cancer (CRC) may be a large contributor to this favourable risk-benefit profile of low-dose aspirin in primary CVD prevention. METHODS: Using The Health Improvement Network, we estimated the incidence of CRC in individuals free of CVD and either prescribed or not prescribed prophylactic low-dose aspirin. Two cohorts - new-users of low-dose aspirin (N=109,426) and a comparator cohort of non-users (N=154,056) at start of follow-up - were followed (maximum 13years) to identify incident CRC cases. Individuals with a record of CVD, cancer or low-dose aspirin prescription before start of follow-up were excluded. RESULTS: 2330 incident cases of CRC occurred; 885 in the aspirin cohort and 1445 in the comparator cohort, after mean follow-ups of 5.43years and 5.17years, respectively. Incidence rates of CRC per 10,000 person-years (95% confidence interval) were 14.90 (13.95-15.92) in the aspirin cohort and 18.15 (17.24-19.12) in the comparator cohort; incidence rate ratio 0.82 (0.76-0.89) adjusted for age, sex and primary care practitioner (PCP) visits in the previous year. Lower incidence rates were seen in the aspirin cohort for all strata evaluated (gender, age group and number of PCP visits in the previous year) except those aged ≥80years. CONCLUSION: Among most individuals without established CVD, initiation of low-dose aspirin is associated with a reduced incidence of CRC.

Birth size and colorectal cancer risk: a prospective population based study.

OBJECTIVE: To study whether birth size influences colorectal cancer risk in adulthood. DESIGN: A cohort of Norwegian men and women identified from midwives' birth records with long term cancer follow up through the Norwegian Cancer Registry. SETTING: St Olav's University Hospital, Trondheim, Norway. PARTICIPANTS: 16,016 women and 19 681 men born between 1920 and 1958 and alive in 1960. OUTCOME MEASURES: Incidence rate ratios (RRs) for colorectal cancer with 95% confidence intervals (CIs) and two sided p values for trend across categories of birth dimensions. RESULTS: Men whose birth length was less than 51 cm had a nearly twofold higher risk of colorectal cancer (RR 1.9 (95% CI 1.0-3.7)) compared with men who were 53 cm or more, after adjustment for birth cohort, maternal age at childbearing, length of gestation, gestational hypertension or pre-eclampsia, birth order, maternal height, and indicators of maternal socioeconomic status. The association displayed a linear trend across categories of birth length (p(trend) = 0.03). Among men, similar associations were found for birth weight and head circumference, but for women there was no association between any of these birth dimensions and risk of colorectal cancer. CONCLUSION: The results suggest that among men, but not women, being relatively short at birth is associated with increased risk of colorectal cancer in adulthood, indicating that intrauterine growth could be important for colorectal carcinogenesis.

Transcriptional regulation in intestinal development. Implications for colorectal cancer.

Deciphering the complex mechanisms of intestinal epithelial development will require multiple cell and molecular approaches in both in vitro and whole animal systems. Additionally, the use of model organisms such as D. melanogaster, C. elegans, and zebrafish will help describe paradigms that may be investigated in mammals as well as serve as test systems for findings from mammals. This manuscript reviewed only one approach to understanding intestinal development. However, the Cdx story and the information to be mined from an understanding of SI gene transcription is not at an end. As the other pieces of the transcriptional puzzle of the SI gene are assembled there will be new information to generate hypotheses on the relationship of transcriptional mechanisms to cancer pathogenesis.

A prospective study of methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms, and risk of colorectal adenoma.

We examined the relationship between a functional polymorphism (667C-->T, ala-->val) of the methylenetetrahydrofolate reductase gene (MTHFR) and the risk of colorectal adenomas in the prospective Nurses' Health Study. Among 257 incident polyp cases and 713 controls, the MTHFR val/val polymorphism [relative risk (RR) = 1.35, 95% confidence interval (CI) 0.84-2.17] was not significantly associated with risk of adenomas. This lack of association was observed for both small (RR = 1.36, 95% CI 0.76-2.45) and large (RR = 1.32, 95% CI 0.66-2.66) adenomas. Furthermore, there was no significant interaction between this polymorphism and consumption of either folate, methionine or alcohol. We also examined the relationship of a newly identified polymorphism (asp919gly) of the methionine synthase gene (MS) with the risk of colorectal adenomas in the same population. The MS gly/gly polymorphism was also not significantly associated with risk of colorectal adenomas (RR = 0.66, 95% CI 0.26-1.70). These results, which need to be confirmed in other studies, suggest that the MTHFR val/val polymorphism, which has been previously inversely associated with risk of colorectal cancer, plays a role only in a late stage (adenoma-->carcinoma) of colorectal tumorigenesis, and/or may protect against malignant transformation in the subset of benign adenomas, which may progress to malignancy.