Immune-related gene signature in predicting prognosis of early-stage colorectal cancer patients

AimImmune-related genes are associated with the prognosis of colorectal cancer (CRC) patients. The aim of this study was to evaluate the impact of an immune-related gene signature (IRGS) in predicting the prognosis of early-stage CRC patients.MethodsIn total, 309 CRC patients were selected for the identification of prognostic IRGS using the CIT/GSE39582 microarray dataset. Five independent datasets including 1587 CRC patients were divided into a training cohort (n = 566) and two validation cohorts (n = 624 in validation-1 and n = 397 in meta-validation). Prognostic analyses were performed to test the predictive value of IRGS.ResultsA prognostic IRGS that included 23 immune-related genes was constructed and significantly stratified patients into immune low-vs. high-risk groups in terms of disease-free survival using patients with early-stage disease (I or II) in the training cohort. Similarly, a higher IRGS was correlated with significantly worse prognosis of early-stage patients in validation-1 and meta-validation cohorts. Compared with Oncotype DX colon, we found that IRGS exhibited an improved survival correlation in the training cohort. After integration with clinical characteristics, IRGS remained as an independent prognostic factor in multivariate analysis. Furthermore, IRGS-stratified immune low-risk group patients gained less benefit from adjuvant chemotherapy in the validation-1 cohort. Several biological processes, including inflammatory response, were enriched among genes in identified the immune high-risk group. Consistent with this finding, the IRGS-identified immune high-risk group exhibited significantly increased immune and stromal cell infiltration.ConclusionThe proposed prognostic IRGS is a promising system for estimating DFS of colorectal cancer patients, especially those with early-stage disease.     

Correction to: Risk of first onset of colorectal cancer associated with alcohol consumption in Lynch syndrome: a multicenter cohort study

Background

Complex interactions among endogenous and exogenous factors influence the incidence of colorectal cancer (CRC). Germline mutations in mismatch repair (MMR) genes causing Lynch syndrome (LS) are major endogenous factors. The exogenous factor, alcohol consumption, is potentially associated with CRC incidence among patients with LS. However, insufficient data are available to determine whether alcohol consumption influences the time of the first onset of CRC associated with sex, MMR gene mutations, and anatomical tumor site.

Methods

Among 316 patients with LS identified in a Japanese LS cohort, we included 288 with data on age, sex, proband status, alcohol status, smoking status, tumor location, and MMR gene mutations. Multivariable analysis assessed the association of alcohol consumption with earlier onset of the first CRC.

Results

Ever drinkers were associated with higher risk of the first onset of CRC than never drinkers (HR 1.54, 95%CI 1.14–2.07, P = 0.004). The association of the first onset of CRC with alcohol consumption was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations (vs those with pathogenic MSH6, PMS2 and EPCAM mutations), and tumors in the proximal colon cancer (vs distal colon and rectal cancer).

Conclusions

Alcohol consumption was associated with earlier onset of the first CRC in Japanese LS cohort. The association was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations, and tumors located in the proximal colon. Our findings illuminate the mechanism of LS-associated carcinogenesis and serve as a recommendation for discontinuing or ceasing alcohol consumption.

     

Brain Metastases from Colorectal Cancer: Risk Factors,Incidence, and the Possible Role of Chemokines

BackgroundBrain metastases from colorectal cancer (CRC) are uncommon. There has been relatively little published on the host and tumor factors that might lead to this clinical scenario. We reviewed all cases of brain metastases from CRC at Dartmouth-Hitchcock Medical Center over a more than 20-year period to establish incidence and to identify patient and cancer characteristics which were associated with their development.Patients and MethodsWe present a retrospective review of 39 confirmed cases of brain metastases from CRC diagnosed between 1984 and 2006. Immunohistochemical staining for CXCR4 was performed on all available brain metastasis biopsy specimens.ResultsThe incidence of brain metastases from CRC was 2.3%. Left-sided primary colon tumors predominated. The majority of patients had pulmonary metastases at the time brain metastases were identified, and those with preexisting pulmonary metastases had progression of that disease. All patients were symptomatic from brain metastases, and the cerebellum was the most common area of brain involvement. Immunohistochemical analysis confirmed strong expression of CXCR4 in all brain metastases sampled.ConclusionThe incidence of brain metastases from CRC is low. Primary tumor in the left colon, long-standing pulmonary metastases, especially those with recent progression, and CXCR4 expression by tumor cells are all associated with increased risk of brain metastases. Increased survival among patients with metastatic CRC will likely result in an increased incidence of brain metastases. Further characterization of the role of tumor and host factors might yield better insight into the development, and potentially the prevention, of this devastating situation.     

Prognosis model of colorectal cancer patients based on NOTCH3, KMT2C,and CREBBP mutations

BackgroundColorectal cancer (CRC) is one of the most common cancers. The aim of our study was to explore its related mutations, identify novel mutation markers, and construct predictive models for postoperative CRC patients, so as to provide evidence for the diagnosis, treatment, and prognosis of CRC.MethodsA total 50 CRC patients were collected, and the mutations in tissue samples were detected through next-generation sequencing (NGS). Meanwhile, 246 CRC cases with complete mutation data were downloaded from The Cancer Genome Atlas (TCGA) database. Afterwards, the co-mutations in both clinical and TCGA cohorts were identified, and the high-frequency mutation genes were selected. Subsequently, functional enrichment analysis was performed, and overall survival (OS) and progression-free survival (PFS) predictive models were constructed.ResultsIn all, 18 out of 238 co-mutation genes mutated in at least 20% of the samples and were selected out as common high-frequency mutation genes. They were significantly enriched in 460 Gene Ontology (GO) terms and 87 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (P<0.05), which were closely related to the occurrence and development of CRC. Among the 18 genes, NOTCH3, histone lysine methyltransferase 2C (KMT2C), and cAMP-response element binding protein-BP (CREBBP) were respectively associated with tumor position, stage, and PFS (P<0.05), and could be considered as potential biomarkers of CRC. Finally, OS and PFS predictive models were constructed and verified using the 50 clinical cases, with both models demonstrating high fitting degrees useful for predicting the OS and PFS of CRC patients.ConclusionsNOTCH3, KMT2C, and CREBBP were found to be prospective biomarkers for the diagnosis and prognosis of CRC. The prognosis prediction models had high sensitivity and could be used to predict the OS and PFS of CRC patients.     

PRDM14 promotes malignant phenotype and correlates with poor prognosis in colorectal cancer

Background

Emerging evidence suggests that stemness in cancer cells is a cause of drug resistance or metastasis and is an important therapeutic target. PR [positive regulatory domain I-binding factor 1 (PRDI-BF1) and retinoblastoma protein-interacting zinc finger gene (RIZ1)] domain containing 14 (PRDM14), that regulates pluripotency in primordial germ cell, has reported the overexpression and function of stemness in various malignancies, suggesting it as the possible therapeutic target. However, to our knowledge, there have been no reports on the expression and function of PRDM14 in colorectal cancer (CRC). Therefore, we investigated the expression and the role of PRDM14 in CRC.

Methods

We performed immunohistochemistry evaluations and assessed PRDM14 expression on 414 primary CRC specimens. Colon cancer cell lines were subjected to functional and stemness assays in vitro and in vivo.

Results

We found that PRDM14 positive staining exhibited heterogeneity in the CRC primary tumor, especially at the tumor invasion front. The aberrant expression of PRDM14 at the invasion front was associated with lymph node metastasis and disease stage in patients with CRC. Furthermore, the multivariate analysis revealed high PRDM14 expression as an independent prognostic factor in the patients with Stage III CRC. Overexpression of PRDM14 enhanced the invasive, drug-resistant and stem-like properties in colon cancer cells in vitro and tumorigenicity in vivo.

Conclusion

Our findings suggest that PRDM14 is involved in progression and chemoresistance of CRC, and is a potential prognostic biomarker and therapeutic target in the CRC patients.

     

Proximal Shift of Colorectal Cancer Along With Aging

IntroductionAlthough several reports have documented the increased incidence of right-sided colorectal cancer (CRC) in the elderly, especially in women, the gender-specific, age-related changes in the characteristics of CRCs, especially related to the cancer localization, have not been fully investigated. This study evaluated the age-related changes in the clinicopathologic features of CRCs, according to the gender.Materials and MethodsA total of 1059 consecutive patients with CRCs who were admitted to the authors' surgical department between February 2005 and June 2012 were retrospectively reviewed. The patients were divided into male (n = 632) and female (n = 427) groups and then according to the age group, and the correlation between the age group and the other clinicopathologic features was analyzed by univariate and multivariate analysis.ResultsThe number of concomitant adenomas found was significantly increased along with increasing age in men, and the presence of concomitant adenoma was the only independent age-related factor of male CRC in the multivariate analysis (P = .0044). In contrast, in women, the location of the CRC progressively shifted to the right side (proximal colon) with increasing age, and the presence of right-sided CRC was the only independent factor of female CRC in the multivariate analysis (P < .0001).ConclusionThere was a significant gender-specific difference in the age-related changes in the characteristics of CRC. Increasing the number of concomitant adenomas and the shift of CRC localization to the proximal colon were the gender-specific characteristics of male and female CRC, respectively.     

On-going improvement and persistent differences in the survival for patients with colon and rectum cancer across Europe 1999–2007 – Results from the EUROCARE-5 study

BackgroundPrevious population-based studies revealed major variation in survival for patients with colorectal cancer (CRC) in Europe by age and between different countries and regions, but also a sustained improvement in survival for patients with CRC in recent years. This EUROCARE-5 paper aims to update available knowledge from previous studies and to provide the latest survival estimates for CRC patients from Europe.MethodsThe study analysed data of patients diagnosed with CRC from population-based cancer registries diagnosed in 29 European countries. Estimates of 1-year and 5-year relative survival (RS) were derived for patients diagnosed in 2000–2007 by European region, country and age at diagnosis. Additionally to these cohort estimates, time trends in 5-year RS were obtained for the calendar periods 1999–2001 and 2005–2007, using the period analysis methodology.ResultsEuropean average 5-year RS for patients diagnosed with colon and rectum cancer was 57% and 56%, respectively. The analyses showed persistent differences in cancer survival across Europe with lowest survival for CRC patients observed in Eastern Europe. The analyses further showed a strong gradient in age-specific survival. Even though the study revealed sustained improvement in patient survival between 1999–2001 and 2005–2007 (absolute increase of 4 and 6 percentage points for colon and rectum, respectively), the differences in the survival for CRC patients observed at the beginning of the millennium persisted over time.ConclusionAlthough survival for CRC patients in Europe improved markedly in the study period, significant geographic variations and a strong age gradient still persisted. Enhanced access to effective diagnostic procedures and treatment options might be the keys to reducing the existing disparities in the survival of CRC patients across Europe.     

Postoperative mortality in elderly patients with colorectal cancer: The impact of age,time-trends and competing risks of dying

BackgroundWorse prognosis in elderly colorectal cancer (CRC) patients may be cancer or treatment related, or death from other causes. This population-based study aimed to compare survival among non-metastatic CRC patients between age groups and notice time trends in mortality rates.MethodsPrimary stage I-III CRC patients who underwent resection between 2008 and 2013 were selected from the Netherlands Cancer Registry. Patients were divided into three equally distributed age groups and a separated group including the oldest old (<65, 65–74, 75–84 and ≥ 85 years). Survival rates were calculated by age groups and tumour localization. Relative excess risks of death, 30-day, 1-year mortality and 1-year excess mortality were calculated.Results52296 patients were included. Age-related differences in 5-year overall survival were observed (colon cancer: 82%, 73%, 56% and 35%; rectal cancer: 82%, 74%, 56% and 38%; p < 0.0001). Age-related differences were less prominent in relative survival and disappeared in conditional relative survival (condition of surviving 1 year). Thirty-day mortality rates decreased over time (colon cancer: 4.9%–3.4%; rectal cancer: 3.0%–1.7%); 1-year mortality rates decreased from 11.9% to 9.6% in colon cancer and from 8.0% to 6.4% in rectal cancer. One-year excess mortality increased with age (17.3% and 12.9% in patients with colon or rectal cancer aged ≥85 years).ConclusionOne-year mortality rates remain high in elderly patients. Age-related differences in survival disappeared after adjustment for expected death from other causes and first-year mortality. Beneficial time trends in 1-year mortality rates underline that survival in elderly after CRC surgery is modifiable.     

Conditional survival for long-term colorectal cancer survivors in the Netherlands: who do best?

AimWith the increase in the number of long-term colorectal cancer (CRC) survivors, there is a growing need for subgroup-specific analysis of conditional survival.MethodsAll 137,030 stage I–III CRC patients diagnosed in the Netherlands between 1989 and 2008 aged 15–89 years were selected from the Netherlands Cancer Registry. We determined conditional 5-year relative survival rates, according to age, subsite and tumour stage for each additional year survived up to 15 years after diagnosis as well as trends in absolute risks for and distribution of causes of death during follow-up.ResultsMinimal excess mortality (conditional 5-year relative survival >95%) was observed 1 year after diagnosis for stage I colon cancer patients, while for rectal cancer patients this was seen after 6 years. For stage II and III CRC, minimal excess mortality was seen 7 years after diagnosis for colon cancer, while for rectal cancer this was 12 years. The differences in conditional 5-year relative survival between colon and rectal cancer diminished over time for all patients, except for stage III patients aged 60–89 years. The absolute risk to die from CRC diminished sharply over time and was below 5% after 5 years. The proportion of patients dying from CRC decreased over time after diagnosis while the proportions of patients dying from other cancers, cardiovascular disease and other causes increased.ConclusionPrognosis for CRC survivors improved with each additional year survived, with the largest improvements in the first years after diagnosis. Quantitative insight into conditional relative survival estimates is useful for caregivers to inform and counsel patients with stage I–III colon and rectal cancer during follow-up.     

High expression of the cysteine proteinase legumain in colorectal cancer – Implications for therapeutic targeting

BackgroundThe cysteine proteinase legumain is highly expressed in cancer. Legumain is a potential biomarker and has been suggested to be utilised for prodrug activation in cancer therapy. However, to define the suitability of legumain for such purposes, detailed knowledge of cell type-specific and subcellular expression together with proteolytic activity patterns in tumour tissue is necessary.MethodsExpression of legumain was examined in a panel of 277 primary tumours from colorectal cancer (CRC) patients using immunohistochemistry. Tumour (cytoplasmic diffuse, cytoplasmic granulated, and nuclear) and stromal cell expression of legumain was quantified, and associations with clinicopathological parameters and outcome were analysed. Additionally, normal colon tissue and spontaneous mouse tumours were stained for legumain.ResultsLegumain was highly expressed in tumour and stromal cells. Nuclear legumain was detected in 30% of the tumours. In colon cancer patients, high legumain expression was associated with overall and metastasis-free survival (OS; MFS) in uni- and multivariate analysis. Nuclear legumain was associated with poor OS, but not MFS in the colon cancer subgroup. Cytoplasmic granulated or diffuse expression was not associated with OS or MFS. Normal epithelial cells exhibited granulated legumain mainly at the apical pole, and legumain was highly expressed in CD68 positive macrophages.ConclusionsLegumain is a highly expressed proteinase in CRC and associated with poor outcome in colon cancer. Diversified localisation of legumain expression in tumour and stromal cells suggests multiple functions in CRC, representing both a challenge and an opportunity for use in therapeutic targeting.     

Survival of surgical and non-surgical older patients with non-metastatic colorectal cancer: A population-based study in the Netherlands

BackgroundSurgery is the primary treatment for non-metastatic colorectal cancer (CRC) but is omitted in a proportion of older patients. Characteristics and prognosis of non-surgical patients are largely unknown.ObjectiveTo examine the characteristics and survival of surgical and non-surgical older patients with non-metastatic CRC in the Netherlands.MethodsAll patients aged ≥70 years and diagnosed with non-metastatic CRC between 2014 and 2018 were identified in the Netherlands Cancer Registry. Patients were divided based on whether they underwent surgery or not. Three-year overall survival (OS) and relative survival (RS) were calculated for both groups separately. Relative survival and relative excess risks (RER) of death were used as measures for cancer-related survival.ResultsIn total, 987/20.423 (5%) colon cancer patients and 1.459/7.335 (20%) rectal cancer patients did not undergo surgery. Non-surgical treatment increased over time from 3.7% in 2014 to 4.8% in 2018 in colon cancer patients (P = 0.01) and from 17.1% to 20.2% in rectal cancer patients (P = 0.03). 3 year RS was 91% and 9% for surgical and non-surgical patients with colon cancer, respectively. For rectal cancer patients this was 93% and 37%, respectively. In surgical patients, advanced age (≥80 years) did not decrease RS (colon; RER 0.9 (0.7–1.0), rectum; RER 0.9 (0.7–1.1)). In non-surgical rectal cancer patients, higher survival rates were observed in patients treated with chemoradiotherapy (OS 56%, RS 65%), or radiotherapy (OS 19%, RS 27%), compared to no treatment (OS 9%, RS 10%).ConclusionNon-surgical treatment in older Dutch CRC patients has increased over time. Because survival of patients with colon cancer is very poor in the absence of surgery, this treatment decision must be carefully weighed. (Chemo-)radiotherapy may be a good alternative for rectal cancer surgery in older frail patients.     

Predictors of undergoing multivisceral resection,margin status and survival in Dutch patients with locally advanced colorectal cancer

BackgroundThe aim of this nationwide observational study was to evaluate factors associated with multivisceral resection (MVR), margin status and overall survival in locally advanced colorectal cancer (CRC).Material and methodsPatients with (y)pT4, cM0 CRC between 2006 and 2017 were selected from the Netherlands Cancer Registry. Cox-proportional hazards modelling was used for survival analysis, stratified for T4a and T4b. Annual hospital volume cut-off was 75 for colon and 40 for rectal resections.ResultsA total of 11.930 patients were included and 2410 patients (20.2%) underwent MVR. Factors associated with MVR for colon and rectal cancer besides cT4 category were more recent diagnosis (OR 3.61, CI 95% 3.06–4.25 (colon) and OR 2.72, CI 95% 1.82–4.08 (rectum)) and high hospital volume (OR 1.20, CI 95% 1.05–1.38 (colon) and OR 2.17, CI 95% 1.55–3.04 (rectum)). Patients ≥70 year were less likely to undergo MVR for colon cancer (OR 0.80, 95% CI 0.70–0.90). Risk factors for incomplete resection were cT4 (OR 3.08, CI 95% 2.35–4.04 (colon) and OR 1.82, CI 95% 1.13–2.94 (rectum)) and poor/undifferentiated tumors (OR 1.41, CI 95% 1.14–1.72 (colon) and OR 1.69, CI 95% 1.05–2.74 (rectum)). More recent diagnosis was independently associated with less incomplete resections in colon cancer (OR 0.58, CI 95% 0.40–0.76). Independent predictors of survival were age, resection margin, nodal status and adjuvant chemotherapy, but not MVR.ConclusionTreatment of locally advanced CRC with MVR at population level was influenced by year of diagnosis and hospital volume. Margin status in colon cancer improved substantially over time.     

A Study of the MTHFR Gene Polymorphism C677T in Colorectal Cancer

PurposeThe aim of this study was to examine the clinical significance of the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T in colorectal cancer (CRC). The hypothesis was that the genotype could affect the risk of cancer development and the results of cancer treatment.Patients and MethodsGenotyping was made for a random 30% (n = 544) of all patients treated for CRC at our unit from 1999 to 2006 (n = 1812). Basic clinical and pathologic factors were analyzed by genotype group and also compared with those of the entire cohort. Tolerability of chemotherapy and possible side effects were analyzed by genotype. Survival was analyzed by genotype for all stages for patients treated between 1999 and 2003. The genotype prevalence was also compared with a control material of healthy blood donors.ResultsNo genotype was associated with an increased risk of CRC or higher cancer stage. The patients with CT/TT genotype had significantly greater risk of suffering side effects from fluoropyrimidine (5-fluorouracil) treatment (P < .05). In stage III colon cancer, the patients with CT/TT genotype had a poorer prognosis than those with the CC genotype. The difference was significant in univariate (P < .003) and multivariate (P < .040) analysis. Though the genotype-associated side effect risks remained in stage IV, the effect on survival was not significant (P < .1).ConclusionThe MTHFR polymorphism C677T does, in our material, not affect the risk of CRC; however, it can affect the sensitivity to chemotherapy and the risk of side-effects and therefore survival in stage III and possibly stage IV colon cancer. It could be a future predictive factor in the choice of a treatment regimen.     

Cruciferous vegetables intake and the risk of colorectal cancer: a meta-analysis of observational studies

BackgroundEpidemiological studies have reported inconsistent associations between cruciferous vegetable (CV) intake and colorectal cancer (CRC) risk. To our knowledge, a comprehensive and quantitative assessment of the association between CV intake and CRC has not been reported.MethodsRelevant articles were identified by searching MEDLINE. We pooled the relative risks (RR) from individual studies using a random-effect model and carried out heterogeneity and publication bias analyses.ResultsTwenty-four case–control and 11 prospective studies were included in our analysis. When all studies were pooled, we yielded a significantly inverse association between CV (RR: 0.82; 95% confidence interval 0.75–0.90) intake and CRC risk. Specific analysis for cabbage and broccoli yielded similar result. When separately analyzed, case–control studies of CV intake yield similar results, and the results from the prospective studies showed borderline statistical significance. Moreover, significant inverse associations were also observed in colon cancer and its distal subsite both among prospective and case–control studies.ConclusionsFindings from this meta-analysis provide evidence that high intake of CV was inversely associated with the risk of CRC and colon cancer in humans. Further analysis on other specific CV, food preparation methods, stratified results by anatomic cancer site, and subsite of colon cancer should be extended in future study.     

Early genetic aberrations in patients with sporadic colorectal cancer

Chromosome instability (CIN) is widely observed in both sporadic and hereditary colorectal cancer (CRC). Defects in APC and WNT signaling are primarily associated with CIN in hereditary CRC, but the genetic causes for CIN in sporadic CRC remain elusive. Using high‐density SNP array and exome data from The Cancer Genome Atlas (TCGA), we characterized loss of heterozygosity (LOH) and copy number variation (CNV) in the peripheral blood, normal colon, and corresponding tumor tissue in 15 CRC patients with proficient mismatch repair (MMR) and 24 CRC patients with deficient MMR. We found a high frequency of 18q LOH in tumors and arm‐specific enrichment of genetic aberrations on 18q in the normal colon (primarily copy neutral LOH) and blood (primarily copy gain). These aberrations were specific to the sporadic, pMMR CRC. Though in tumor samples genetic aberrations were observed for genes commonly mutated in hereditary CRC (eg, APC, CTNNB1, SMAD4, BRAF), none of them showed LOH or CNV in the normal colon or blood. DCC located on 18q21.1 topped the list of genes with genetic aberrations in the tumor. In an independent cohort of 13 patients subjected to Whole Genome Sequencing (WGS), we found LOH and CNV on 18q in adenomatous polyp and tumor tissues. Our data suggests that patients with sporadic CRC may have genetic aberrations preferentially enriched on 18q in their blood, normal colon epithelium, and non‐malignant polyp lesions that may prove useful as a clinical marker for sporadic CRC detection and risk assessment.     

<Emphasis Type="Italic">IL6</Emphasis> genotypes and colon and rectal cancer

Inflammation appears to play a key role in the development of colorectal cancer (CRC). In this study we examine factors involved in the regulation of inflammation and risk of CRC. Data from a multi-center case–control study of colon (N = 1579 cases and N = 1977 controls) and rectal (N = 794 cases and N = 1005 controls) cancer were used to evaluate the association between the rs1800795 and rs1800796 IL6 polymorphisms and CRC. We evaluated the joint effects of IL6 single nucleotide polymorphisms and regular use of aspirin/NSAIDs and vitamin D receptor (VDR) genotype. Having a C allele of the rs1800796 IL6 polymorphisms and the GG genotype of the rs1800795 IL6 polymorphisms was associated with a statistically significantly reduced the risk of colon (OR 0.76 95% CI 0.57, 1.00), but not rectal (OR 1.49 95% CI 1.02,2.16) cancer. Both IL6 polymorphisms were associated with significant interaction with current use of aspirin/NSAIDs to alter risk of colon cancer: individuals with a C allele in either polymorphism who were current users of aspirin/NSAIDs had the lowest colon cancer risk. CRC risk also was associated with an interaction between VDR and IL6 genotypes that was modified by current use of aspirin/NSAIDs. This study provides further support for inflammation-related factors in the etiology of CRC. Other studies are needed to explore other genes in this and other inflammation-related pathways.     

Hereditary evaluation and genetic counselling in young individuals with colorectal cancer in a population-based cohort

AimEarly-onset colorectal cancer should raise suspicions of a hereditary colorectal cancer (CRC) syndrome, including Lynch syndrome (LS) and Familial Adenomatous Polyposis (FAP). Collection of family history and genetic counselling (GC) is mandatory but previous studies have revealed low awareness of hereditary CRC among clinicians why there has been an incentive to implement universal LS screening. In this population-based cohort study, we aimed to observe the uptake of GC in the Swedish South-Eastern medical care region for young CRC patients and to investigate the frequency of patients diagnosed with LS.MethodsPatients below 50 years of age diagnosed with CRC between 2008 and 2017 were identified from the national Swedish Colorectal Cancer Registry. Medical records were reviewed regarding family history, co-morbidity and referral for GC, with a follow-up time of at least three years.ResultsThe analysis included 278 patients with 287 tumours, 108 (38%) located in rectum and 179 (62%) in colon. One hundred sixteen (42%) individuals were referred to the Regional Clinical Genetics service, whereof 74 (27%) underwent complete investigation. Thirteen (18%) patients were identified with a mutation, eleven (15%) had LS and two (3%) FAP. The remaining 61 (82%), without proven mutation, were considered as familial CRC. Younger age correlated with a higher chance of referral for GC.ConclusionThe study found that only a minority of young CRC patients underwent genetic counselling, contrary to clinical guidelines. Hereditary CRC is therefore probably underdiagnosed even among young individuals.     

RCN3 Expression Indicates Prognosis in Colorectal Cancers

Background: Reticulocalbin 3 (RCN3) has been associated with several malignancies. However, its role in colorectal cancer (CRC) remains controversial. Thus, this study aimed to investigate the role of RCN3 in CRC prognosis. Methods: The clinical significance of RCN3 expression in CRC was evaluated in a large cohort of 483 patients. Normal tissues, carcinoma, para-carcinoma, adenoma, and metastatic tissues were evaluated by immunohistochemistry. We investigated the association between RCN3 expression and CRC occurrence in tumors and other tissues. Prognostic factors were also evaluated by Kaplan-Meier survival analysis and the Cox regression model. Results: RCN3 was significantly overexpressed in CRC and metastatic tissues. Patients with high RCN3 expression had shorter disease-free survival than those with low RCN3 expression. Multivariate Cox regression analysis showed a risk ratio HR], 0.607; confidence interval [CI], 0.362–1.016; p < 0.05 after adjusting for other prognostic factors. HighRCN3 expression was also associated with a worse chemotherapeutic response in the colon (p < 0.01) or rectal (p < 0.05) cancer patients who received adjuvant chemotherapy. Conclusion: RCN3 expression level is an independent risk factor and serves as a prognostic biomarker for CRC. High RCN3 expression predicts poor prognosis and chemotherapeutic response.     

Downregulation of Ascl2 promotes cell apoptosis by enhancing autophagy in colorectal cancer cells

BackgroundColorectal cancer (CRC) is the third most common cancer, according to recently published literature. While the incidence and the mortality of CRC has decreased due to effective cancer screening measures, there has been an increase in the number of young patients diagnosed with colon cancer due to unclear reasons. As a target molecule of the Wnt signaling pathway, Ascl2 is an important marker of CRC stem cells and plays an important role in maintaining the nature of colon cancer stem/precursor cells. However, the role of Ascl2 in autophagy in CRC cells is rarely elucidated.MethodsIn this study, we found that Ascl2 was increased in CRC compared with adjacent tissue. Downregulation of Ascl2 in CRC cells could suppress proliferation and invasion, and induce apoptosis, of CRC cells. Moreover, we found that autophagy-relative protein LC3 increased after Ascl2 knockdown. Furthermore, we treated CRC cells with autophagy inhibitors 3-MA (3-Methyladenine) and CQ (Chloroquine).ResultsThe results showed that autophagy inhibitors could prevent apoptosis, which was induced by Ascl2 knockdown. Finally, we confirmed that the downregulation of Ascl2 in CRC cells could alleviate the pathological process in vivo by xenograft experiment.ConclusionsOur findings indicated that si-Ascl2 (small/short interfering) exerted a tumor suppression function in CRC by inducing autophagic cell death, and suggest that Ascl2 targeted therapy represents a novel strategy for CRC treatment.