Metastasis causes the vast majority of colorectal carcinoma (CRC)-related deaths. However, little is known about the specific traits and underlying mechanisms of metastasis-initiating cells in ...primary CRC. And whether or not circular RNAs (circRNAs) take part in this particular event remain not adequately stated yet.
A screening method based on Transwell assay was first applied to build CRC subgroups with different metastatic potential. High throughput RNA sequencing was used to find out novel metastatic drivers in CRC metastasis-initiating step. A series of in vitro and in vivo assays were further applied to elucidate the functions and underlying molecular mechanisms of circRNAs in CRC metastasis.
A circRNA consisting of exon 8-11 of LONP2, termed as circLONP2, was upregulated in metastasis-initiating CRC subgroups. Aberrant higher expression of circLONP2 was observed in primary CRC tissues with established metastasis, and along the invasive margin in metastatic site. High expression of circLONP2 predicted unfavorable overall survival. Functional studies revealed that circLONP2 could enhance the invasiveness of CRC cells in vitro, and targeting circLONP2 through anti-sense oligonucleotide (ASO) dramatically reduced the penetrance of metastasis to foreign organs in vivo. Mechanically, circLONP2 directly interacted with and promoted the processing of primary microRNA-17 (pri-miR-17), through recruiting DiGeorge syndrome critical region gene 8 (DGCR8) and Drosha complex in DDX1-dependent manner. Meanwhile, upregulated mature miR-17-5p could be assembled into exosomes and internalized by neighboring cells to enhance their aggressiveness.
Our data indicate that circLONP2 acts as key metastasis-initiating molecule during CRC progression through modulating the intracellular maturation and intercellular transfer of miR-17, resulting in dissemination of metastasis-initiating ability in primary site and acceleration of metastasis formation in foreign organs. circLONP2 could serve as an effective prognostic predictor and/or novel anti-metastasis therapeutic target in CRC treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Several polygenic risk scores (PRSs) have been developed to predict the risk of colorectal cancer (CRC) in European descendants. We used genome‐wide association study (GWAS) data from 22 702 cases ...and 212 486 controls of Asian ancestry to develop PRSs and validated them in two case‐control studies (1454 Korean and 1736 Chinese). Eleven PRSs were derived using three approaches: GWAS‐identified CRC risk SNPs, CRC risk variants identified through fine‐mapping of known risk loci and genome‐wide risk prediction algorithms. Logistic regression was used to estimate odds ratios (ORs) and area under the curve (AUC). PRS115‐EAS, a PRS with 115 GWAS‐reported risk variants derived from East‐Asian data, validated significantly better than PRS115‐EUR derived from European descendants. In the Korea validation set, OR per SD increase of PRS115‐EAS was 1.63 (95% CI = 1.46‐1.82; AUC = 0.63), compared with OR of 1.44 (95% CI = 1.29‐1.60, AUC = 0.60) for PRS115‐EUR. PRS115‐EAS/EUR derived using meta‐analysis results of both populations slightly improved the AUC to 0.64. Similar but weaker associations were found in the China validation set. Individuals among the highest 5% of PRS115‐EAS/EUR have a 2.52‐fold elevated CRC risk compared with the medium (41‐60th) risk group and have a 12% to 20% risk of developing CRC by age 85. PRSs constructed using results from fine‐mapping and genome‐wide algorithms did not perform as well as PRS115‐EAS and PRS115‐EAS/EUR in risk prediction, possibly due to a small sample size. Our results indicate that CRC PRSs are promising in predicting CRC risk in East Asians and highlights the importance of using population‐specific data to build CRC risk prediction models.
What's new?
Several polygenic risk scores (PRS) have been developed to predict colorectal cancer risk in European‐ancestry populations. Using data from large genome‐wide association studies, here the authors developed and validated PRSs for colorectal cancer risk prediction in East Asians. The PRS derived from this study showed a similar discriminatory ability in classifying cases and controls as that previously reported in European‐ancestry populations. The findings support the utility of PRSs in identifying high‐risk individuals for colorectal cancer prevention in Asians and highlight the importance of using population‐specific data to build colorectal cancer risk prediction models.
Universal germline testing in patients with colorectal cancer (CRC) with a multigene panel can detect various hereditary cancer syndromes. This study was performed to understand how to choose a ...testing panel and whether the result would affect clinical management.
We prospectively enrolled 486 eligible patients with CRC, including all patients with CRC diagnosed under age 70 years and patients with CRC diagnosed over 70 years with hereditary risk features between November 2017 and January 2018. All participants received germline testing for various hereditary cancer syndromes.
The prevalence of germline pathogenic variants (PVs) in cancer susceptibility genes was 7.8% (38/486), including 25 PVs in genes with high-risk CRC susceptibility (the minimal testing set) and 13 PVs in genes with moderate-risk CRC susceptibility or increased cancer risk other than CRC (the additional testing set). All the clinically relevant PVs were found in patients diagnosed under age 70 years. Among them, 11 patients would not have been diagnosed if testing reserved to present guidelines. Most (36/38) of the patients with PVs benefited from enhanced surveillance and tailored treatment. PVs in genes from the minimal testing set were found in all age groups, while patients carried PVs in genes from the additional testing set were older than 40 years.
Universal germline testing for cancer susceptibility genes should be recommended among all patients with CRC diagnosed under age 70 years. A broad panel including genes from the additional testing set might be considered for patients with CRC older than 40 years to clarify inheritance risks.
NCT03365986.
Rationale: Hepatectomy and adjuvant chemotherapy after resection of colorectal liver metastases (CRLM) may improve survival, however, patients which may benefit cannot currently be identified. ...Postoperative circulating tumor DNA (ctDNA) analysis can detect minimal residual disease (MRD) and predict the prognosis and efficacy of adjuvant chemotherapy. Our study aims to determine the impact of serial ctDNA analysis to predict the outcome among patients undergoing resection of CRLM. Methods: Between May 2018 and October 2019, 91 CRLM patients were prospectively enrolled. Whole exome sequencing was performed in 50 primary and 48 metastatic liver tissues. Targeted sequencing of 451 cancer relevant genes was performed in 50 baseline plasma to determine plasma-tissue concordance. We prospectively investigated changes in the amount and constitution of ctDNA in 271 serial plasma samples taken at different time points (baseline, pre-operation, post-operation, post-operative adjuvant chemotherapy (post-ACT) and recurrence) during the treatment of CRLM. Results: Detected molecular alterations were highly consistent among baseline ctDNA, primary and liver metastases tissue. Patients with a higher variant allele frequency (VAF) level at baseline ctDNA represent a higher tumor burden, and decreased ctDNA during pre-operative chemotherapy predicted better tumor response. Patients with detectable post-operative and post-ACT ctDNA were associated with significantly shorter recurrence-free survival (RFS). ROC analysis showed that post-ACT ctDNA status was superior to post-operative ctDNA status in predicting RFS with an AUROC of 0.79. A significant difference in overall recurrence rate was observed in patients with detectable vs undetectable levels of ctDNA after resection of CRLM (79.4% vs 41.7%) and after completion of adjuvant chemotherapy (77.3% vs 40.7%). During adjuvant chemotherapy, patients with decreased ctDNA VAF after adjuvant chemotherapy had a recurrence rate of 63.6%, compared to 92.3% in patients with increased ctDNA VAF. Conclusions: We envision that dynamic ctDNA analysis, especially in a post-ACT setting, might be used to not only reflect MRD but also to determine rational personalized adjuvant therapy after the resection of CRLM.
A study in rodent models showed that phytosterols protected against colon carcinogenesis, probably by inhibiting dysregulated cell cycle progression and inducing cellular apoptosis. However, ...epidemiological studies on the relationship between phytosterols and colorectal cancer risk are quite limited. The aim of this study was to investigate dietary phytosterol intake in relation to colorectal cancer risk in the Chinese population. A case–control study was conducted from July 2010 to June 2016, recruiting 1802 eligible colorectal cancer cases plus 1813 age (5-year interval) and sex frequency-matched controls. Dietary information was collected by using a validated FFQ. The OR and 95 % CI of colorectal cancer risk were assessed by multivariable logistic regression models. A higher total intake of phytosterols was found to be associated with a 50 % reduction in colorectal cancer risk. After adjusting for various confounders, the OR of the highest quartile intake compared with the lowest quartile intake was 0·50 (95 % CI 0·41, 0·61, P
trend<0·01) for total phytosterols. An inverse association was also found between the consumption of β-sitosterol, campesterol, campestanol and colorectal cancer risk. However, stigmasterol intake was related to an increased risk of colorectal cancer. No statistically significant association was found between β-sitostanol and colorectal cancer risk. Stratified analysis by sex showed that the positive association of stigmasterol intake with colorectal cancer risk was found only in women. These data indicated that the consumption of total phytosterols, β-sitosterol, campesterol and campestanol is inversely associated with colorectal cancer risk in a Chinese population.
Colorectal carcinoma (CRC) is the second most deadly cancer worldwide. Therapies that take advantage of DNA repair defects have been explored in various tumors but not yet systematically in CRC. ...Here, we found that Diphosphoinositol Pentakisphosphate Kinase 2 (PPIP5K2), an inositol pyrophosphate kinase, was highly expressed in CRC and associated with a poor prognosis of CRC patients. In vitro and in vivo functional studies demonstrated that PPIP5K2 could promote the proliferation and migration ability of CRC cells independent of its inositol pyrophosphate kinase activity. Mechanically, S1006 dephosphorylation of PPIP5K2 could accelerate its dissociation with 14-3-3 in the cytoplasm, resulting in more nuclear distribution. Moreover, DNA damage treatments such as doxorubicin (DOX) or irradiation (IR) could induce nuclear translocation of PPIP5K2, which subsequently promoted homologous recombination (HR) repair by binding and recruiting RPA70 to the DNA damage site as a novel scaffold protein. Importantly, we verified that S1006 dephosphorylation of PPIP5K2 could significantly enhance the DNA repair ability of CRC cells through a series of DNA repair phenotype assays. In conclusion, PPIP5K2 is critical for enhancing the survival of CRC cells via facilitating DNA HR repair. Our findings revealed an unrecognized biological function and mechanism model of PPIP5K2 dependent on S1006 phosphorylation and provided a potential therapeutic target for CRC patients.
According to the EPOC study, chemotherapy could improve 5-year disease-free survival of stage IV colon cancer patients by 8.1%. However, more molecular biomarkers are required to identify patients ...who need neoadjuvant chemotherapy. DENND2D expression was evaluated by immunohistochemistry in 181 stage IV colon cancer patients. The prognosis was better for patients with DENND2D expression than patients without DENND2D expression (5-year overall survival OS: 42% vs. 12%, p = 0.038; 5-year disease-free survival: 20% vs. 10%, p = 0.001). Subgroup analysis of the DENND2D-negative group showed that patients treated with neoadjuvant chemotherapy achieved longer OS than patients without neoadjuvant chemotherapy (RR = 0.179; 95% CI = 0.054-0.598; p = 0.003). DENND2D suppressed CRC proliferation in vitro and in vivo. Downregulation of DENND2D also promoted metastasis to distant organs in vivo. Mechanistically, DENND2D suppressed the MAPK pathway in CRC. Colon cancer patients who were DENND2D negative always showed a worse prognosis and were more likely to benefit from neoadjuvant chemotherapy. DENND2D may be a new prognostic factor and a predictor of the need for neoadjuvant chemotherapy in stage IV colon cancer.
The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who ...had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety‐three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.
What's new?
The prevalence of Lynch syndrome (LS) varies significantly in different ethnic populations. In this study, the authors screened more than 3000 Chinese colorectal cancer patients for mutations associated with LS, including mismatch repair (MMR) and BRAFV600E mutations. They found that, while the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of mutations is different, including many not previously reported. Older patients had a decreased risk of LS, suggesting that germline sequencing may not be necessary in this population.
Background
The Immunoscore was initially established to evaluate the prognosis of stage I/II/III colorectal cancer patients. However, the feasibility of the Immunoscore for the prognosis of ...colorectal cancer liver metastases (CRCLM) has not been reported.
Methods
Liver metastases in 249 CRCLM patients were retrospectively analyzed. The Immunoscore was assessed according to the counts and densities of CD3+ and CD8+ T cells in the central- and peritumoral areas by immunohistochemistry. The prognostic role of the Immunoscore for relapse–free survival (RFS) and overall survival (OS) was analyzed with Kaplan–Meier curves and Cox multivariate models, and confirmed via an internal validation. Receiver operating characteristic (ROC) curves were plotted to compare the prognostic values of the Immunoscore and the clinical risk score (CRS) system.
Results
CRCLM patients with high Immunoscores (> 2) had significantly longer RFS median RFS (95% confidence interval; 95% CI) 21.4 (7.8–35.1) vs. 8.7 (6.8–10.5) months,
P
< 0.001 and OS median OS (95% CI): not reached vs. 28.7 (23.2–34.2) months,
P
< 0.001 than those with low Immunoscores (≤ 2). After stratification by CRS, the Immunoscore retained a statistically significant prognostic value for OS. The areas under the ROC curves (AUROCs) of the Immunoscore and the CRS system for RFS were 0.711 95% CI 0.642–0.781 and 0.67595% CI 0.601–0.749 (
P
= 0.492), whereas the AUROC of the Immunoscore system for OS was larger than that of the CRS system 0.759 (95% CI 0.699–0.818) vs. 0.660 (95% CI 0.592–0.727);
P
= 0.029.
Conclusions
The Immunoscore of liver metastases can be applied to predict the prognosis of CRCLM patients following liver resection.
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