Clinically implemented prognostic biomarkers are lacking for the 80% of colorectal cancers (CRCs) that exhibit chromosomal instability (CIN). CIN is characterised by chromosome segregation errors and ...double-strand break repair defects that lead to somatic copy number aberrations (SCNAs) and chromosomal rearrangement-associated structural variants (SVs), respectively. We hypothesise that the number of SVs is a distinct feature of genomic instability and defined a new measure to quantify SVs: the tumour break load (TBL). The present study aimed to characterise the biological impact and clinical relevance of TBL in CRC.
Disease-free survival and SCNA data were obtained from The Cancer Genome Atlas and two independent CRC studies. TBL was defined as the sum of SCNA-associated SVs. RNA gene expression data of microsatellite stable (MSS) CRC samples were used to train an RNA-based TBL classifier. Dichotomised DNA-based TBL data were used for survival analysis.
TBL shows large variation in CRC with poor correlation to tumour mutational burden and fraction of genome altered. TBL impact on tumour biology was illustrated by the high accuracy of classifying cancers in TBL-high and TBL-low (area under the receiver operating characteristic curve AUC: 0.88; p < 0.01). High TBL was associated with disease recurrence in 85 stages II–III MSS CRCs from The Cancer Genome Atlas (hazard ratio HR: 6.1; p = 0.007) and in two independent validation series of 57 untreated stages II–III (HR: 4.1; p = 0.012) and 74 untreated stage II MSS CRCs (HR: 2.4; p = 0.01).
TBL is a prognostic biomarker in patients with non-metastatic MSS CRC with great potential to be implemented in routine molecular diagnostics.
•Tumour break load (TBL) is a distinct feature of genomic instability.•TBL status (high or low) has a large impact on tumour biology.•TBL is a prognostic biomarker for patients with resected stage II and III microsatellite stable colorectal cancer.•TBL has the potential to be implemented in routine molecular diagnostics.
First line chemotherapy is effective in 75 to 80% of patients with metastatic colorectal cancer (mCRC). We studied whether microRNA (miR) expression profiles can predict treatment outcome for first ...line fluoropyrimidine containing systemic therapy in patients with mCRC.
MiR expression levels were determined by next generation sequencing from snap frozen tumor samples of 88 patients with mCRC. Predictive miRs were selected with penalized logistic regression and posterior forward selection. The prediction co-efficients of the miRs were re-estimated and validated by real-time quantitative PCR in an independent cohort of 81 patients with mCRC.
Expression levels of miR-17-5p, miR-20a-5p, miR-30a-5p, miR-92a-3p, miR-92b-3p and miR-98-5p in combination with age, tumor differentiation, adjuvant therapy and type of systemic treatment, were predictive for clinical benefit in the training cohort with an AUC of 0.78. In the validation cohort the addition of the six miR signature to the four clinicopathological factors demonstrated a significant increased AUC for predicting treatment response versus those with stable disease (SD) from 0.79 to 0.90. The increase for predicting treatment response versus progressive disease (PD) and for patients with SD versus those with PD was not significant. in the validation cohort. MiR-17-5p, miR-20a-5p and miR-92a-3p were significantly upregulated in patients with treatment response in both the training and validation cohorts.
A six miR expression signature was identified that predicted treatment response to fluoropyrimidine containing first line systemic treatment in patients with mCRC when combined with four clinicopathological factors. Independent validation demonstrated added predictive value of this miR-signature for predicting treatment response versus SD. However, added predicted value for separating patients with PD could not be validated. The clinical relevance of the identified miRs for predicting treatment response has to be further explored.
Altered glycosylation in epithelial cancers may play an important role in tumour progression, as it may affect tumour cell migration and antigen presentation by antigen presenting cells. We ...specifically characterise the glycosylation patterns of two tumour antigens that are highly expressed in cancer tissue and often detected in their secreted form in serum: the epithelial mucin MUC1 and carcinoembryonic antigen (CEA, also called CEACAM5). We analysed 48 colorectal cancer patients, comparing normal colon and tumour epithelium within each patient. Lectin binding was studied by a standardised CEA/MUC1 capture ELISA, using several plant lectins, and the human C‐type lectins MGL and DC‐SIGN, and Galectin‐3. Peanut agglutinin (PNA) bound to MUC1 from tumour tissue in particular, suggests increased expression of the Thomsen‐Friedenreich antigen (TF‐antigen) (Core 1, Galβ1‐3GalNAc‐Ser/Thr). Only small amounts of Tn‐antigen (GalNAcα‐Ser/Thr) expression was observed, but the human C‐type lectin MGL showed increased binding to tumour‐associated MUC1. Furthermore, sialylation was greatly enhanced. In sharp contrast, tumour‐associated CEA (CEACAM5) contained high levels of the blood‐group related carbohydrates, Lewis X and Lewis Y. This correlated strongly with the interaction of the human C‐type lectin DC‐SIGN to tumour‐associated CEA, suggesting that CEA can be recognized and taken up by antigen presenting cells. In addition, increased mannose expression was observed and branched N‐glycans were prominent, and this correlated well with human Galectin‐3 binding. These data demonstrate that individual tumour antigens contain distinct glycan structures associated with cancer and, since glycans affect cellular interactions with its microenvironment, this may have consequences for progression of the disease.
Rapid advancements in the area of early cancer detection have brought us closer to achieving the goals of finding cancer early enough to treat or cure it, while avoiding harms of overdiagnosis. We ...evaluate progress in the development of early cancer detection tests in the context of the current principles for cancer screening. We review cell-free DNA (cfDNA)-based approaches using mutations, methylation, or fragmentomes for early cancer detection. Lastly, we discuss the challenges in demonstrating clinical utility of these tests before integration into routine clinical care.
Background & Aims After careful pilot studies and planning, the national screening program for colorectal cancer (CRC), with biennial fecal immunochemical tests (FITs), was initiated in The ...Netherlands in 2014. A national information system for real-time monitoring was developed to allow for timely evaluation. Data were collected from the first year of this screening program to determine the importance of planning and monitoring for optimal screening program performance. Methods The national information system of the CRC screening program kept track of the number of invitations sent in 2014, FIT kits returned, and colonoscopies performed. Age-adjusted rates of participation, the number of positive test results, and positive predictive values (PPVs) for advanced neoplasia were determined weekly, quarterly, and yearly. Results In 2014, there were 741,914 persons invited for FIT; of these, 529,056 (71.3%; 95% confidence interval CI, 71.2%–71.4%) participated. A few months into the program, real-time monitoring showed that rates of participation and positive test results (10.6%; 95% CI, 10.5%–10.8%) were higher than predicted and the PPV was lower (42.1%; 95% CI, 41.3%–42.9%) than predicted based on pilot studies. To reduce the burden of unnecessary colonoscopies and alleviate colonoscopy capacity, the cut-off level for a positive FIT result was increased from 15 to 47 μg Hb/g feces halfway through 2014. This adjustment decreased the percentage of positive test results to 6.7% (95% CI, 6.6%–6.8%) and increased the PPV to 49.1% (95% CI, 48.3%–49.9%). In total, the first year of the Dutch screening program resulted in the detection of 2483 cancers and 12,030 advanced adenomas. Conclusions Close monitoring of the implementation of the Dutch national CRC screening program allowed for instant adjustment of the FIT cut-off levels to optimize program performance.
BackgroundReported incidence rates of oesophageal adenocarcinoma (OAC) in Barrett's oesophagus (BO) vary widely. As the effectiveness of BO surveillance is crucially dependent on this rate, its ...clarification is essential.MethodsTo estimate the rate of malignant progression in patients with BO, all patients with a first diagnosis of BO with no dysplasia (ND) or low-grade dysplasia (LGD) between 1991 and 2006 were identified in the Dutch nationwide registry of histopathology (PALGA). Follow-up data were evaluated up to November 2007.Results42 207 patients with BO were included; 4132 (8%) of them had LGD. Re-evaluation endoscopies at least 6 months after initial diagnosis were performed in 16 365 patients (39%), who were significantly younger than those not re-examined (58±13 vs 63±16 years, p<0.001). These patients were followed-up for a total of 78 131 person-years, during which 666 (4%) high-grade dysplasia (HGD)/OACs occurred, affecting 4% of the surveillance patient population (mean age: 69±12 years, 76% male). After excluding HGD/OAC cases detected within 1 year after BO diagnosis (n=212, 32%), incidence rates per 1000 person-years were 4.3 (95% CI 3.4 to 5.5) for OAC and 5.8 (95% CI 4.6 to 7.0) for HGD/OAC combined. Risk factors for HGD/OAC were increased age (eg, >75 years HR 12; 95% CI 8.0 to 18), male sex (2.01; 1.68 to 2.60) and presence of LGD at baseline (1.91; 1.53 to 2.40).ConclusionIn this largest reported cohort of unselected patients with BO, the annual risk of OAC was 0.4%. Male sex, older age and LGD at diagnosis are independent predictors of malignant progression, and should enable an improved risk assessment in BO.
Hodgkin lymphoma (HL) survivors are at increased risk of developing second primary esophageal squamous cell cancer (ESCC). We aimed to gain insight in the driving events of ESCC in HL survivors ...(hESCC) by using RNA sequencing and NanoString profiling. Objectives were to investigate differences in RNA signaling between hESCC and sporadic ESCC (sESCC), and to look for early malignant changes in non-neoplastic esophageal tissue of HL survivors (hNN-tissue). We analyzed material of 26 hESCC cases, identified via the Dutch pathology registry (PALGA) and 17 sESCC cases from one academic institute and RNA sequencing data of 44 sESCC cases from TCGA. Gene expression profiles for the NanoString panel PanCancer IO 360 were obtained from 16/26 hESCC and four hNN-tissue, while non-neoplastic squamous tissue of four sporadic cases (sNN-tissue) served as reference profile. Hierarchical clustering, differential expression and pathway analyses were performed. Overall, the molecular profiles of hESCC and sESCC were similar. There was increased immune, HMGB1 and ILK signaling compared to sNN-tissue. The profiles of hNN-tissue were distinct from sNN-tissue, indicating early field effects in the esophagus of HL survivors. The BRCA1 pathway was upregulated in hESCC tissue, compared to hNN tissue. Analysis of expression profiles reveals overlap between hESCC and sESCC, and differences between hESCC and its surrounding hNN-tissue. Further research is required to validate our results and to investigate whether the changes observed in hNN-tissue are already detectable before development of hESCC. In the future, our findings could be used to improve hESCC patient management.
There is limited information present to explain temporal improvements in colon cancer survival. This nationwide study investigates the temporal changes in survival over a 35‐year period (1970–2004) ...in Iceland and uses incidence, mortality, surgery rate, stage distribution, lymph node yield, tumor location and histological type to find explanations for these changes. Patients diagnosed with colon cancer in Iceland 1970–2004 were identified (n = 1962). All histopathology was reassessed. Proportions, age‐standardized incidence and mortality, relative, cancer‐specific and overall survival and conditional survival were calculated. When comparing first and last diagnostic periods (1970–1978 and 1997–2004), 5‐year relative survival improved by 12% for men and 9% for women. At the same time surgery rate increased by 12% and the proportion of stage I increased by 9%. Stage‐stratified, improved 5‐year relative survival was mainly observed in stages II and III and coincided with higher lymph node yields, proportional reduction of stage II cancers and proportional increase of stage III cancers, indicating stage migration between these stages. Improvement in 1‐year survival was mainly observed in stages III and IV. Five‐year survival improvement for patients living beyond 1 year was minimum to none. There were no changes in histology that coincided with neither increased incidence nor possibly influencing improved survival. Concluding, as a novel finding, 1‐year mortality, which previously has been identified as an important variable in explaining international survival differences, is in this study identified as also being important in explaining temporal improvements in colon cancer survival in Iceland.
What's new?
Icelanders are surviving colon cancer more often than they used to; between 1970 and 2004, the survival rate increased by 12% for men and 9% for women. What changed? For this article, the authors collected data on factors like incidence, mortality, surgery rate, stage, and histological type to pinpoint how the improvement came about. The biggest gains, they found, occurred within the first year after diagnosis; 1‐year survival improved, particularly for patients with later stage tumors, while the 5‐year survival rate of those surviving beyond 1 year did not change.
Abstract
Secretory leukocyte protease inhibitor (SLPI) is a pleiotropic protein produced by healthy intestinal epithelial cells. SLPI regulates NF-κB activation, inhibits neutrophil proteases and has ...broad antimicrobial activity. Recently, increased SLPI expression was found in various types of carcinomas and was suggested to increase their metastatic potential. Indeed, we demonstrated that SLPI protein expression in colorectal cancer (CRC) liver metastases and matched primary tumors is associated with worse outcome, suggesting that SLPI promotes metastasis in human CRC. However, whether SLPI plays a role in CRC before distant metastases have formed is unclear. Therefore, we examined whether SLPI expression is associated with prognosis in CRC patients with localized disease. Using a cohort of 226 stage II and 160 stage III CRC patients we demonstrate that high SLPI protein expression is associated with reduced disease recurrence in patients with stage III micro-satellite stable tumors treated with adjuvant chemotherapy, independently of established clinical risk factors (hazard rate ratio 0.54,
P
-value 0.03). SLPI protein expression was not associated with disease-free survival in stage II CRC patients. Our data suggest that the role of SLPI in CRC may be different depending on the stage of disease. In stage III CRC, SLPI expression may be unfavorable for tumors, whereas SLPI expression may be beneficial for tumors once distant metastases have established.
The risk of recurrence after resection of a stage II or III colon cancer, and therefore qualification for adjuvant chemotherapy (ACT), is traditionally based on clinicopathological parameters. ...However, the parameters used in clinical practice are not able to accurately identify all patients with or without minimal residual disease. Some patients considered 'low-risk' do develop recurrence (undertreatment), whilst other patients receiving ACT might not have developed recurrence at all (overtreatment). We previously analysed tumour tissue expression of 28 protein biomarkers that might improve identification of patients at risk of recurrence. In the present study we aimed to build a prognostic classifier based on these 28 biomarkers and clinicopathological parameters.
Classification and regression tree (CART) analysis was used to build a prognostic classifier based on a well described cohort of 386 patients with stage II and III colon cancer. Separate classifiers were built for patients who were or were not treated with ACT. Routine clinicopathological parameters and tumour tissue immunohistochemistry data were included, available for 28 proteins previously published. Classification trees were pruned until lowest misclassification error was obtained. Survival of the identified subgroups was analysed, and robustness of the selected CART variables was assessed by random forest analysis (1000 trees).
In patients not treated with ACT, prognosis was estimated best based on expression of KCNQ1. Poor disease-free survival (DFS) was observed in those with loss of expression of KCNQ1 (HR = 3.38 (95% CI 2.12 - 5.40); p < 0.001). In patients treated with ACT, key prognostic factors were lymphovascular invasion (LVI) and expression of KCNQ1. Patients with LVI showed poorest DFS, whilst patients without LVI and high expression of KCNQ1 showed most favourable survival (HR = 7.50 (95% CI 3.57-15.74); p < 0.001). Patients without LVI and loss of expression of KCNQ1 had intermediate survival (HR = 3.91 (95% CI 1.76 - 8.72); p = 0.001).
KCNQ1 and LVI were identified as key features in prognostic classifiers for disease-free survival in stage II and III colon cancer patients.
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