Publications by authors named "Gerrit A Meijer"

227 Publications

Detection and characterization of lung cancer using cell-free DNA fragmentomes.

Nat Commun 2021 08 20;12(1):5060. Epub 2021 Aug 20.

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an opportunity for cancer detection and intervention. Here, we use a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation in a prospective study of 365 individuals at risk for lung cancer. We validate the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation features, clinical risk factors, and CEA levels, followed by CT imaging, detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites distinguished individuals with small cell lung cancer from those with non-small cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score represented an independent prognostic indicator of survival. This approach provides a facile avenue for non-invasive detection of lung cancer.
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http://dx.doi.org/10.1038/s41467-021-24994-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379179PMC
August 2021

Postoperative circulating tumour DNA is associated with pathologic response and recurrence-free survival after resection of colorectal cancer liver metastases.

EBioMedicine 2021 Aug 29;70:103498. Epub 2021 Jul 29.

Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, the Netherlands. Electronic address:

Background: Recurrence rates after resection of colorectal cancer liver metastases (CRLM) are high and correlate with worse survival. Postoperative circulating tumour DNA (ctDNA) is a promising prognostic biomarker. Focusing on patients with resected CRLM, this study aimed to evaluate the association between the detection of postoperative ctDNA, pathologic response and recurrence-free survival (RFS).

Methods: Twenty-three patients were selected from an ongoing phase-3 trial who underwent resection of RAS-mutant CRLM after induction systemic treatment. CtDNA analysis was performed by droplet digital PCR using blood samples collected at baseline, before and after resection. Pathologic response of CRLM was determined via the Tumour Regression Grading system.

Findings: With a median follow-up of 19.6 months, the median RFS for patients with detectable (N = 6, [26%]) and undetectable (N = 17, [74%]) postoperative ctDNA was 4.8 versus 12.1 months, respectively. Among 21 patients with available tumour tissue, pathologic response in patients with detectable compared to undetectable postoperative ctDNA was found in one of six (17%) and 15 of 15 (100%) patients, respectively (p < 0.001). In univariable Cox regression analyses both postoperative detectable ctDNA (HR = 3.3, 95%CI = 1.1-9.6, p = 0.03) and pathologic non-response (HR = 4.6, 95%CI = 1.4-15, p = 0.01) were associated with poorer RFS and were strongly correlated (r = 0.88, p < 0.001). After adjusting for clinical characteristics in pairwise multivariable analyses, postoperative ctDNA status remained associated with RFS.

Interpretation: The detection of postoperative ctDNA after secondary resection of CRLM is a promising prognostic factor for RFS and appeared to be highly correlated with pathologic response.

Funding: None.
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http://dx.doi.org/10.1016/j.ebiom.2021.103498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340125PMC
August 2021

Clinical Validation of a Multitarget Fecal Immunochemical Test for Colorectal Cancer Screening : A Diagnostic Test Accuracy Study.

Ann Intern Med 2021 09 20;174(9):1224-1231. Epub 2021 Jul 20.

Netherlands Cancer Institute, Amsterdam, the Netherlands (L.J.B., R.J.F., B.C., M.d.W., G.A.M.).

Background: The fecal immunochemical test (FIT) is used in colorectal cancer (CRC) screening, yet it leaves room for improvement.

Objective: To develop a multitarget FIT (mtFIT) with better diagnostic performance than FIT.

Design: Diagnostic test accuracy study.

Setting: Colonoscopy-controlled series.

Participants: Persons ( = 1284) from a screening ( = 1038) and referral ( = 246) population were classified by their most advanced lesion (CRC [ = 47], advanced adenoma [ = 135], advanced serrated polyp [ = 30], nonadvanced adenoma [ = 250], and nonadvanced serrated polyp [ = 53]), along with control participants ( = 769).

Measurements: Antibody-based assays were developed and applied to leftover FIT material. Classification and regression tree (CART) analysis was applied to biomarker concentrations to identify the optimal combination for detecting advanced neoplasia. Performance of this combination, the mtFIT, was cross-validated using a leave-one-out approach and compared with FIT at equal specificity.

Results: The CART analysis showed a combination of hemoglobin, calprotectin, and serpin family F member 2-the mtFIT-to have a cross-validated sensitivity for advanced neoplasia of 42.9% (95% CI, 36.2% to 49.9%) versus 37.3% (CI, 30.7% to 44.2%) for FIT ( = 0.025), with equal specificity of 96.6%. In particular, cross-validated sensitivity for advanced adenomas increased from 28.1% (CI, 20.8% to 36.5%) to 37.8% (CI, 29.6% to 46.5%) ( = 0.006). On the basis of these results, early health technology assessment indicated that mtFIT-based screening could be cost-effective compared with FIT.

Limitation: Study population is enriched with persons from a referral population.

Conclusion: Compared with FIT, the mtFIT showed better diagnostic accuracy in detecting advanced neoplasia because of an increased detection of advanced adenomas. Moreover, early health technology assessment indicated that these results provide a sound basis to pursue further development of mtFIT as a future test for population-based CRC screening. A prospective screening trial is in preparation.

Primary Funding Source: Stand Up to Cancer/Dutch Cancer Society, Dutch Digestive Foundation, and HealthHolland.
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http://dx.doi.org/10.7326/M20-8270DOI Listing
September 2021

Clinicopathological features and risk factors for developing colorectal neoplasia in Hodgkin's lymphoma survivors.

Dig Endosc 2021 Apr 30. Epub 2021 Apr 30.

Departments of, Department of, Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: Hodgkin's lymphoma (HL) survivors treated with abdominal radiotherapy and/or procarbazine have an increased risk of developing colorectal neoplasia.

Aims: We evaluated the clinicopathological characteristics and risk factors for developing (advanced) neoplasia (AN) in HL survivors.

Methods: In all, 101 HL survivors (median age 51 years, median age of HL diagnosis 25 years) underwent colonoscopy and 350 neoplasia and 44 AN (classified as advanced adenomas/serrated lesions or colorectal cancer), mostly right-sided, were detected, as published previously. An average-risk asymptomatic cohort who underwent screening colonoscopy were controls (median age 60 years). Clinicopathological characteristics of AN were evaluated in both groups. Mismatch repair (MMR) status was assessed using immunohistochemistry (MLH1/MSH2/MSH6/PMS2). Logistic regression analysis was performed to evaluate the risk factors for AN in HL survivors, including age at HL diagnosis and interval between HL and colonoscopy.

Results: In 101 colonoscopies in HL survivors, AN was primarily classified based on polyp size ≥10 mm, whereas (high-grade)dysplasia was more often seen in AN in controls. An interval between HL diagnosis and colonoscopy >26 years was associated with more AN compared with an interval of <26 years, with an odds ratio for AN of 3.8 (95% confidence interval 1.4-9.1) (p < 0.01). All 39 AN that were assessed were MMR proficient.

Conclusions: Colorectal neoplasia in HL survivors differ from average-risk controls; classification AN was primarily based on polyp size (≥10 mm) in HL survivors. Longer follow-up between HL diagnosis and colonoscopy was associated with a higher prevalence of AN in HL survivors.
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http://dx.doi.org/10.1111/den.14004DOI Listing
April 2021

Identification of DNA methylation markers for early detection of CRC indicates a role for nervous system-related genes in CRC.

Clin Epigenetics 2021 04 15;13(1):80. Epub 2021 Apr 15.

Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.

Purpose: Colonoscopy and the fecal immunochemical test (FIT) are currently the most widely used screening modalities for colorectal cancer (CRC), however, both with their own limitations. Here we aim to identify and validate stool-based DNA methylation markers for the early detection of CRC and investigate the biological pathways prone to DNA methylation.

Methods: DNA methylation marker discovery was performed using The Cancer Genome Atlas (TCGA) colon adenocarcinoma data set consisting of normal and primary colon adenocarcinoma tissue. The performance of the five best candidate markers and a previously identified marker, NDRG4, was evaluated on tissues and whole stool samples of healthy subjects and CRC patients using quantitative MSP assays. The results were compared and combined with FIT data. Finally, pathway and gene ontology enrichment analyses were performed using ToppFun, GOrilla and clusterProfiler.

Results: GDNF, HAND2, SLC35F3, SNAP91 and SORCS1 were ranked as the best performing markers. Gene combinations of all five markers, NDRG4 and FIT were evaluated to establish the biomarker panel with the highest diagnostic potential, resulting in the identification of GDNF/SNAP91/NDRG4/FIT as the best performing marker panel. Pathway and gene ontology enrichment analyses revealed that genes associated with the nervous system were enriched in the set of best performing CRC-specific biomarkers.

Conclusion: In silico discovery analysis using TCGA-derived data yielded a novel DNA-methylation-based assay for the early detection of CRC, potentially improving current screening modalities. Additionally, nervous system-related pathways were enriched in the identified genes, indicating an epigenetic regulation of neuronal genes in CRC.
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http://dx.doi.org/10.1186/s13148-021-01067-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048074PMC
April 2021

An Automated Correction Algorithm (ALPACA) for ddPCR Data Using Adaptive Limit of Blank and Correction of False Positive Events Improves Specificity of Mutation Detection.

Clin Chem 2021 Jul;67(7):959-967

Department of Laboratory Medicine, Netherlands Cancer Institute, Amsterdam, the Netherlands.

Background: Bio-Rad droplet-digital PCR is a highly sensitive method that can be used to detect tumor mutations in circulating cell-free DNA (cfDNA) of patients with cancer. Correct interpretation of ddPCR results is important for optimal sensitivity and specificity. Despite its widespread use, no standardized method to interpret ddPCR data is available, nor have technical artifacts affecting ddPCR results been widely studied.

Methods: False positive rates were determined for 6 ddPCR assays at variable amounts of input DNA, revealing polymerase induced false positive events (PIFs) and other false positives. An in silico correction algorithm, known as the adaptive LoB and PIFs: an automated correction algorithm (ALPACA), was developed to remove PIFs and apply an adaptive limit of blank (LoB) to individual samples. Performance of ALPACA was compared to a standard strategy (no PIF correction and static LoB = 3) using data from commercial reference DNA, healthy volunteer cfDNA, and cfDNA from a real-life cohort of 209 patients with stage IV nonsmall cell lung cancer (NSCLC) whose tumor and cfDNA had been molecularly profiled.

Results: Applying ALPACA reduced false positive results in healthy cfDNA compared to the standard strategy (specificity 98 vs 88%, P = 10-5) and stage IV NSCLC patient cfDNA (99 vs 93%, P = 10-11), while not affecting sensitivity in commercial reference DNA (70 vs 68% P = 0.77) or patient cfDNA (82 vs 88%, P = 0.13). Overall accuracy in patient samples was improved (98 vs 92%, P = 10-7).

Conclusions: Correction of PIFs and application of an adaptive LoB increases specificity without a loss of sensitivity in ddPCR, leading to a higher accuracy in a real-life cohort of patients with stage IV NSCLC.
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http://dx.doi.org/10.1093/clinchem/hvab040DOI Listing
July 2021

High CD8 tumour-infiltrating lymphocyte density associates with unfavourable prognosis in oesophageal adenocarcinoma following poor response to neoadjuvant chemoradiotherapy.

Histopathology 2021 Aug 27;79(2):238-251. Epub 2021 Apr 27.

Department of Pathology, Antoni van Leeuwenhoek, the Netherlands Cancer Institute, Amsterdam, the Netherlands.

Aims: Determining prognosis following poor response to neoadjuvant chemoradiotherapy (nCRT) in oesophageal adenocarcinoma (OAC) remains challenging. An immunosuppressive tumour microenvironment (TME) as well as immune infiltrate density and composition are considered to play a critical role in the immune interaction between host and tumour and can predict therapy response and survival in many cancers, including gastrointestinal malignancies. The aim of this study was to establish the TME characteristics associated with survival following a poor response to nCRT.

Methods And Results: The prognostic significance of OAC-associated CD3 , CD4 , CD8 , forkhead box protein 3 (FoxP3 ) and programmed cell death ligand 1 (PD-L1) expression was studied by immunohistochemistry and quantified by automated image analysis in 123 patients who underwent nCRT and curative resection. Results from good and poor responders were contrasted and immune infiltration was related to disease course in both groups. Subsequently a cohort of 57 patients with a moderate response to nCRT was analysed in a similar fashion. Tumour cell percentage positively correlated to immune infiltration markers. In good and moderate responders, none of the immune infiltrate parameters was associated with survival; in poor responders CD8 was an independent negative predictor of OS in univariate analysis (P = 0.03) and high CD8 infiltration was associated with worse OS (15 versus 32 months, P = 0.042).

Conclusion: A high CD8 density is an independent biomarker of poor OS in poor responders to nCRT, but not in good and moderate responders. Our results suggest that patients with a poor response to nCRT but concomitant high CD8 counts in the resection specimen require adjuvant therapy.
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http://dx.doi.org/10.1111/his.14361DOI Listing
August 2021

Detection of tumor-derived cell-free DNA from colorectal cancer peritoneal metastases in plasma and peritoneal fluid.

J Pathol Clin Res 2021 May 26;7(3):203-208. Epub 2021 Feb 26.

Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Tumor-derived cell-free DNA (cfDNA) is an emerging biomarker for guiding the personalized treatment of patients with metastatic colorectal cancer (CRC). While patients with CRC liver metastases (CRC-LM) have relatively high levels of plasma cfDNA, little is known about patients with CRC peritoneal metastases (CRC-PM). This study evaluated the presence of tumor-derived cfDNA in plasma and peritoneal fluid (i.e. ascites or peritoneal washing) in 20 patients with isolated CRC-PM and in the plasma of 100 patients with isolated CRC-LM. Among tumor tissue KRAS/BRAF mutation carriers, tumor-derived cfDNA was detected by droplet digital polymerase chain reaction (ddPCR) in plasma of 93% of CRC-LM and 20% of CRC-PM patients and in peritoneal fluid in all CRC-PM patients. Mutant allele fraction (MAF) and mutant copies per ml (MTc/ml) were lower in CRC-PM plasma than in CRC-LM plasma (median MAF = 0.28 versus 18.9%, p < 0.0001; median MTc/ml = 21 versus 1,758, p < 0.0001). Within patients with CRC-PM, higher cfDNA levels were observed in peritoneal fluid than in plasma (median MAF = 16.4 versus 0.28%, p = 0.0019; median MTc/ml = 305 versus 21, p = 0.0034). These data imply that tumor-derived cfDNA in plasma is a poor biomarker to monitor CRC-PM. Instead, cfDNA detection in peritoneal fluid may offer an alternative to guide CRC-PM treatment decisions.
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http://dx.doi.org/10.1002/cjp2.207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073000PMC
May 2021

Diagnostic yield of colonoscopy surveillance in testicular cancer survivors treated with platinum-based chemotherapy: study protocol of a prospective cross-sectional cohort study.

BMC Gastroenterol 2021 Feb 12;21(1):67. Epub 2021 Feb 12.

Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Background: Testicular cancer (TC) survivors have an increased risk of various second primary malignancies. A recent cohort study detected an increased risk of colorectal cancer (CRC) in TC survivors treated with platinum-based chemotherapy with a hazard ratio of 3.9. CRC risk increased with higher cisplatin-dose. We know that colonoscopy surveillance in high-risk populations results in reduced incidence and mortality of CRC. TC survivors treated with platinum-based chemotherapy can potentially benefit from colonoscopy surveillance; however, to which extent is unknown. Furthermore, the pathogenesis of these secondary CRCs is unknown, and better insights into the carcinogenesis may affect surveillance decisions.

Methods: This prospective multicenter study will be performed in four Dutch hospitals. TC survivors are eligible if treated with ≥ 3 cycles of cisplatin before age 50. Colonoscopy will be performed ≥ 8 years after initial treatment (minimum and maximum ages at colonoscopy, 35 and 75 years, respectively). The primary aim of the study is the diagnostic yield of advanced neoplasia detected during colonoscopy. As secondary aim, we will evaluate the molecular profile of advanced colorectal neoplasia and will assess current platinum levels in blood and urine and correlate blood-platinum levels with prevalence of colorectal lesions. Furthermore, we will investigate effectiveness of fecal immunochemical testing (FIT) and burden of colonoscopy by two questionnaires. Demographic data, previous history, results of colonoscopy, hemoglobin level of FIT and results of molecular and platinum levels will be obtained. Yield of colonoscopy will be determined by detection rate of adenoma and serrated lesions, advanced adenoma detection rate and CRC detection rate. The MISCAN model will be used for cost-effectiveness analyses of CRC surveillance. With 234 participants undergoing colonoscopy, we can detect an absolute difference of 6% of advanced neoplasia with 80% power.

Discussion: TC survivors treated with cisplatin-based chemotherapy can benefit from CRC surveillance. Evaluation of the diagnostic performance and patient acceptance of CRC surveillance is of importance to develop surveillance recommendations. Insight into the carcinogenesis of cisplatin-related advanced colorectal lesions will contribute to CRC prevention in the increasing number of TC survivors. The results may also be important for the many other cancer survivors treated with platinum-based chemotherapy.

Trial Registration: Clinical Trials: NCT04180033, November 27, 2019, https://clinicaltrials.gov/ct2/show/NCT04180033 .
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http://dx.doi.org/10.1186/s12876-021-01639-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881638PMC
February 2021

Gene expression profiles of esophageal squamous cell cancers in Hodgkin lymphoma survivors versus sporadic cases.

PLoS One 2020 21;15(12):e0243178. Epub 2020 Dec 21.

Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243178PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751872PMC
January 2021

Quantitative analysis of CDX2 protein expression improves its clinical utility as a prognostic biomarker in stage II and III colon cancer.

Eur J Cancer 2021 02 17;144:91-100. Epub 2020 Dec 17.

Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands. Electronic address:

Aim: Better stratification of patients with stage II and stage III colon cancer for risk of recurrence is urgently needed. The present study aimed to validate the prognostic value of CDX2 protein expression in colon cancer tissue by routine immunohistochemistry and to evaluate its performance in a head-to-head comparison with tandem mass spectrometry-based proteomics.

Patient And Methods: CDX2 protein expression was evaluated in 386 stage II and III primary colon cancers by immunohistochemical staining of tissue microarrays and by liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis using formalin-fixed paraffin-embedded tissue sections of a matched subset of 23 recurrent and 23 non-recurrent colon cancers. Association between CDX2 expression and disease-specific survival (DSS) was investigated.

Results: Low levels of CDX2 protein expression in stage II and III colon cancer as determined by immunohistochemistry was associated with poor DSS (hazard ratio [HR] = 1.97 (95% confidence interval [CI]: 1.26-3.06); p = 0.002). Based on analysis of a selected sample subset, CDX2 prognostic value was more pronounced when detected by LC-MS/MS (HR = 7.56 (95% CI: 2.49-22.95); p < 0.001) compared to detection by immunohistochemistry (HR = 1.60 (95% CI: 0.61-4.22); p = 0.34).

Conclusion: This study validated CDX2 protein expression as a prognostic biomarker in stage II and III colon cancer, conform previous publications. CDX2 prognostic value appeared to be underestimated when detected by routine immunohistochemistry, probably due to the semiquantitative and subjective nature of this methodology. Quantitative analysis of CDX2 substantially improved its clinical utility as a prognostic biomarker. Therefore, development of routinely applicable quantitative assays for CDX2 expression is needed to facilitate its clinical implementation.
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http://dx.doi.org/10.1016/j.ejca.2020.10.029DOI Listing
February 2021

Study protocol: Whole genome sequencing Implementation in standard Diagnostics for Every cancer patient (WIDE).

BMC Med Genomics 2020 11 10;13(1):169. Epub 2020 Nov 10.

Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: 'Precision oncology' can ensure the best suitable treatment at the right time by tailoring treatment towards individual patient and comprehensive tumour characteristics. In current molecular pathology, diagnostic tests which are part of the standard of care (SOC) only cover a limited part of the spectrum of genomic changes, and often are performed in an iterative way. This occurs at the expense of valuable patient time, available tissue sample, and interferes with 'first time right' treatment decisions. Whole Genome Sequencing (WGS) captures a near complete view of genomic characteristics of a tumour in a single test. Moreover, WGS facilitates faster implementation of new treatment relevant biomarkers. At present, WGS mainly has been applied in study settings, but its performance in a routine diagnostic setting remains to be evaluated. The WIDE study aims to investigate the feasibility and validity of WGS-based diagnostics in clinical practice.

Methods: 1200 consecutive patients in a single comprehensive cancer centre with (suspicion of) a metastasized solid tumour will be enrolled with the intention to analyse tumour tissue with WGS, in parallel to SOC diagnostics. Primary endpoints are (1) feasibility of implementation of WGS-based diagnostics into routine clinical care and (2) clinical validation of WGS by comparing identification of treatment-relevant variants between WGS and SOC molecular diagnostics. Secondary endpoints entail (1) added clinical value in terms of additional treatment options and (2) cost-effectiveness of WGS compared to SOC diagnostics through a Health Technology Assessment (HTA) analysis. Furthermore, the (3) perceived impact of WGS-based diagnostics on clinical decision making will be evaluated through questionnaires. The number of patients included in (experimental) therapies initiated based on SOC or WGS diagnostics will be reported with at least 3 months follow-up. The clinical efficacy is beyond the scope of WIDE. Key performance indicators will be evaluated after every 200 patients enrolled, and procedures optimized accordingly, to continuously improve the diagnostic performance of WGS in a routine clinical setting.

Discussion: WIDE will yield the optimal conditions under which WGS can be implemented in a routine molecular diagnostics setting and establish the position of WGS compared to SOC diagnostics in routine clinical care.
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http://dx.doi.org/10.1186/s12920-020-00814-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654005PMC
November 2020

Expression of the immune modulator secretory leukocyte protease inhibitor (SLPI) in colorectal cancer liver metastases and matched primary tumors is associated with a poorer prognosis.

Oncoimmunology 2020 10 13;9(1):1832761. Epub 2020 Oct 13.

Laboratory of Pediatrics, Division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands.

Secretory leukocyte protease inhibitor (SLPI), a pleiotropic protein expressed by healthy intestinal epithelial cells, functions as an inhibitor of NF-κB and neutrophil proteases and exerts antimicrobial activity. We previously showed SLPI suppresses intestinal epithelial chemokine production in response to microbial contact. Increased SLPI expression was recently detected in various types of carcinoma. In addition, accumulating evidence indicates SLPI expression is favorable for tumor cells. In view of these findings and the abundance of SLPI in the colonic epithelium, we hypothesized SLPI promotes colorectal cancer (CRC) growth and metastasis. Here, we aimed to establish whether SLPI expression in CRC is related to clinical outcome. Using a cohort of 507 patients with CRC who underwent resection of liver metastases, we show that high SLPI protein expression in both liver metastases and primary CRC is associated with significantly shorter overall survival after resection of liver metastases. The prognostic value of SLPI in CRC patients with liver metastases implies a role for SLPI in the formation of metastasis of human CRC. Based on the immune regulatory functions of SLPI, we anticipate that expression of SLPI provides tumors with a mechanism to evade infiltration by immune cells.
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http://dx.doi.org/10.1080/2162402X.2020.1832761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556627PMC
October 2020

RNF43 mutation analysis in serrated polyposis, sporadic serrated polyps and Lynch syndrome polyps.

Histopathology 2021 Apr 25;78(5):749-758. Epub 2020 Dec 25.

Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.

Aims: RNF43 is suggested to be involved in the serrated pathway towards colorectal cancer and encodes a transmembrane Ring-type E3 ubiquitin ligase that negatively regulates the Wnt pathway. This study aimed to elucidate the role of RNF43 gene variants in serrated polyposis syndrome (SPS) and serrated polyps.

Methods And Results: Three cohorts were tested. The first cohort included germline DNA of 26 SPS patients tested for pathogenic variants in RNF43 by Sanger sequencing all exons. In the second cohort we tested somatic DNA for RNF43 mutations from sporadic serrated lesions: 25 hyperplastic polyps, 35 sessile serrated lesions and 38 traditional serrated adenomas (TSA). In the third cohort we investigated RNF43 mutations in 49 serrated polyps and 60 conventional adenomas from 40 patients with Lynch syndrome. No germline RNF43 pathogenic variants were detected in our SPS cohort. In sporadic colorectal lesions we detected RNF43 deleterious frameshift mutations in three TSA and one SSL. The RNF43 mutations in previously described homopolymeric hot-spots were detected in microsatellite-instable (MSI) polyps and the other RNF43 mutations in microsatellite-stable (MSS) serrated polyps. RNF43 hot-spot mutations were discovered in seven serrated polyps and 12 conventional adenomas from Lynch patients.

Conclusion: Truncating germline RNF43 mutations are uncommon in SPS patients. Somatic mutations in RNF43 were found in sporadic TSA and SSL and both serrated polyps and adenomas from Lynch syndrome patients, suggesting that they do not develop early in the pathway to CRC and are not specific for serrated polyp subtypes.
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http://dx.doi.org/10.1111/his.14286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048817PMC
April 2021

Diagnostic Strategies toward Clinical Implementation of Liquid Biopsy RAS/BRAF Circulating Tumor DNA Analyses in Patients with Metastatic Colorectal Cancer.

J Mol Diagn 2020 12 19;22(12):1430-1437. Epub 2020 Sep 19.

Department of Pathology, the Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address:

Detection of KRAS, NRAS, and BRAF mutations in tumor tissue is currently used to predict resistance to treatment with anti-epidermal growth factor receptor (EGFR) antibodies in patients with metastatic colorectal cancer (mCRC). Liquid biopsies are minimally invasive, and cell-free circulating tumor DNA (ctDNA) mutation analyses may better represent tumor heterogeneity. This study examined the incorporation of liquid biopsy RAS/BRAF ctDNA analyses into diagnostic strategies to determine mCRC patient eligibility for anti-EGFR therapy. Tumor tissue and liquid biopsies were collected from 100 mCRC patients with liver-only metastases in a multicenter prospective clinical trial. Three diagnostic strategies incorporating droplet digital PCR ctDNA analyses were compared with routine tumor tissue RAS/BRAF mutation profiling using decision tree analyses. Tissue DNA mutations in KRAS, NRAS, and BRAF were present in 54%, 0%, and 3% of mCRC patients, respectively. A 93% concordance was observed between tissue DNA and liquid biopsy ctDNA mutations. The proportion of patients with RAS/BRAF alterations increased from 57% to 60% for diagnostic strategies that combined tissue and liquid biopsy mutation analyses. Consecutive RAS/BRAF ctDNA analysis followed by tissue DNA analysis in case of a liquid biopsy-negative result appeared to be the most optimal diagnostic strategy to comprehensively determine eligibility for anti-EGFR therapy in a cost-saving manner. These results highlight the potential clinical utility of liquid biopsies for detecting primary resistance to anti-EGFR-targeted therapies.
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http://dx.doi.org/10.1016/j.jmoldx.2020.09.002DOI Listing
December 2020

Driver mutations occur frequently in metastases of well-differentiated small intestine neuroendocrine tumours.

Histopathology 2021 Mar 3;78(4):556-566. Epub 2020 Nov 3.

Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Aims: To investigate the clinicopathological significance of driver mutations in metastatic well-differentiated small intestine neuroendocrine tumours (SI-NETs).

Methods And Results: Whole genome sequencing (WGS) of 35 metastatic SI-NETs and next-generation sequencing (NGS) of eight metastatic SI-NETs were performed. Biopsies were obtained between 2015 and 2019. Tumours were classified according to the 2019 World Health Organization classification. WGS included assessment of somatic mutations in all cancer-related driver genes, the tumour mutational burden (TMB), and microsatellite status. NGS entailed a cancer hotspot panel of 58 genes. Our cohort consisted of 21% grade 1, 60% grade 2 and 19% grade 3 SI-NETs. Driver mutations were identified in ~50% of SI-NETs. In total, 27 driver mutations were identified, of which 74% were in tumour suppressor genes (e.g. TP53, RB1, and CDKN1B) and 22% were in proto-oncogenes (e.g. KRAS, NRAS, and MET). Allelic loss of chromosome 18 (63%), complete loss of CDKN2A and CDKN1B (both 6%) and CDKN1B mutations (9%) were most common. Potential targetable genetic alterations were detected in 21% of metastasised SI-NETs. All tumours were microsatellite-stable and showed low TMBs (median 1.10; interquartile range 0.87-1.35). The Ki67 proliferation index was significantly associated with the presence of driver mutations (P = 0.015).

Conclusion: Driver mutations occur in 50% of metastasised SI-NETs, and their presence is associated with a high Ki67 proliferation index. The identification of targetable mutations make these patients potentially eligible for targeted therapy.
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http://dx.doi.org/10.1111/his.14252DOI Listing
March 2021

Can a biomarker triage test reduce colonoscopy burden in fecal immunochemical test screening?

J Comp Eff Res 2020 06 28;9(8):563-571. Epub 2020 May 28.

Department of Epidemiology & Biostatistics, Decision Modeling Center, Amsterdam UMC - Vrije Universiteit Amsterdam, The Netherlands.

To assess the potential of biomarker triage testing (BM-TT) in the Dutch colorectal cancer (CRC) screening program. Using the Adenoma and Serrated pathway to Colorectal CAncer model, we simulated fecal immunochemical test (FIT)-screening and various FIT plus BM-TT screening scenarios in which only individuals with both a positive FIT and BM-TT are referred to colonoscopy. Adding a low polyp sensitivity BM-TT to FIT-screening reduced colonoscopy burden (89-100%) while increasing CRC mortality (27-41%) compared with FIT-screening only. The FIT plus high polyp sensitivity BM-TT scenarios also decreased colonoscopy burden (71-89%) while hardly affecting CRC mortality (FIT 0-4% increase, FIT 2-7% decrease). Adding a BM-TT to FIT-screening considerably reduces colonoscopy burden, but could also decrease screening effectiveness. Combining FIT with a high polyp sensitivity BM-TT seems most promising.
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http://dx.doi.org/10.2217/cer-2019-0130DOI Listing
June 2020

Modeling Personalized Adjuvant TreaTment in EaRly stage coloN cancer (PATTERN).

Eur J Health Econ 2020 Sep 26;21(7):1059-1073. Epub 2020 May 26.

Department of Epidemiology and Biostatistics, Amsterdam UMC, VU University, MF F-wing, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.

Aim: To develop a decision model for the population-level evaluation of strategies to improve the selection of stage II colon cancer (CC) patients who benefit from adjuvant chemotherapy.

Methods: A Markov cohort model with a one-month cycle length and a lifelong time horizon was developed. Five health states were included; diagnosis, 90-day mortality, death other causes, recurrence and CC death. Data from the Netherlands Cancer Registry were used to parameterize the model. Transition probabilities were estimated using parametric survival models including relevant clinical and pathological covariates. Subsequently, biomarker status was implemented using external data. Treatment effect was incorporated using pooled trial data. Model development, data sources used, parameter estimation, and internal and external validation are described in detail. To illustrate the use of the model, three example strategies were evaluated in which allocation of treatment was based on (A) 100% adherence to the Dutch guidelines, (B) observed adherence to guideline recommendations and (C) a biomarker-driven strategy.

Results: Overall, the model showed good internal and external validity. Age, tumor growth, tumor sidedness, evaluated lymph nodes, and biomarker status were included as covariates. For the example strategies, the model predicted 83, 87 and 77 CC deaths after 5 years in a cohort of 1000 patients for strategies A, B and C, respectively.

Conclusion: This model can be used to evaluate strategies for the allocation of adjuvant chemotherapy in stage II CC patients. In future studies, the model will be used to estimate population-level long-term health gain and cost-effectiveness of biomarker-based selection strategies.
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http://dx.doi.org/10.1007/s10198-020-01199-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423797PMC
September 2020

White blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer.

Nat Commun 2020 Jan 27;11(1):525. Epub 2020 Jan 27.

Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.

Liquid biopsies are providing new opportunities for detection of residual disease in cell-free DNA (cfDNA) after surgery but may be confounded through identification of alterations arising from clonal hematopoiesis. Here, we identify circulating tumor-derived DNA (ctDNA) alterations through ultrasensitive targeted sequencing analyses of matched cfDNA and white blood cells from the same patient. We apply this approach to analyze samples from patients in the CRITICS trial, a phase III randomized controlled study of perioperative treatment in patients with operable gastric cancer. After filtering alterations from matched white blood cells, the presence of ctDNA predicts recurrence when analyzed within nine weeks after preoperative treatment and after surgery in patients eligible for multimodal treatment. These analyses provide a facile method for distinguishing ctDNA from other cfDNA alterations and highlight the utility of ctDNA as a predictive biomarker of patient outcome to perioperative cancer therapy and surgical resection in patients with gastric cancer.
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http://dx.doi.org/10.1038/s41467-020-14310-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985115PMC
January 2020

Proteins in stool as biomarkers for non-invasive detection of colorectal adenomas with high risk of progression.

J Pathol 2020 03 13;250(3):288-298. Epub 2020 Jan 13.

Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Screening to detect colorectal cancer (CRC) in an early or premalignant state is an effective method to reduce CRC mortality rates. Current stool-based screening tests, e.g. fecal immunochemical test (FIT), have a suboptimal sensitivity for colorectal adenomas and difficulty distinguishing adenomas at high risk of progressing to cancer from those at lower risk. We aimed to identify stool protein biomarker panels that can be used for the early detection of high-risk adenomas and CRC. Proteomics data (LC-MS/MS) were collected on stool samples from adenoma (n = 71) and CRC patients (n = 81) as well as controls (n = 129). Colorectal adenoma tissue samples were characterized by low-coverage whole-genome sequencing to determine their risk of progression based on specific DNA copy number changes. Proteomics data were used for logistic regression modeling to establish protein biomarker panels. In total, 15 of the adenomas (15.8%) were defined as high risk of progressing to cancer. A protein panel, consisting of haptoglobin (Hp), LAMP1, SYNE2, and ANXA6, was identified for the detection of high-risk adenomas (sensitivity of 53% at specificity of 95%). Two panels, one consisting of Hp and LRG1 and one of Hp, LRG1, RBP4, and FN1, were identified for high-risk adenomas and CRCs detection (sensitivity of 66% and 62%, respectively, at specificity of 95%). Validation of Hp as a biomarker for high-risk adenomas and CRCs was performed using an antibody-based assay in FIT samples from a subset of individuals from the discovery series (n = 158) and an independent validation series (n = 795). Hp protein was significantly more abundant in high-risk adenoma FIT samples compared to controls in the discovery (p = 0.036) and the validation series (p = 9e-5). We conclude that Hp, LAMP1, SYNE2, LRG1, RBP4, FN1, and ANXA6 may be of value as stool biomarkers for early detection of high-risk adenomas and CRCs. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065084PMC
March 2020

Prognostic value of microvessel density in stage II and III colon cancer patients: a retrospective cohort study.

BMC Gastroenterol 2019 Aug 16;19(1):146. Epub 2019 Aug 16.

Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.

Background: Microvessel density (MVD), as a derived marker for angiogenesis, has been associated with poor outcome in several types of cancer. This study aimed to evaluate the prognostic value of MVD in stage II and III colon cancer and its relation to tumour-stroma-percentage (TSP) and expression of HIF1A and VEGFA.

Methods: Formalin-fixed paraffin-embedded (FFPE) colon cancer tissues were collected from 53 stage II and 54 (5-fluorouracil-treated) stage III patients. MVD was scored by digital morphometric analysis of CD31-stained whole tumour sections. TSP was scored using haematoxylin-eosin stained slides. Protein expression of HIF1A and VEGFA was determined by immunohistochemical evaluation of tissue microarrays.

Results: Median MVD was higher in stage III compared to stage II colon cancers (11.1% versus 5.6% CD31-positive tissue area, p < 0.001). High MVD in stage II patients tended to be associated with poor disease free survival (DFS) in univariate analysis (p = 0.056). In contrast, high MVD in 5FU-treated stage III patients was associated with better DFS (p = 0.006). Prognostic value for MVD was observed in multivariate analyses for both cancer stages.

Conclusions: MVD is an independent prognostic factor associated with poor DFS in stage II colon cancer patients, and with better DFS in stage III colon cancer patients treated with adjuvant chemotherapy.
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http://dx.doi.org/10.1186/s12876-019-1063-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698008PMC
August 2019

Molecular characterization of colorectal adenomas reveals POFUT1 as a candidate driver of tumor progression.

Int J Cancer 2020 04 30;146(7):1979-1992. Epub 2019 Aug 30.

See Appendix for consortium members.

Removal of colorectal adenomas is an effective strategy to reduce colorectal cancer (CRC) mortality rates. However, as only a minority of adenomas progress to cancer, such strategies may lead to overtreatment. The present study aimed to characterize adenomas by in-depth molecular profiling, to obtain insights into altered biology associated with the colorectal adenoma-to-carcinoma progression. We obtained low-coverage whole genome sequencing, RNA sequencing and tandem mass spectrometry data for 30 CRCs, 30 adenomas and 18 normal adjacent colon samples. These data were used for DNA copy number aberrations profiling, differential expression, gene set enrichment and gene-dosage effect analysis. Protein expression was independently validated by immunohistochemistry on tissue microarrays and in patient-derived colorectal adenoma organoids. Stroma percentage was determined by digital image analysis of tissue sections. Twenty-four out of 30 adenomas could be unambiguously classified as high risk (n = 9) or low risk (n = 15) of progressing to cancer, based on DNA copy number profiles. Biological processes more prevalent in high-risk than low-risk adenomas were related to proliferation, tumor microenvironment and Notch, Wnt, PI3K/AKT/mTOR and Hedgehog signaling, while metabolic processes and protein secretion were enriched in low-risk adenomas. DNA copy number driven gene-dosage effect in high-risk adenomas and cancers was observed for POFUT1, RPRD1B and EIF6. Increased POFUT1 expression in high-risk adenomas was validated in tissue samples and organoids. High POFUT1 expression was also associated with Notch signaling enrichment and with decreased goblet cells differentiation. In-depth molecular characterization of colorectal adenomas revealed POFUT1 and Notch signaling as potential drivers of tumor progression.
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http://dx.doi.org/10.1002/ijc.32627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027554PMC
April 2020

IBD-Associated Dysplastic Lesions Show More Chromosomal Instability Than Sporadic Adenomas.

Inflamm Bowel Dis 2020 01;26(2):167-180

Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.

Background: Patients with longstanding inflammatory bowel disease (IBD; ie, ulcerative colitis and Crohn's disease) have an increased risk of colorectal cancer (CRC). Due to ongoing inflammation, IBD-associated dysplastic lesions can develop. These lesions have an increased risk to progress to cancer compared with sporadic adenomas, which are also found in these patients. Differentiating between these 2 types of dysplasia remains challenging, both clinically and histologically, while treatment strategies may differ. Therefore, the aim of this study was to investigate molecular alterations associated with colorectal dysplasia to cancer progression in IBD and evaluate to what extent these alterations differ from sporadic adenomas.

Methods: DNA copy number aberrations and mutation analyses of 48 genes were performed by next-generation sequencing in 43 IBD-associated dysplastic lesions, 30 of which were dysplastic and 13 of which were cancers. Results were compared with existing DNA copy number and mutation data from 118 sporadic adenomas and 24 sporadic cancers.

Results: Inflammatory bowel disease-associated dysplastic lesions harbor patterns of DNA copy number aberrations comparable to carcinomas, which are rare in sporadic adenomas. TP53 mutation was the most frequent mutation observed in IBD-associated dysplastic lesions and in cancers. FBXW7 was mutated significantly more often in IBD-associated dysplastic lesions than in sporadic adenomas.

Conclusions: Inflammatory bowel disease-associated dysplastic lesions show more DNA copy number aberrations than sporadic adenomas. TP53 and FBXW7 mutations appear to be involved in the development of IBD-associated dysplastic lesions and cancer. These findings indicate that IBD-associated dysplastic lesions are more genomically unstable, possibly reflecting a faster progression toward cancer.
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http://dx.doi.org/10.1093/ibd/izz171DOI Listing
January 2020

The landscape of genomic copy number alterations in colorectal cancer and their consequences on gene expression levels and disease outcome.

Mol Aspects Med 2019 10 6;69:48-61. Epub 2019 Aug 6.

Gastrointestinal and Pancreatic Oncology Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBEREHD, Barcelona, Spain; Unitat de Biologia Cel·lular i Genètica Mèdica, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Electronic address:

Aneuploidy, the unbalanced state of the chromosome content, represents a hallmark of most solid tumors, including colorectal cancer. Such aneuploidies result in tumor specific genomic imbalances, which emerge in premalignant precursor lesions. Moreover, increasing levels of chromosomal instability have been observed in adenocarcinomas and are maintained in distant metastases. A number of studies have systematically integrated copy number alterations with gene expression changes in primary carcinomas, cell lines, and experimental models of aneuploidy. In fact, chromosomal aneuploidies target a number of genes conferring a selective advantage for the metabolism of the cancer cell. Copy number alterations not only have a positive correlation with expression changes of the majority of genes on the altered genomic segment, but also have effects on the transcriptional levels of genes genome-wide. Finally, copy number alterations have been associated with disease outcome; nevertheless, the translational applicability in clinical practice requires further studies. Here, we (i) review the spectrum of genetic alterations that lead to colorectal cancer, (ii) describe the most frequent copy number alterations at different stages of colorectal carcinogenesis, (iii) exemplify their positive correlation with gene expression levels, and (iv) discuss copy number alterations that are potentially involved in disease outcome of individual patients.
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http://dx.doi.org/10.1016/j.mam.2019.07.007DOI Listing
October 2019

Genome-wide cell-free DNA fragmentation in patients with cancer.

Nature 2019 06 29;570(7761):385-389. Epub 2019 May 29.

Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.
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http://dx.doi.org/10.1038/s41586-019-1272-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774252PMC
June 2019

CD31-positive microvessel density within adenomas of Lynch Syndrome patients is similar compared to adenomas of non-Lynch patients.

Endosc Int Open 2019 May 8;7(5):E701-E707. Epub 2019 May 8.

Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, location Academic Medical Center, Amsterdam, the Netherlands.

 Microsatellite instability accelerates colorectal cancer development in patients with Lynch syndrome (LS). Previous research showed that virtual chromoendoscopy increases detection of adenomas during colonoscopy surveillance of patients with LS. Because previous research revealed that Lynch patients have an increased vascular network in the oral mucosa, we hypothesized that increased vascularization of LS-associated adenomas is the cause of better detection with virtual chromoendoscopy.  In this pilot study, patients with LS having a proven germline mutation were selected from two tertiary referral hospitals and non-LS patients from an outpatient colonoscopy center. Adenomas from patients with LS were exactly matched in size and histology with adenomas from non-LS patients. Initial adenoma diagnosis was confirmed by a specialist pathologist. All adenomas were stained with CD31 and adenomatous tissue was annotated by the specialist pathologist. Image analysis of CD31-positive microvessel density was conducted using FIJI software.  Colonoscopy of 63 patients with LS and 24 non-LS patients provided 40 adenomas that could be exactly matched in size and histology. In image-analysis, the CD31-positive microvessel density (2.49 % vs. 2.47 %,  = 0.96), the average size of CD31-positive structures (514 μm vs. 523 μm ,  = 0.26) nor the amount of vascular structures per mm (183 vs. 176,  = 0.50) differed between adenomas of LS patients and non-Lynch patients.  The outcomes of this pilot case-control study did not provide further insights into the mechanism of increased adenoma detection in LS patients using virtual chromoendoscopy techniques.
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http://dx.doi.org/10.1055/a-0832-8283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506331PMC
May 2019

Cell-free DNA in the supernatant of pleural effusion can be used to detect driver and resistance mutations, and can guide tyrosine kinase inhibitor treatment decisions.

ERJ Open Res 2019 Feb 25;5(1). Epub 2019 Mar 25.

Dept of Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

Objectives: Molecular profiling of tumours has become the mainstay of diagnostics for metastasised solid malignancies and guides personalised treatment, especially in nonsmall cell lung cancer (NSCLC). In current practice, it is often challenging to obtain sufficient tumour material for reliable molecular analysis. Cell-free DNA (cfDNA) in blood or other bio-sources could present an alternative approach to obtain genetic information from the tumour. In a retrospective cohort we analysed the added value of cfDNA analysis in pleural effusions for molecular profiling.

Methods: We retrospectively analysed both the supernatant and the cell pellet of 44 pleural effusions sampled from 39 stage IV patients with (n=23) or (n=16) mutated tumours to detect the original driver mutation as well as for T790M resistance mutations. Patients were diagnosed with either NSCLC (n=32), colon carcinoma (n=4), appendiceal carcinoma (n=2) or adenocarcinoma of unknown primary (n=1). Samples collected in the context of routine clinical care were stored at the Netherlands Cancer Institute biobank. We used droplet digital PCR for analysis.

Results: The driver mutation could be detected in 36 of the 44 pleural effusions by analysis of both the supernatant (35 out of 44 positive) and the cell pellet (31 out of 44 positive). In seven out of 20 pleural effusions from patients with mutation-positive tumours, a T790M mutation was detected. All seven supernatants and cell pellets were positive.

Conclusions: cfDNA in pleural effusion can be used to detect driver mutations as well as resistance mechanisms like T790M in pleural effusion with high accuracy and is therefore a valuable bio-source.
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http://dx.doi.org/10.1183/23120541.00016-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431750PMC
February 2019

American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange: From Inception to First Data Release and Beyond-Lessons Learned and Member Institutions' Perspectives.

JCO Clin Cancer Inform 2018 12;2:1-14

Christine M. Micheel, Michele L. LeNoue-Newton, and Mia A. Levy, Vanderbilt University Medical Center, Nashville, TN; Shawn M. Sweeney, American Association for Cancer Research, Philadelphia, PA; Fabrice André, Institut Gustave Roussy, Villejuif, France; Philippe L. Bedard, University of Toronto, Toronto, Ontario, Canada; Justin Guinney, Sage Bionetworks, Seattle, WA; Gerrit A. Meijer, Netherlands Cancer Institute, Amsterdam, the Netherlands; Barrett J. Rollins, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Charles L. Sawyers and Nikolaus Schultz, Memorial Sloan Kettering Cancer Center, New York, NY; Charles L. Sawyers, Howard Hughes Medical Institute, Chevy Chase, MD; Victor E. Velculescu, Johns Hopkins University School of Medicine, Baltimore, MD; and Kenna R. Mills Shaw, The University of Texas MD Anderson Cancer Center, Houston, TX.

The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) is an international data-sharing consortium focused on enabling advances in precision oncology through the gathering and sharing of tumor genetic sequencing data linked with clinical data. The project's history, operational structure, lessons learned, and institutional perspectives on participation in the data-sharing consortium are reviewed. Individuals involved with the inception and execution of AACR Project GENIE from each member institution described their experiences and lessons learned. The consortium was conceived in January 2014 and publicly released its first data set in January 2017, which consisted of 18,804 samples from 18,324 patients contributed by the eight founding institutions. Commitment and contributions from many individuals at AACR and the member institutions were crucial to the consortium's success. These individuals filled leadership, project management, informatics, data curation, contracts, ethics, and security roles. Many lessons were learned during the first 3 years of the consortium, including on how to gather, harmonize, and share data; how to make decisions and foster collaboration; and how to set the stage for continued participation and expansion of the consortium. We hope that the lessons shared here will assist new GENIE members as well as others who embark on the journey of forming a genomic data-sharing consortium.
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http://dx.doi.org/10.1200/CCI.17.00083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873906PMC
December 2018

High prevalence of advanced colorectal neoplasia and serrated polyposis syndrome in Hodgkin lymphoma survivors.

Cancer 2019 03 18;125(6):990-999. Epub 2018 Dec 18.

Department of Gastroenterology, Netherlands Cancer Institute, Amsterdam, the Netherlands.

Background: Hodgkin lymphoma (HL) survivors treated with abdominal radiotherapy and/or alkylating chemotherapy have an increased risk of colorectal cancer (CRC). This study was aimed at evaluating the prevalence of colorectal neoplasia in HL survivors.

Methods: This multicenter cohort study assessed the diagnostic yield of advanced colorectal neoplasia detected by a first surveillance colonoscopy among HL survivors treated with abdominal radiotherapy and/or procarbazine. Advanced colorectal neoplasia included advanced adenomas (high-grade dysplasia, ≥25% villous component, or ≥10-mm diameter), advanced serrated lesions (dysplasia or ≥10-mm diameter), and CRC. The results were compared with those for a Dutch general population cohort that underwent a primary screening colonoscopy (1426 asymptomatic individuals 50-75 years old). This study demonstrated the results of a predefined interim analysis.

Results: A colonoscopy was performed in 101 HL survivors, who were significantly younger (median, 51 years; interquartile range [IQR], 45-57 years) than the general population controls (median, 60 years; IQR, 55-65 years; P < .001). The prevalence of advanced neoplasia was higher in HL survivors than controls (25 of 101 [25%] vs 171 of 1426 [12%]; P < .001). Advanced adenomas were detected in 14 of 101 HL survivors (14%) and in 124 of 1426 controls (9%; P = .08). The prevalence of advanced serrated lesions was higher in HL survivors than controls (12 of 101 [12%] vs 55 of 1426 [4%]; P < .001). Serrated polyposis syndrome was present in 6% of HL survivors and absent in controls (P < .001).

Conclusions: HL survivors treated with abdominal radiotherapy and/or procarbazine have a high prevalence of advanced colorectal neoplasia. The implementation of a colonoscopy surveillance program should be considered.
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http://dx.doi.org/10.1002/cncr.31903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590398PMC
March 2019

Combination of a six microRNA expression profile with four clinicopathological factors for response prediction of systemic treatment in patients with advanced colorectal cancer.

PLoS One 2018 3;13(8):e0201809. Epub 2018 Aug 3.

Department of Medical Oncology, VUmc Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201809PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075783PMC
February 2019
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