Search

Introduction: Protein tyrosine phosphatases (PTPs) are important regulators of signal transduction in immune cells. While most analytical methods focus on the detection of these crucial enzymes at the RNA or protein level, a method was lacking to monitor multiple enzymatic activities in patient-derived materials like blood and (tumor) tissues. Such a substrate-specific assay is a new tool for biomarker discovery in immuno-oncology (I-O), because the I-O targets - checkpoint and immune receptors like PD1, CTLA4, LAG3, 4-1BB, CD40, CD20, OX40, TIGIT and GITR - are controlled by phosphatases. The aim of this study was to develop a multiplex PTP assay and investigate the phosphatase activity in metastatic renal cell carcinoma (mRCC) tissues with high and low levels of TILs (tumor-infiltrating lymphocytes). Methods: On the basis of hematoxylin and eosin staining of mRCC tissues, 9 tissues with high TILS-scores were selected, as well as 10 tissues without TILS, matched on basis of the percentage of viable tumor cells. The technology used is a second generation peptide microarray, which is fully automated with short turnaround times and a high throughput of clinical samples in a 96-well setup. Arrays comprise 46 unique nitrophosphotyrosine containing peptides derived from known phosphosites. When a clinical sample is applied to this peptide microarray, this will lead to a pattern of peptide dephosphorylations, which is monitored in real time (kinetic readout). Results: The PTP assay was first developed for PBMC profiling. 0.10 ug protein/array was used, corresponding to 10000 cells. The signals were concentration dependent and could be inhibited by PTP inhibitors. For tissue profiling 2.0 µg protein input (0.02 mm3 tissue) was used. A 2-group comparison analysis of the phosphatase activity in tissues with high scores of TILs (massive infiltration, N=9) vs. without (N=10), revealed that 29 of 46 peptide substrates showed significantly higher dephosphorylation (PTP) activities in the tissues with high levels of lymphocyte infiltrates. A PCA revealed a clear separation between the groups of high and low TILS scores. Discriminating phosphosites (p Conclusions: Proof of concept was shown in mRCC samples that high PTP activity correlates with high levels of TILS. As a TILS-score itself is already regarded to be a candidate biomarker for I-O therapy response, the observed correlation is a basis for the development of more mechanistic biomarkers predicting therapy response. This method can be a starting point for the development of an enzymatic and thus sensitive and quantitative TILS test. This study has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 259939. Citation Format: Rob Ruijtenbeek, Liesbeth Houkes-van Kerkhoff, Jeannette Oosterwijk, Liesbeth Hovestad-Bijl1, Riet Hilhorst, Alejandro H. Gomez, Juan F. Rodriguez, Jesus Garcia-Donas, Bart Kiemeney, Egbert Oosterwijk. Correlation of phosphatase activity with lymphocyte infiltrates in metastatic renal cell carcinoma tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5608. doi:10.1158/1538-7445.AM2017-5608

A two-locus segregation and linkage-analysis approach was used to characterize the genetic control of a complex trait (Q1) and to localize the genes that have detectable effects. The results suggested that a two-locus Mendelian model fit the data significantly better than a one-locus model. The linkage results based on the most parsimonious two-locus model revealed linkage of Q1 to two areas (MG2 and MG3), while there was less evidence for linkage using one-locus models. Results also suggested that the subphenotypes (Q2 and Q3) provided useful information for further analysis of Q1 using two-locus models. © 1995 Wiley-Liss, Inc.

The Dutch Cancer Society developed the 'KWF Kanker Risico Test' (Cancer Risk Test) to improve the information available to the Dutch population regarding cancer risk factors. This Internet test, based under licence on the American 'Your Disease Risk' test, informs users about risk factors for 12 common types of cancer. The test provides an estimate of individual risk of a specific type of cancer and gives specific lifestyle advice that could lower that risk. This paper describes the development of the test, how it works, and its strengths and limitations.

Contains fulltext : 70874.pdf (Publisher’s version ) (Closed access) The aim of our study was to interpret the changing incidence, and to describe the mortality of patients with testicular cancer in the south of the Netherlands between 1970 and 2004. On the basis of data from the Eindhoven Cancer Registry and Statistics Netherlands, 5-year moving average standardised incidence and mortality rates were calculated. An age-period-cohort (APC) Poisson regression analysis was performed to disentangle time and birth cohort effects on incidence. The incidence rate remained stable for all ages at about 3 per 100,000 person-years until 1989 but increased annually thereafter by 4% to 6 in 2004. This increase can almost completely be attributed to an increase in localised tumours. The largest increase was found for seminoma testicular cancer (TC) patients aged 35-39 and non-seminoma TC patients aged 20-24 years. Relatively more localised and tumours with lymph node metastases were detected in the later periods. APC analysis showed the best fit with an age-cohort model. An increase in incidence of TC was found for birth cohorts since 1950. The mortality rate dropped from 1.0 per 100,000 person-years in 1970 to 0.3 in 2005, with a steep annual decline of 12% in the period 1979-1986. In conclusion, the increase in incidence of TC was strongly correlated with birth cohorts since 1945. The increase in incidence is possibly caused by in utero or early life exposure to a yet unknown risk factor. There was a steep decline in mortality in the period 1979-1986.

Recent research does not show an association between fruit and vegetable consumption and bladder cancer risk. None of these studies looked at the variety in fruit and vegetable consumption, which may capture different aspects of fruit and vegetable consumption. We investigated whether the quantity and the variety in vegetable and fruit consumption are associated with bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition study. Data on usual food consumption and complete follow-up for cancer occurrence was available for 478,533 participants, who were recruited in 10 European countries. A calibration study was conducted in an 8% representative subsample. After a mean follow-up of 8.7 years, 1015 participants were diagnosed with bladder cancer. Diet Diversity Scores (DDSs) were used to quantify the variety in fruit and/or vegetable consumption by counting the number of different fruit and vegetable products eaten at least every two weeks. Multivariable Cox proportional hazard models were used to assess the effect of fruit and vegetable consumption and DDSs on the risk of bladder cancer. Increments of 100 gram/day in fruit and vegetable consumption did not affect bladder cancer risk (calibrated hazard ratio (HR) 0.98; 95%CI: 0.95–1.01). A slightly stronger, although statistically non-significant, inverse association was observed among never smokers (calibrated HR=0.92; 95%CI: 0.79–1.06 with increments of 100 g/day). Unexpectedly, more variety in fruit and vegetable products consumed increased bladder cancer risk (HR=1.30 95%CI=1.00–1.69 comparing the highest with the lowest tertile; p-trend=0.05), which was strongest among never smokers (HR=1.72; 95%CI: 1.00–2.97). Continuous risk estimates did not reach statistical significance (HR for whole cohort 1.02 (95%CI 0.99–1.06 per 2 products increment); HR in never smokers 1.04 (95%CI 0.98–1.11 per 2 products increment)). The quantity and variety of fruit or vegetable consumption separately were not associated with bladder cancer risk. We conclude that in EPIC quantity and variety of vegetable and fruit consumption is not associated with bladder cancer risk. Increased categorical risks for variety in vegetables and fruits without statistical significant findings in the continuous analyses may be due to chance. Our results provide further evidence that fruit and vegetable consumption does not strongly alter bladder cancer risk. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B103.