Perceptions about screening for prostate cancer using genetic lifetime risk assessment: a qualitative study

Background Most health authorities do not recommend screening for prostate cancer with PSA tests in asymptomatic patients who are not at increased risk. However, opportunistic screening for prostate cancer is still wanted by many patients and it is widely used in primary care clinics, with potential for overdiagnosis and overtreatment. Better tools for risk assessment have been called for, to better target such opportunistic screening. Our aim was to explore perceptions about prostate cancer risk and subsequent opportunistic screening among patients who were not at increased risk of prostate cancer after a first PSA test plus a genetic lifetime risk assessment. Methods We undertook semi-structured patient interviews with recording and verbatim transcription of interviews. Data were analysed thematically. Results Three themes were identified: uncertainty of the nature of prostate cancer; perceived benefits of testing; and conflicting public health recommendations. Prostate cancer was spoken of as an inescapable risk in older age. The aphorism “you die with it, not from it” was prominent in the interviews but patients focused on the benefits of testing now rather than the future risks associated with treatment relating to potential overdiagnosis. Many expressed frustration with perceived mixed messages about early detection of cancer, in which on one side men feel that they are encouraged to seek medical testing to act responsibly regarding the most common cancer disease in men, and on the other side they are asked to refrain from opportunistic testing for prostate cancer. Taken together, personal risks of prostate cancer were perceived as high in spite of a normal PSA test and a genetic lifetime risk assessment showing no increased risk. Conclusion Patients saw prostate cancer risk as high and increasing with age. They focused on the perceived benefit of early detection using PSA testing. It was also commonly acknowledged that most cases are indolent causing no symptoms and not shortening life expectancy. There was a frustration with mixed messages about the benefit of early detection and risk of overdiagnosis. These men’s genetic lifetime risk assessment showing no increased risk did not appear to influence current intentions to get PSA testing in the future

<i>mi</i>R-625-3<i>p</i> regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells

Oxaliplatin resistance in colorectal cancers (CRC) is a major medical problem, and predictive markers are urgently needed. Recently, miR-625-3p was reported as a promising predictive marker. Herein, we show that miR-625-3p functionally induces oxaliplatin resistance in CRC cells, and identify the signalling networks affected by miR-625-3p. We show that the p38 MAPK activator MAP2K6 is a direct target of miR-625-3p, and, accordingly, is downregulated in non-responder patients of oxaliplatin therapy. miR-625-3p-mediated resistance is reversed by anti-miR-625-3p treatment and ectopic expression of a miR-625-3p insensitive MAP2K6 variant. In addition, reduction of p38 signalling by using siRNAs, chemical inhibitors or expression of a dominant-negative MAP2K6 protein induces resistance to oxaliplatin. Transcriptome, proteome and phosphoproteome profiles confirm inactivation of MAP2K6-p38 signalling as one likely mechanism of oxaliplatin resistance. Our study shows that miR-625-3p induces oxaliplatin resistance by abrogating MAP2K6-p38-regulated apoptosis and cell cycle control networks, and corroborates the predictive power of miR-625-3p

miRNA profiling of circulating EpCAM(+) extracellular vesicles:promising biomarkers of colorectal cancer

Cancer cells secrete small membranous extracellular vesicles (EVs) into their microenvironment and circulation. These contain biomolecules, including proteins and microRNAs (miRNAs). Both circulating EVs and miRNAs have received much attention as biomarker candidates for non-invasive diagnostics. Here we describe a sensitive analytical method for isolation and subsequent miRNA profiling of epithelial-derived EVs from blood samples of patients with colorectal cancer (CRC). The epithelial-derived EVs were isolated by immunoaffinity-capture using the epithelial cell adhesion molecule (EpCAM) as marker. This approach mitigates some of the specificity issues observed in earlier studies of circulating miRNAs, in particular the negative influence of miRNAs released by erythrocytes, platelets and non-epithelial cells. By applying this method to 2 small-scale patient cohorts, we showed that blood plasma isolated from CRC patients prior to surgery contained elevated levels of 13 EpCAM+-EV miRNAs compared with healthy individuals. Upon surgical tumour removal, the plasma levels of 8 of these were reduced (miR-16-5p, miR-23a-3p, miR-23b-3p, miR-27a-3p, miR-27b-3p, miR-30b-5p, miR-30c-5p and miR-222-3p). These findings indicate that the miRNAs are of tumour origin and may have potential as non-invasive biomarkers for detection of CRC. This work describes a non-invasive blood-based method for sensitive detection of cancer with potential for clinical use in relation to diagnosis and screening. We used the method to study CRC; however, it is not restricted to this disease. It may in principle be used to study any cancer that release epithelial-derived EVs into circulation

Distribution of <i>RET</i> Mutations in Multiple Endocrine Neoplasia 2 in Denmark 1994-2014:A Nationwide Study

Background: Germline mutations of the REarranged during Transfection (RET) proto-oncogene cause multiple endocrine neoplasia 2 (MEN2). It is unclear whether the distribution of RET mutations varies among populations. The first nationwide study of the distribution of RET mutations was conducted, and the results were compared to those of other populations. Methods: This retrospective cohort study included 1583 patients who underwent RET gene testing in one of three centers covering all of Denmark between September 1994 and December 2014. Primary testing method was Sanger sequencing, which included exons 8–11 and 13–16. Mutations were defined according to the ARUP database July 1, 2016. Results: RET mutations were identified in 163 patients from 36 apparently unrelated families. Among the 36 families 13 (36.1%) carried mutations in codon 611, four (11.1%) in codon 618, three (8.3%) in codon 620, one (2.8%) in codon 631, six (16.7%) in codon 634, one (2.8%) in codon 790, one (2.8%) in codon 804, one (2.8%) in codon 852, one (2.8%) in codon 883, and five (13.9%) in codon 918. Among the 13 families with codon 611 mutations, 12 had the p.C611Y mutation. Conclusions: The distribution of RET mutations in Denmark appears to differ from that of other populations. Mutations in codon 611 were the most prevalent, followed by more frequently reported mutations. This might be due to a possible founder effect for the p.C611Y mutation. However, further studies are needed to find possible explanations for the skewed mutational spectrum in Denmark