GREM1 and POLE variants in hereditary colorectal cancer syndromes.

Hereditary factors are thought to play a role in at least one third of patients with colorectal cancer (CRC) but only a limited proportion of these have mutations in known high-penetrant genes. In a relatively large part of patients with a few or multiple colorectal polyps the underlying genetic cause of the disease is still unknown. Using exome sequencing in combination with linkage analyses together with detection of copy-number variations (CNV), we have identified a duplication in the regulatory region of the GREM1 gene in a family with an attenuated/atypical polyposis syndrome. In addition, 107 patients with colorectal cancer and/or polyposis were analyzed for mutations in the candidate genes identified. We also performed screening of the exonuclease domain of the POLE gene in a subset of these patients. The duplication of 16 kb in the regulatory region of GREM1 was found to be disease-causing in the family. Functional analyses revealed a higher expression of the GREM1 gene in colorectal tissue in duplication carriers. Screening of the exonuclease domain of POLE in additional CRC patients identified a probable causative novel variant c.1274A>G, p.Lys425Arg. In conclusion a high penetrant duplication in the regulatory region of GREM1, predisposing to CRC, was identified in a family with attenuated/atypical polyposis. A POLE variant was identified in a patient with early onset CRC and a microsatellite stable (MSS) tumor. Mutations leading to increased expression of genes can constitute disease-causing mutations in hereditary CRC syndromes.

Experiences of living with increased risk of developing colorectal and gynaecological cancer in individuals with no identified gene mutation.

BACKGROUND: In most families with familial cancers, mutations have not been demonstrated; thus, healthy individuals cannot be tested for mutation status. As a consequence, many persons at risk of familial cancer live with an unknown, but presumably high, risk of developing cancer. AIM: The aim of this study was to describe individuals' perceptions of living with an increased risk of colorectal and gynaecologic cancer where the gene mutation is unknown. METHODS: Interviews were conducted with 30 individuals with familial colorectal cancer. These persons have no known mutation and therefore should be considered presumptive carriers. In connection with the interviews, all participants were offered to take part in a surveillance programme consisting of a colonoscopy and gynaecological examinations. The interview transcriptions were analysed by the use of qualitative content analysis. RESULTS: Two themes emerged from the analyses: first, living under a threat with two subthemes, threat awareness and distancing oneself from the threat. The second theme, living with uncertainty, was divided into four subthemes: influencing one's family, being on the safe side, facing emotions evoked by examinations and trust and disappointment to the medical services. CONCLUSION: These persons live with a lifelong uncertainty with a varying intensity depending on what happens throughout the life trajectory. They have no diagnosis or patient group to relate to; therefore, the entire situation is often perceived as abstract. Thus, providing information and counselling needs to be more deeply elucidated, and we need to address both situational and existential ways of uncertainty. This will, however, require professionals of all disciplines to understand the meaning of uncertainty and help ensure that its adverse effects are decreased with adequate nursing interventions.

Elicitation of Health-Related Utility in Perianal Fistula in Crohn's Disease.

BACKGROUND AND OBJECTIVE: Perianal fistulae are a common complication of Crohn's disease (CD) and pose a substantial burden on quality of life. Data capturing health-related utility associated with perianal fistulae in CD are scarce. The current study aims to value health states related to different stages of the disease to quantitatively evaluate the impact of complex perianal fistulae on CD patients' quality of life. METHODS: Eight health state descriptions associated with complex perianal fistulae in CD were developed following qualitative research with patients and validation by clinicians. Following pre-testing, a survey was administered online in two samples of UK respondents: the general population and patients with CD. A choice-based valuation technique, the time trade-off (TTO), was used for direct utility measurement. CD patients also valued their current health state using the TTO. Exclusion criteria for respondents displaying logical inconsistencies were applied. RESULTS: Usable responses were received from 835 respondents, reflective of the UK population in age and sex, in the general population survey and 162 CD patients in the patient survey. Non-remission states were valued much lower than the remission state by both samples, ranging from 0.20 for proctectomy with a negative outcome to 0.66 for chronic symptomatic fistulae with mild symptoms. Patients currently experiencing fistulae reported lower values for current health than those without fistulae. CONCLUSION: Low utility values were assigned to the non-remission health states for perianal fistulae in CD by the general public and patients with CD. This demonstrates the high humanistic burden of inadequately managed perianal fistula in CD.

Increasing peripheral artery intima thickness from childhood to seniority.

BACKGROUND: Using new, very high-resolution ultrasound biomicroscopy, we examined the thickness of artificial layers of silicone and intima thickness (IT) of radial and anterior tibial arteries in healthy subjects and in patients with vascular disease. METHODS AND RESULTS: Silicone layers of varying thicknesses and mesenteric artery specimens obtained from 18 patients undergoing colectomy were measured by both ultrasound biomicroscopy (55 MHz) and morphometry. There was high correlation (r>0.9; P<0.0001) between IT and intima area versus ultrasound biomicroscopy. In 90 healthy subjects (aged between 10 and 90 years), radial and anterior tibial arterial IT and intima-media thickness were measured, as was carotid intima-media thickness in 56 of these subjects. Age was strongly related with both media thickness and IT of both peripheral arteries. Correlations were found between carotid intima-media thickness and both radial and anterior tibial IT/intima-media thickness (r=0.44 to 0.53; P<0.0001). The IT-to-lumen diameter ratio increased with age and was larger at all ages in the anterior tibial artery (0.067+/-0.034) versus the radial artery (0.036+/-0.012; P<0.0001). A thicker radial intimal layer was found in patients with peripheral artery disease. CONCLUSION: This study is the first to our knowledge in humans to show the feasibility of measuring IT of the radial and anterior tibial arteries using very high-resolution ultrasound. IT progresses with age, and the IT-to-lumen diameter ratio is largest in the arteries of the foot. Assessment of IT by ultrasound biomicroscopy may aid in detecting early peripheral vascular abnormalities.

Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing.

Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Targeted NGS-based sequencing of the whole gene regions including introns of the 19 genes was used. The individuals had a family history of CRC or had a phenotype consistent with a known CRC syndrome. The purpose of the study was to demonstrate the diagnostic difficulties linked to genotype-phenotype diversity and the benefits of using a gene panel. Pathogenicity classification was carried out on 46 detected variants. In total we detected sixteen pathogenic or likely pathogenic variants and 30 variants of unknown clinical significance. Four of the pathogenic or likely pathogenic variants were found in BMPR1A in patients with unexplained familial adenomatous polyposis or atypical adenomatous polyposis, which extends the genotype-phenotype spectrum for this gene. Nine patients had more than one variant remaining after the filtration, including three with truncating mutations in BMPR1A, PMS2 and AXIN2. CNVs were found in three patients, in upstream regions of SMAD4, MSH3 and CTNNB1, and one additional individual harbored a 24.2 kb duplication in CDH1 intron1.

A mutation in POLE predisposing to a multi-tumour phenotype.

Somatic mutations in the POLE gene encoding the catalytic subunit of DNA polymerase ε have been found in sporadic colorectal cancers (CRCs) and are most likely of importance in tumour development and/or progression. Recently, families with dominantly inherited colorectal adenomas and colorectal cancer were shown to have a causative heterozygous germline mutation in the proofreading exonuclease domain of POLE. The highly penetrant mutation was associated with predisposition to CRC only and no extra-colonic tumours were observed. We have identified a mutation in a large family in which the carriers not only developed CRC, they also demonstrate a highly penetrant predisposition to extra-intestinal tumours such as ovarian, endometrial and brain tumours. The mutation, NM_006231.2:c.1089C>A, p.Asn363Lys, also located in the proofreading exonuclease domain is directly involved in DNA binding. Theoretical prediction of the amino acid substitution suggests a profound effect of the substrate binding capability and a more severe impairment of the catalytic activity compared to the previously reported germline mutation. A possible genotype to phenotype correlation for deleterious mutations in POLE might exist that needs to be considered in the follow-up of mutation carriers.

Epidermal growth factor levels are related to diastolic blood pressure and carotid artery stiffness.

OBJECTIVES: The epidermal growth factor (EGF) is believed to be involved in vascular remodelling. EGF receptors are expressed in human atherosclerotic tissue. DESIGN: In order to study the role of EGF in vascular remodelling and early progression of atherosclerosis, 17 men and 16 women aged 20 to 45 years were recruited. Common Carotid Artery Stiffness index (CCA SI) and blood pressure were evaluated. In addition, serum levels of EGF and blood lipids were measured. RESULTS: The levels of serum EGF were significantly correlated to diastolic blood pressure (p<0.05) and CCA SI (p<0.05). Subjects with EGF concentrations in the upper median had significantly lower levels of HDL (High Density Lipoproteins) (p<0.05) and ApoA1 (Apolipoprotein) (p<0.05) than those with EGF concentrations in the lower median. DISCUSSION: High serum level of EGF is associated with elevated diastolic blood pressure and increased vessel stiffness suggesting a possible functional role of EGF in the cardiovascular system in a healthy population.