Diagnostic yield of multigene panel testing in an Israeli cohort: enrichment of low-penetrance variants.

BACKGROUND: Carriers of pathogenic variants (PVs) in moderate-high-penetrance cancer susceptibility genes are offered tailored surveillance schemes for early cancer diagnosis. The clinical implications of low-penetrance variant carriers are less clear. METHODS: Clinical and demographic data were retrieved for a cohort of Israeli individuals who underwent oncogenetic testing by the 30-gene cancer panel at Color Genomics laboratory, between 04/2013 and 12/2018. RESULTS: Of 758 genotyped individuals, 504 had been diagnosed with cancer prior to testing: 283 (56%) had breast cancer and 106 (21%) colorectal cancer. Pathogenic or likely pathogenic (P/LP) variants were detected in 123 (16%) individuals. Overall, 44 different P/LP variants were detected in 18/30 cancer susceptibility genes; 20 of them were founder/recurrent mutations. Of the carriers, 39 (32%), 10 (8%), and 74 (60%) carried high-, moderate-, or low-penetrance variants, respectively. After excluding low-penetrance variants, 7% (33/504) of all cancer patients, 6% of breast or ovarian cancer patients were found to be carriers, as well as 7% (14/203) of individuals with colonic polyps, and 4% (11/254) of cancer-free individuals. CONCLUSIONS: The diagnostic yield of moderate- and high-penetrance PVs using multigene panel testing was 6%, with 3.7% carriers of non-recurrent PVs. This yield should be discussed during pre-test counseling, and emphasizes the need for harmonized recommendations regarding clinical implications of low-penetrance variants.

Variable Features of Juvenile Polyposis Syndrome With Gastric Involvement Among Patients With a Large Genomic Deletion of BMPR1A.

OBJECTIVES: Loss-of-function mutations of BMPR1A cause juvenile polyposis syndrome (JPS), but large genomic deletions in BMPR1A are rare, reported in few families only, and data regarding the associated phenotype are limited. METHODS: We investigated clinical features and genomic data of 7 extended seemingly unrelated families with a genomic deletion of the entire coding region of BMPR1A. We defined mutation size, mutation prevalence, and tumor pathogenesis using whole-genome sequencing, targeted genotyping, and haplotype analysis. RESULTS: Patients with JPS from 7 families of Bukharin Jewish ancestry carried a deletion of 429 kb, encompassing the BMPR1A coding sequence and 8 downstream genes. Haplotype analysis and testing controls identified this as a common founder mutation occurring in 1/124 individuals of Bukharin origin. Tumor testing did not demonstrate loss of heterozygosity. Among carriers, JPS was almost fully penetrant, but clinical features varied widely, ranging from mild to very severe, including pan-enteric polyps, gastritis, and colorectal, esophageal, and testicular cancer, and carriers with phenotypes, which would not have raised suspicion of JPS. DISCUSSION: The phenotype in this large cohort was extremely variable, although all carriers shared the same variant and the same genetic background. New observations include a preponderance of adenomatous rather than juvenile polyps, possible association with testicular cancer, and unexpected upper gastrointestinal involvement.

Personalized prostate cancer screening among men with high risk genetic predisposition- study protocol for a prospective cohort study.

BACKGROUND: Prostate cancer screening among the general population is highly debatable. Nevertheless, screening among high-risk groups is appealing. Prior data suggests that men carrying mutations in the BRCA1& 2 genes may be at increased risk of developing prostate cancer. Additionally, they appear to develop prostate cancer at a younger age and with a more aggressive course. However, prior studies did not systematically perform prostate biopsies and thus cannot determine the true prevalence of prostate cancer in this population. METHODS: This will be a prospective diagnostic trial of screening for prostate cancer among men with genetic predisposition. The target population is males (40-70 year old) carrying a BRCA1 and/or BRCA2 germ line mutation. They will be identified via our Genetic counseling unit. All men after signing an informed consent will undergo the following tests: PSA, free to total PSA, MRI of prostate and prostate biopsy. The primary endpoint will be to estimate the prevalence, stage and grade of prostate cancer in this population. Additionally, the study aims to estimate the impact of these germ line mutations on benign prostatic hyperplasia. Furthermore, this study aims to create a bio-bank of tissue, urine and serum of this unique cohort for future investigations. Finally, this study will identify an inception cohort for future interventional studies of primary and secondary prevention. DISCUSSION: The proposed research is highly translational and focuses not only on the clinical results, but on the future specimens that will be used to advance our understanding of prostate cancer patho-physiology. Most importantly, these high-risk germ-line mutation carriers are ideal candidates for primary and secondary prevention initiatives. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02053805.

Use of a mild sedative helps to identify true non-dippers by ABPM: a study in patients with diabetes mellitus and hypertension.

BACKGROUND: The interplay between the continuity or quality of sleep and diurnal variation in blood pressure has not been directly examined before. We examined the influence of a mild, non-hypotensive sedative on nocturnal dipping. DESIGN: This was a randomized, single-blind study. SETTING: The study took place in an out-patient clinic in an academic hospital. INTERVENTION: Zolpidem 10 mg or placebo was given randomly for the first or second night, and ambulatory blood pressure monitoring was instigated for 48 h. PATIENTS: The population under study comprised 96 male patients with type 2 diabetes mellitus and hypertension (mean age 54 +/- 6 years, mean blood pressure 158/94 +/- 9/6 mmHg). MAIN OUTCOME MEASURE: Nocturnal dipping (nocturnal blood pressure >/= 10% lower than daytime pressure) was found in 71% of the patients taking the sedative compared with 27% of those on placebo (P=0.001). RESULTS: On placebo, non-dippers and dippers had similar profiles of cardiovascular risk parameters. In contrast, non-dippers taking zolpidem had significantly higher values for most cardiovascular risk parameters compared with dippers: higher systolic blood pressure, higher low-density lipoproteins, lower high-density lipoproteins, higher serum creatinine, a higher urinary albumin:creatinine ratio, higher serum insulin and insulin resistance. CONCLUSION: The use of a mild sedative during ambulatory blood pressure monitoring may help to identify the patients with a very high cardiovascular risk. These are the patients with a blunted nocturnal hypotension despite sedation.

Omapatrilat, an angiotensin-converting enzyme and neutral endopeptidase inhibitor, attenuates early atherosclerosis in diabetic and in nondiabetic low-density lipoprotein receptor-deficient mice.

Omapatrilat inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). ACE inhibitors have been shown to inhibit atherosclerosis in apoE-deficient mice and in several other animal models but failed in low-density lipoprotein (LDL) receptor-deficient mice despite effective inhibition of the renin-angiotensin-aldosterone system. The aim of the present study was to examine the effect of omapatrilat on atherogenesis in diabetic and nondiabetic LDL receptor-deficient mice. LDL receptor-deficient male mice were randomly divided into 4 groups (n = 11 each). Diabetes was induced in 2 groups by low-dose STZ, the other 2 groups served as nondiabetic controls. Omapatrilat (70 mg/kg/day) was administered to one of the diabetic and to one of the nondiabetic groups. The diabetic and the nondiabetic mice were sacrificed after 3 and 5 weeks, respectively. The aortae were examined and the atherosclerotic plaque area was measured. The atherosclerotic plaque area was significantly smaller in the omapatrilat-treated mice, both diabetic and nondiabetic, as compared to nontreated controls. The mean plaque area of omapatrilat-treated nondiabetic mice was 9357 +/- 7293 microm2, versus 71977 +/- 34610 microm2 in the nontreated mice (P = .002). In the diabetic animals, the plaque area was 8887 +/- 5386 microm2 and 23220 +/- 10400 microm2, respectively for treated and nontreated mice (P = .001). Plasma lipids were increased by omapatrilat: Mean plasma cholesterol in treated mice, diabetic and nondiabetic combined, was 39.31 +/- 6.00 mmol/L, versus 33.12 +/- 7.64 mmol/L in the nontreated animals (P = .008). The corresponding combined mean values of triglycerides were 4.83 +/- 1.93 versus 3.00 +/- 1.26 mmol/L (P = .02). Omapatrilat treatment did not affect weight or plasma glucose levels. Treatment with omapatrilat inhibits atherogenesis in diabetic as well as nondiabetic LDL receptor-deficient mice despite an increase in plasma lipids, suggesting a direct effect on the arterial wall.

Low-dose interferon-alpha accelerates atherosclerosis in an LDL receptor-deficient mouse model.

Background: Solid evidence suggests that atheroscleosis is associated with immune reactions. Most of the activated T cells in the plaque are T helper 1 subtype (Th1), which secrete interferon-gamma (IFN-gamma), now generally accepted as a proatherogenic cytokine. Interferon-alpha (IFN-alpha) has been found to inhibit the secretion of IL-12 and IFN-gamma and to increase IL-10 production. It may, therefore, be atheroprotective. The aim of the present study was to clarify the effect of IFN-alpha on atherogenesis in a transgenic mouse model of atherosclerosis. Methods: 8-week-old low-density lipoprotein (LDL) receptor-deficient mice were allocated randomly into treatment and control groups (n=13 each). The treatment group received 1000 units of IFN-alpha i.p. every other day for 5 weeks and the control mice received 0.9% NaCl. The mice were fed a Western diet. Results: The IFN-alpha-treated and the control mice showed a similar weight gain (mean 3.9+/-1.0 g vs. 3.4+/-1.8 g, respectively). Treatment with IFN-alpha significantly increased the plasma cholesterol levels in both treated and untreated mice (mean 31.03+/-5.53 mmol/l vs. 24.91+/-6.03 mmol/l, respectively; p<0.022) as well as the plasma triglyceride levels (mean 4.79+/-1.57 mmol/l vs. 3.10+/-1.85 mmol/l, respectively; p<0.033). The IFN-alpha treated mice had a significantly increased atherosclerotic plaque area (mean 61,590+/-22,368 microm(2) vs. 37,272+/-15,469 microm(2), respectively; p<0.008). Conclusion: The putative atheroprotective effect of IFN-alpha by the decrease in IL-10 and IFN-gamma is abolished by hyperlipidemia. Therefore, the net effect of IFN-alpha in this murine model is the exacerbation of atherosclerosis.