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The care for patients with serious conditions is increasingly guided by genomic medicine, and genomic medicine may equally transform care for healthy individual if genomic population screening is implemented. This study examines the medical impact of opportunistic genomic screening (OGS) in a cohort of patients undergoing comprehensive genomic germline DNA testing for childhood cancer, including the impact on their relatives. Medical actionability and uptake after cascade testing in the period following disclosure of OGS results was quantified. A secondary finding was reported to 19/595 (3.2%) probands primarily in genes related to cardiovascular and lipid disorders. After a mean follow up time of 1.6 years (Interquartile range (IQR): 0.57-1.92 yrs.) only 12 (63%) of these variants were found to be medically actionable. Clinical follow up or treatment was planned in 16 relatives, and as in the probands, the prescribed treatment was primarily betablockers or cholesterol lowering therapy. No invasive procedures or implantation of medical devices were performed in probands or relatives, and no reproductive counseling was requested. After an average of 1.6 years of follow-up 2.25 relatives per family with an actionable finding had been tested. This real-world experience of OGS grants new insight into the practical implementation effects and derived health care demands of genotype-first screening. The resulting health care effect and impact on demand for genetic counseling and workup in relatives extends beyond the effect in the probands.

BRCA1-associated protein-1 (BAP1) is a recognised tumour suppressor gene. Germline BAP1pathogenic/likely pathogenic variants are associated with predisposition to multiple tumours, including uveal melanoma, malignant pleural and peritoneal mesothelioma, renal cell carcinoma and specific non-malignant neoplasms of the skin, as part of the autosomal dominant BAP1-tumour predisposition syndrome. The overall lifetime risk for BAP1carriers to develop at least one BAP1-associated tumour is up to 85%, although due to ascertainment bias, current estimates of risk are likely to be overestimated. As for many rare cancer predisposition syndromes, there is limited scientific evidence to support the utility of surveillance and, therefore, management recommendations for BAP1carriers are based on expert opinion. To date, European recommendations for BAP1carriers have not been published but are necessary due to the emerging phenotype of this recently described syndrome and increased identification of BAP1carriers via large gene panels or tumour sequencing. To address this, the Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom invited European collaborators to collaborate to develop guidelines to harmonize surveillance programmes within Europe. Recommendations with respect to BAP1testing and surveillance were achieved following literature review and Delphi survey completed by a core group and an extended expert group of 34 European specialists including Geneticists, Ophthalmologists, Oncologists, Dermatologists and Pathologists. It is recognised that these largely evidence-based but pragmatic recommendations will evolve over time as further data from research collaborations informs the phenotypic spectrum and surveillance outcomes.

Supplemental Digital Content is available in the text.Chemotherapy-induced nausea and vomiting (CINV) remains a common adverse effect for children with cancer. In children, chemotherapy emetogenicity and patient factors such as susceptibility to motion sickness and age group determine a patient’s risk of CINV. Besides known risk factors, genetic factors may play a role in interindividual variation in the occurrence of CINV. We investigated the influence of candidate gene polymorphisms on the efficacy of antiemetics and on the background sensitivity to CINV in children. This prospective study included 100 children with cancer (median age 6.4 years, range 0.8–17.9) who received moderately to highly emetogenic chemotherapy. Participants registered nausea and vomiting episodes in a mobile app. Genotypes were determined by whole-genome sequencing (n= 79) or Sanger sequencing (n= 21) for 71 genetic polymorphisms involved in motion sickness and antiemetic pathways. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate associations between acute CINV and genotypes adjusting for susceptibility to motion sickness and age group. Rs3782025 in the 5-hydroxytryptamine type 3 (5-HT3) receptor gene (HTR3B) [minor allele frequency (MAF): 0.48] affected response to 5-HT3receptor antagonists; acute CINV occurred in 76% of patients with GA/AA genotypes and in 41% of patients with GG genotype (OR 5.59; 95% CI 1.74–17.9, dominant genetic model). Rs2975226 in the dopamine transporter gene (SLC6A3) (MAF: 0.54) was associated with acute CINV (OR 5.79; 95% CI 1.09–30.67, recessive genetic model). Polymorphisms in HTR3Band SLC6A3may contribute to the variability in response to antiemetic prophylaxis for CINV in children.

Proinflammatory cytokines are implicated as effector molecules in the pathogenesis of IDDM. Interleukin-6 (IL-6) alone or in combination with IL-1Β inhibits glucose-stimulated insulin release from isolated rat pancreatic islets by [...]

Supplemental Digital Content is available in the text.This study aimed to investigate the microRNA (miRNA) profile in primary tumors from conjunctival melanoma with and without subsequent metastatic spread along with their coupled distant metastases to identify miRNAs likely to be involved in metastatic progression. This observational study included 13 patients with metastatic conjunctival melanoma (follow-up: 1–39 years) treated at a Danish referral center. Twenty-five patients with nonmetastatic conjunctival melanoma (follow-up: 5–17 years) were included for comparison. Global miRNA profiling was performed with the Affymetrix GeneChip 4.1 microarray. Taqman qPCR arrays were used for validation. Significant differentially expressed miRNAs were defined as having a false discovery rate of less than 0.05. Primary conjunctival melanoma with and without subsequent metastatic spread clustered separately according to miRNA expression, and 15 miRNAs were found to have significant differential expression. Six miRNAs (hsa-miR-4528, hsa-miR-1270, hsa-miR-1290, hsa-mir-548f-4, hsa-mir-4278, and hsa-miR-34a-3p) were downregulated and nine miRNAs were upregulated (hsa-mir-575, hsa-miR-527, hsa-miR-518a-5p, hsa-miR-6759-5p, hsa-miR-8078, hsa-mir-4501, hsa-mir-622, hsa-mir-4698, and hsa-mir-4654) in primary conjunctival melanoma with subsequent metastatic spread. A comparison of primary conjunctival melanoma with their pair-matched metastases identified six significant differentially expressed miRNAs (hsa-miR-1246 and hsa-miR-302d-5p, hsa-mir-6084, hsa-miR-184, hsa-mir-658, and hsa-mir-4427). qPCR confirmed downregulation of hsa-miR-184 in the distant metastases when compared with the corresponding primary tumor. Primary conjunctival melanoma with and without subsequent metastatic spread separated clearly on the miRNA level when profiled with microarray-based methods. qPCR was able to replicate expression levels of one miRNA (hsa-miR-184) that was downregulated in metastases when compared with corresponding primary tumors.

Supplemental Digital Content is available in the text.Germline mutations of BRCA1and BRCA2predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1or BRCA2by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1and BRCA2germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N= 763). We identified one individual with a deleterious BRCA1variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2mutations and UM susceptibility represents a rare source of increased risk.

Uveal melanoma is a clinically distinct and particularly lethal subtype of melanoma originating from melanocytes in the eye. Here, we performed multi-region DNA sequencing of primary uveal melanomas and their matched metastases from 35 patients. We observed previously unknown driver mutations and established the order in which these and known driver mutations undergo selection. Metastases had genomic alterations distinct from their primary tumors; metastatic dissemination sometimes occurred early during the development of the primary tumor. Our study offers new insights into the genetics and evolution of this melanoma subtype, providing potential biomarkers for progression and therapy. Multi-region sequencing of 35 primary uveal melanomas and their matched metastases yields new insights into the genetics and evolution of these tumors and provides potential biomarkers for progression and therapy.

Germline mutations in CDKN2Aare frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2Amutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2Amutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18–2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92–1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94–1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75–4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2Aand may influence carcinogenesis.

Interleukin-1β (IL-1β) is cytotoxic to rat pancreatic β-cells by inhibiting glucose oxidation, causing DNA damage and inducing apoptosis. Nitric oxide (NO) is a necessary but not sufficient mediator of these effects. IL-1β induced kinase activity toward Elk-1, activation transcription factor 2, c-Jun, and heat shock protein 25 in rat islets. By Western blotting with phosphospecific antibodies and by immunocomplex kinase assay, IL-1β was shown to activate extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (p38) in islets and rat insulinoma cells. Specific ERK1/2 and p38 inhibitors individually reduced but in combination blocked IL-1β-mediated islet NO synthesis, and reverse transcription-polymerase chain reaction of inducible NO synthase mRNA showed that ERK1/2 and p38 controlled IL-1β-induced islet inducible NO synthase expression at the transcriptional level. Hyperosmolarity caused phosphorylation of Elk-1, activation transcription factor 2, and heat shock protein 25 and activation of ERK1/2 and p38 in islets comparable to that induced by IL-1β but did not lead to NO synthesis. Inhibition of p38 but not of ERK1/2 attenuated IL-1β-mediated inhibition of glucose-stimulated insulin release. We conclude that ERK1/2 and p38 activation is necessary but not sufficient for IL-1β-mediated β-cell NO synthesis and that p38 is involved in signaling of NO-independent effects of IL-1β in β-cells.

Gorlin syndrome is mainly caused by pathogenic germline variants in the tumour suppressor genes PTCH1 and SUFU, both regulatory genes in the hedgehog pathway. However, the phenotypes of patients with PTCH1 and SUFU pathogenic variants seem to differ. We present a family with a frameshift variant in the SUFU gene c.954del, p.Asn319Thrfs∗42 leading to meningiomas and multiple basal cell-carcinomas.