Association of Tagging Single Nucleotide Polymorphisms on 8 Candidate Genes in Dopaminergic Pathway with Schizophrenia in Croatian Population

Aim To perform a comprehensive evaluation of association of common genetic variants in candidate genes in the dopaminergic pathway with schizophrenia in a sample from Croatian population. Methods A case-control association study was performed on 104 unrelated patients with schizophrenia recruited from a psychiatric hospital in Zagreb and 131 phenotypically normal Croatian subjects. Forty-nine tagging single nucleotide polymorphisms (tagSNPs) in 8 candidate genes in the dopaminergic pathway were identified from the HapMap database and tested for association. Genotyping was performed using the SNPlex platform. Statistical analysis was conducted to assess allelic and genotypic associations between cases and controls using a goodness of fit χ2 test and trend test, respectively; adjustment for multiple testing was done by permutation based analysis. Results Significant allele frequency differences between schizophrenia cases and controls were observed at 4 tag- SNPs located in the genes DRD5, HTR1B1, DBH, and TH1 (P < 0.005). A trend test also confirmed the genotypic association (P < 0.001) of these 4 tagSNPs. Additionally, moderate association (P < 0.05) was observed with 8 tagSNPs on SLC6A3, DBH, DRD4, SLC6A4, and COMT. Conclusions Common genetic variants in genes involved in the dopaminergic pathway are associated with schizophrenia in the populations of Caucasian descent

Subarachnoid hemorrhage: tests of association with apolipoprotein E and elastin genes

<p>Abstract</p> <p>Background</p> <p>Apolipoprotein E (<it>APOE</it>) and elastin (<it>ELN</it>) are plausible candidate genes involved in the pathogenesis of stroke. We tested for association of variants in <it>APOE </it>and <it>ELN </it>with subarachnoid hemorrhage (SAH) in a population-based study. We genotyped 12 single nucleotide polymorphisms (SNPs) on <it>APOE </it>and 10 SNPs on <it>ELN </it>in a sample of 309 Caucasian individuals, of whom 107 are SAH cases and 202 are age-, race-, and gender-matched controls from the Greater Cincinnati/Northern Kentucky region. Associations were tested at genotype, allele, and haplotype levels. A genomic control analysis was performed to check for spurious associations resulting from population substructure.</p> <p>Results</p> <p>At the <it>APOE </it>locus, no individual SNP was associated with SAH after correction for multiple comparisons. Haplotype analysis revealed significant association of the major haplotype (Hap1) in <it>APOE </it>with SAH (<it>p </it>= 0.001). The association stemmed from both the 5' promoter and the 3' region of the <it>APOE </it>gene. <it>APOE </it>ε2 and ε 4 were not significantly associated with SAH. No association was observed for <it>ELN </it>at genotype, allele, or haplotype level and our study failed to confirm previous reports of <it>ELN </it>association with aneurysmal SAH.</p> <p>Conclusion</p> <p>This study suggests a role of the <it>APOE </it>gene in the etiology of aneurysmal SAH.</p

Association of Circulating Tumor DNA Testing Before Tissue Diagnosis With Time to Treatment Among Patients With Suspected Advanced Lung Cancer: The ACCELERATE Nonrandomized Clinical Trial.

IMPORTANCE Liquid biopsy has emerged as a complement to tumor tissue profiling for advanced non-small cell lung cancer (NSCLC). The optimal way to integrate liquid biopsy into the diagnostic algorithm for patients with newly diagnosed advanced NSCLC remains unclear. OBJECTIVE To evaluate the use of circulating tumor DNA (ctDNA) genotyping before tissue diagnosis among patients with suspected advanced NSCLC and its association with time to treatment. DESIGN, SETTING, AND PARTICIPANTS This single-group nonrandomized clinical trial was conducted among 150 patients at the Princess Margaret Cancer Centre-University Health Network (Toronto, Ontario, Canada) between July 1, 2021, and November 30, 2022. Patients referred for investigation and diagnosis of lung cancer were eligible if they had radiologic evidence of advanced lung cancer prior to a tissue diagnosis. INTERVENTIONS Patients underwent plasma ctDNA testing with a next-generation sequencing (NGS) assay before lung cancer diagnosis. Diagnostic biopsy and tissue NGS were performed per standard of care. MAIN OUTCOME AND MEASURES The primary end point was time from referral to treatment initiation among patients with advanced nonsquamous NSCLC using ctDNA testing before diagnosis (ACCELERATE [Accelerating Lung Cancer Diagnosis Through Liquid Biopsy] cohort). This cohort was compared with a reference cohort using standard tissue genotyping after tissue diagnosis. RESULTS Of the 150 patients (median age at diagnosis, 68 years [range, 33-91 years]; 80 men [53%]) enrolled, 90 (60%) had advanced nonsquamous NSCLC. The median time to treatment was 39 days (IQR, 27-52 days) for the ACCELERATE cohort vs 62 days (IQR, 44-82 days) for the reference cohort (P < .001). Among the ACCELERATE cohort, the median turnaround time from sample collection to genotyping results was 7 days (IQR, 6-9 days) for plasma and 23 days (IQR, 18-28 days) for tissue NGS (P < .001). Of the 90 patients with advanced nonsquamous NSCLC, 21 (23%) started targeted therapy before tissue NGS results were available, and 11 (12%) had actionable alterations identified only through plasma testing. CONCLUSIONS AND RELEVANCE This nonrandomized clinical trial found that the use of plasma ctDNA genotyping before tissue diagnosis among patients with suspected advanced NSCLC was associated with accelerated time to treatment compared with a reference cohort undergoing standard tissue testing. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04863924

A tagging SNP in INSIG2 is associated with obesity-related phenotypes among Samoans

<p>Abstract</p> <p>Background</p> <p>A genome wide association study found significant association of a sequence variant, rs7566605, in the insulin-induced gene 2 (<it>INSIG2</it>) with obesity. However, the association remained inconclusive in follow-up studies. We tested for association of four tagging SNPs (tagSNPs) including this variant with body mass index (BMI) and abdominal circumference (ABDCIR) in the Samoans of the Western Pacific, a population with high levels of obesity.</p> <p>Methods</p> <p>We studied 907 adult Samoan participants from a longitudinal study of adiposity and cardiovascular disease risk in two polities, American Samoa and Samoa. Four tagSNPs were identified from the Chinese HapMap database based on pairwise <it>r</it>^{<it>2 </it>}of ≥0.8 and minor allele frequency of ≥0.05. Genotyping was performed using the TaqMan assay. Tests of association with BMI and ABDCIR were performed under the additive model.</p> <p>Results</p> <p>We did not find association of rs7566605 with either BMI or ABDCIR in any group of the Samoans. However, the most distally located tagSNPs in Intron 3 of the gene, rs9308762, showed significant association with both BMI (p-value 0.024) and ABDCIR (p-value 0.009) in the combined sample and with BMI (p-value 0.038) in the sample from Samoa.</p> <p>Conclusion</p> <p>Although rs7566605 was not significantly associated with obesity in our study population, we can not rule out the involvement of <it>INSIG2 </it>in obesity related traits as we found significant association of another tagSNP in <it>INSIG2 </it>with both BMI and ABDCIR. This study suggests the importance of comprehensive assessment of sequence variants within a gene in association studies.</p

Primary low-grade fibromyxoid sarcoma of the large intestine with lung metastases: A case report and review of the literature

A 70-year old man had multiple lung nodules detected on a computed tomography (CT) performed as part of the work-up for an isolated episode of hematuria of several hours' duration. A CT-guided lung biopsy disclosed a morphologically undifferentiated neoplasm, that could not be further subclassified despite an extensive immunohistochemical panel.Four years previously the patient had undergone a left hemicolectomy in another institution to resect a 4.7 cm polypoid ulcerated area in the splenic flexure. The slides from that resection were retrieved for review at our institution. There was a variably cellular, diffuse spindle cell neoplastic proliferation involving the submucosa, muscularis propria and subserosa of the large bowel, composed of elongated spindle cells, with small, inconspicuous nucleoli, arranged in intersecting fascicles. Occasional areas of the tumor showed myxoid stroma. Mitotic activity was low.Immunohistochemistry showed strong and diffuse cytoplasmic staining for MUC4 in both the large bowel and lung tumors. Molecular profiling identified a FUS-CREB3L1 fusion gene.The constellation of morphological, immunohistochemical and molecular features are of low-grade fibromyxoid sarcoma (LGFMS) of the large bowel, with metastatic fibromyxoid sarcoma to the lung.LGFMS is a malignant, often late-metastasizing tumor, with a misleadingly bland histological appearance, that typically arises in the deep soft tissues of the proximal extremities or trunk of young adults. Accurate classification, requiring morphology and ancillary tests, is required for appropriate clinical follow-up and treatment of patients. Keywords: Colon, Low-grade fibromyxoid sarcoma, Metastasis, Lun

Association of Tagging Single Nucleotide Polymorphisms on 8 Candidate Genes in Dopaminergic Pathway with Schizophrenia in Croatian Population

Aim To perform a comprehensive evaluation of association of common genetic variants in candidate genes in the dopaminergic pathway with schizophrenia in a sample from Croatian population. Methods A case-control association study was performed on 104 unrelated patients with schizophrenia recruited from a psychiatric hospital in Zagreb and 131 phenotypically normal Croatian subjects. Forty-nine tagging single nucleotide polymorphisms (tagSNPs) in 8 candidate genes in the dopaminergic pathway were identified from the HapMap database and tested for association. Genotyping was performed using the SNPlex platform. Statistical analysis was conducted to assess allelic and genotypic associations between cases and controls using a goodness of fit χ2 test and trend test, respectively; adjustment for multiple testing was done by permutation based analysis. Results Significant allele frequency differences between schizophrenia cases and controls were observed at 4 tag- SNPs located in the genes DRD5, HTR1B1, DBH, and TH1 (P < 0.005). A trend test also confirmed the genotypic association (P < 0.001) of these 4 tagSNPs. Additionally, moderate association (P < 0.05) was observed with 8 tagSNPs on SLC6A3, DBH, DRD4, SLC6A4, and COMT. Conclusions Common genetic variants in genes involved in the dopaminergic pathway are associated with schizophrenia in the populations of Caucasian descent

HAVOC: Small-scale histomic mapping of cancer biodiversity across large tissue distances using deep neural networks

Intratumoral heterogeneity can wreak havoc on current precision medicine strategies because of challenges in sufficient sampling of geographically separated areas of biodiversity distributed across centimeter-scale tumor distances.To address this gap, we developed a deep learning pipeline that leverages histomorphologic fingerprints of tissue to create “Histomic Atlases of Variation Of Cancers” (HAVOC). Using a number of objective molecular readouts, we demonstrate that HAVOC can define regional cancer boundaries with distinct biology. Using larger tumor specimens, we show that HAVOC can map biodiversityeven across multiple tissue sections. By guiding profiling of 19 partitionsacross six high-grade gliomas, HAVOC revealed that distinct differentiation states can often coexist and be regionally distributed within these tumors. Last, to highlight generalizability, we benchmark HAVOC on additional tumor types.Together, we establish HAVOC asa versatile tool to generate small-scale maps of tissue heterogeneityand guide regional deployment of molecular resources to relevant biodiverse niches

HAVOC: Small-scale histomic mapping of cancer biodiversity across large tissue distances using deep neural networks

Intratumoral heterogeneity can wreak havoc on current precision medicine strategies because of challenges in sufficient sampling of geographically separated areas of biodiversity distributed across centimeter-scale tumor distances.To address this gap, we developed a deep learning pipeline that leverages histomorphologic fingerprints of tissue to create “Histomic Atlases of Variation Of Cancers” (HAVOC). Using a number of objective molecular readouts, we demonstrate that HAVOC can define regional cancer boundaries with distinct biology. Using larger tumor specimens, we show that HAVOC can map biodiversityeven across multiple tissue sections. By guiding profiling of 19 partitionsacross six high-grade gliomas, HAVOC revealed that distinct differentiation states can often coexist and be regionally distributed within these tumors. Last, to highlight generalizability, we benchmark HAVOC on additional tumor types.Together, we establish HAVOC asa versatile tool to generate small-scale maps of tissue heterogeneityand guide regional deployment of molecular resources to relevant biodiverse niches