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Myoepithelial carcinomas (MECs) of soft tissue are rare and aggressive tumors affecting young adults and children, but their molecular landscape has not been comprehensively explored through genome sequencing. Here, we present the whole-exome sequencing (WES), whole-genome sequencing (WGS), and RNA sequencing findings of two MECs. Patients 1 and 2 (P1, P2), both male, were diagnosed at 27 and 37 yr of age, respectively, with shoulder (P1) and inguinal (P2) soft tissue tumors. Both patients developed metastatic disease, and P2 died of disease. P1 tumor showed a rhabdoid cytomorphology and a complete loss of INI1 (SMARCB1) expression, associated with a homozygous SMARCB1 deletion. The tumor from P2 showed a clear cell/small cell morphology, retained INI1 expression and strong S100 positivity. By WES and WGS, tumors from both patients displayed low tumor mutation burdens, and no targetable alterations in cancer genes were detected. P2's tumor harbored an EWSR1::KLF15 rearrangement, whereas the tumor from P1 showed a novel ASCC2::GGNBP2 fusion. WGS evidenced a complex genomic event involving mainly Chromosomes 17 and 22 in the tumor from P1, which was consistent with chromoplexy. These findings are consistent with previous reports of EWSR1 rearrangements (50% of cases) in MECs and provide a genetic basis for the loss of SMARCB1 protein expression observed through immunohistochemistry in 10% of 40% of MEC cases. The lack of additional driver mutations in these tumors supports the hypothesis that these alterations are the key molecular events in MEC evolution. Furthermore, the presence of complex structural variant patterns, invisible to WES, highlights the novel biological insights that can be gained through the application of WGS to rare cancers., (© 2022 Cyrta et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Since the onset of the SARS-CoV-2 pandemic, most clinical testing has focused on RT-PCR 1 . Host epigenome manipulation post coronavirus infection 2-4 suggests that DNA methylation signatures may differentiate patients with SARS-CoV-2 infection from uninfected individuals, and help predict COVID-19 disease severity, even at initial presentation., Methods: We customized Illumina's Infinium MethylationEPIC array to enhance immune response detection and profiled peripheral blood samples from 164 COVID-19 patients with longitudinal measurements of disease severity and 296 patient controls., Results: Epigenome-wide association analysis revealed 13,033 genome-wide significant methylation sites for case-vs-control status. Genes and pathways involved in interferon signaling and viral response were significantly enriched among differentially methylated sites. We observe highly significant associations at genes previously reported in genetic association studies (e.g. IRF7, OAS1). Using machine learning techniques, models built using sparse regression yielded highly predictive findings: cross-validated best fit AUC was 93.6% for case-vs-control status, and 79.1%, 80.8%, and 84.4% for hospitalization, ICU admission, and progression to death, respectively., Conclusions: In summary, the strong COVID-19-specific epigenetic signature in peripheral blood driven by key immune-related pathways related to infection status, disease severity, and clinical deterioration provides insights useful for diagnosis and prognosis of patients with viral infections., (© 2021. The Author(s).)

Background: Since the onset of the SARS-CoV-2 pandemic, most clinical testing has focused on RT-PCR 1 . Host epigenome manipulation post coronavirus infection 2-4 suggests that DNA methylation signatures may differentiate patients with SARS-CoV-2 infection from uninfected individuals, and help predict COVID-19 disease severity, even at initial presentation., Methods: We customized Illumina's Infinium MethylationEPIC array to enhance immune response detection and profiled peripheral blood samples from 164 COVID-19 patients with longitudinal measurements of disease severity and 296 patient controls., Results: Epigenome-wide association analysis revealed 13,033 genome-wide significant methylation sites for case-vs-control status. Genes and pathways involved in interferon signaling and viral response were significantly enriched among differentially methylated sites. We observe highly significant associations at genes previously reported in genetic association studies ( e.g. IRF7 , OAS1 ). Using machine learning techniques, models built using sparse regression yielded highly predictive findings: cross-validated best fit AUC was 93.6% for case-vs-control status, and 79.1%, 80.8%, and 84.4% for hospitalization, ICU admission, and progression to death, respectively., Conclusions: In summary, the strong COVID-19-specific epigenetic signature in peripheral blood driven by key immune-related pathways related to infection status, disease severity, and clinical deterioration provides insights useful for diagnosis and prognosis of patients with viral infections., Competing Interests: Competing interestsWe declare the following competing interests: B.B., R.P., and A.T. are employees at Illumina, Inc. and B.B., R.P., A.A.M., and A.T. own stock in Illumina, Inc. The rest of the authors declare that they have no relevant conflicts of interest., (© The Author(s) 2021.)

De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father's sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.

Purpose: We developed a precision medicine program for patients with advanced cancer using integrative whole-exome sequencing and transcriptome analysis., Patients and Methods: Five hundred fifteen patients with locally advanced/metastatic solid tumors were prospectively enrolled, and paired tumor/normal sequencing was performed. Seven hundred fifty-nine tumors from 515 patients were evaluated., Results: Most frequent tumor types were prostate (19.4%), brain (16.5%), bladder (15.4%), and kidney cancer (9.2%). Most frequently altered genes were TP53 (33%), CDKN2A (11%), APC (10%), KTM2D (8%), PTEN (8%), and BRCA2 (8%). Pathogenic germline alterations were present in 10.7% of patients, most frequently CHEK2 (1.9%), BRCA1 (1.5%), BRCA2 (1.5%), and MSH6 (1.4%). Novel gene fusions were identified, including a RBM47-CDK12 fusion in a metastatic prostate cancer sample. The rate of clinically relevant alterations was 39% by whole-exome sequencing, which was improved by 16% by adding RNA sequencing. In patients with more than one sequenced tumor sample (n = 146), 84.62% of actionable mutations were concordant., Conclusion: Integrative analysis may uncover informative alterations for an advanced pan-cancer patient population. These alterations are consistent in spatially and temporally heterogeneous samples., Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Alexandros Sigaras Employment: Weill Cornell Medical College Loredana Puca Employment: Petra Pharma Corporation Bishoy M. Faltas Honoraria: Digital Science Press publications Research Funding: Eli Lilly David Rickman Research Funding: Janssen Oncology Eleni Andreopoulou Honoraria: AstraZeneca, Sirtex, SVB Leerink, AbbVie, Eisai, NanoString Technologies Consulting or Advisory Role: AstraZeneca, Sirtex, SVB Leerink, AbbVie, Eisai, NanoString Technologies Speakers’ Bureau: R-Pharm US Travel, Accommodations, Expenses: AstraZeneca, Sirtex, SVB Leerink, AbbVie, Eisai, NanoString Technologies Kevin Holcomb Research Funding: Fujirebio Diagnostics Expert Testimony: Johnson & Johnson Linda T. Vahdat Honoraria: Polyphor, R-Pharm, Athenex, Seattle Genetics, Osmol Therapeutics Consulting or Advisory Role: Berg Pharma Speakers’ Bureau: Eisai Research Funding: Polyphor (Inst), Immunomedics (Inst), Seattle Genetics (Inst) Patents, Royalties, Other Intellectual Property: Patent pending on the application for BMD progenitor cells (Inst) Douglas S. Scherr Research Funding: Urogen Pharma (Inst), Cepheid (Inst), Anchiano (Inst), CryoLife (Inst) Koen van Besien Stock and Other Ownership Interests: Hemogenyx Consulting or Advisory Role: Hemogenyx, Actinium Pharmaceuticals, Cellectis, Tessa Therapeutics Research Funding: Miltenyi Biotec, Actinium Pharmaceuticals, Juno Therapeutics, Fate Therapeutics Christopher E. Barbieri Patents, Royalties, Other Intellectual Property: Coinventor on a patent application filed regarding SPOP mutations in prostate cancer by Weill Cornell Medicine Brian D. Robinson Consulting or Advisory Role: Bristol-Myers Squibb Patents, Royalties, Other Intellectual Property: Methods for diagnosing and treating prostate cancer Allyson J. Ocean Consulting or Advisory Role: Celgene, Tyme Speakers’ Bureau: Daiichi Sankyo Travel, Accommodations, Expenses: Daiichi Sankyo Ana Molina Honoraria: American Society of Clinical Oncology Consulting or Advisory Role: Eisai, Exelixis, Novartis, Janssen Oncology Manish A. Shah Consulting or Advisory Role: Astellas Pharma, Eli Lilly Research Funding: Gilead Sciences (Inst), Merck (Inst), Boston Biomedical (Inst), Oncolys BioPharma (Inst), Bristol-Myers Squibb (Inst) David M. Nanus Consulting or Advisory Role: Genentech Research Funding: Novartis (Inst), Boehringer Ingelheim (Inst), Zenith Epigenetics (Inst) Qiulu Pan Employment: Caris Life Sciences Stock and Other Ownership Interests: Caris Life Sciences Francesca Demichelis Patents, Royalties, Other Intellectual Property: Co-inventor on a patent filed by the University of Michigan and Brigham and Women’s Hospital covering the diagnostic and therapeutic fields for ETS fusions in prostate cancer, diagnostic field licensed to Gen-Probe Scott T. Tagawa Consulting or Advisory Role: Medivation, Astellas Pharma, Dendreon, Janssen Oncology, Bayer, Genentech, Endocyte, Immunomedics, Karyopharm Therapeutics, AbbVie, Tolmar, QED, Amgen, Sanofi, Pfizer Research Funding: Eli Lilly (Inst), Sanofi (Inst), Janssen Oncology (Inst), Astellas Pharma (Inst), Progenics (Inst), Millennium Pharmaceuticals (Inst), Amgen (Inst), Bristol-Myers Squibb (Inst), Dendreon (Inst), Rexahn Pharmaceuticals (Inst), Bayer (Inst), Genentech (Inst), Newlink Genetics (Inst), Inovio Pharmaceuticals (Inst), AstraZeneca (Inst), Immunomedics (Inst), Novartis (Inst), AVEO (Inst), Boehringer Ingelheim (Inst), Merck (Inst), Stem CentRx (Inst), Karyopharm Therapeutics (Inst), AbbVie (Inst), Medivation (Inst), Endocyte (Inst), Exelixis (Inst), Clovis Oncology (Inst) Travel, Accommodations, Expenses: Sanofi, Immunomedics, Amgen Wei Song Employment: Genentech (I), Cytokinetics (I) Honoraria: Foundation Medicine, Loxo Consulting or Advisory Role: Foundation Medicine, Loxo Juan Miguel Mosquera Research Funding: Personal Genome Diagnostics Travel, Accommodations, Expenses: Personal Genome Diagnostics Mark A. Rubin Honoraria: F Hoffmann-La Roche, Novartis, Astellas Pharma Research Funding: Eli Lilly, Janssen Oncology, Millennium Pharmaceuticals, Sanofi Patents, Royalties, Other Intellectual Property: US Patent (7,767,393 and 7,229,774), Expression Profile of Prostate Cancer, 2007; US Patent (7,332,290), Detection of AMACR Cancer Markers in Urine, 2008; US Patent (7,718,369), Recurrent Gene Fusions in Prostate Cancer, 2010; US Patent (7,803,552 and 7,666,595), Biomarkers for Predicting Prostate Cancer Progression, 2010; US Patent (7,981,609 B2), Methods for Identifying and Using SNP Panels, 2011; US Patent (8,106,037 B2), Identification and Treatment of Estrogen Responsive PCa, 2012; US Patent (9,090,899 B2), Methods of Diagnosing and Treating Prostate Cancer Characterized by NDRG1-ERG Fusion, 2015; US Patent (9,458,213 B2), Compositions and Methods for Diagnosing Prostate Cancer Based on Detection of SLC45A3-ELK4 Fusion Transcript, 2016; US Patent (9,568,483 B2), Molecular Subtyping, Prognosis and Treatment of Prostate Cancer, 2017; US Patent (9,678,077 B2), ERG/TFF3/HMWCK Triple Immunostain for Detection of Prostate Cancer, 2017; US Patent (61,408,341), Exploration of Novel Gene Fusion in Prostate Cancer by RNA-Seq Travel, Accommodations, Expenses: F Hoffmann-La Roche, Novartis, Astellas Pharma Olivier Elemento Stock and Other Ownership Interests: Volastra, Owkin, One Three Biotech Himisha Beltran Consulting or Advisory Role: Janssen Oncology, Genzyme, GlaxoSmithKline, AbbVie, Astellas Pharma, AstraZeneca Research Funding: Janssen Oncology (Inst), AbbVie (Inst), Stemcentrx (Inst), Eli Lilly (Inst) Travel, Accommodations, Expenses: Janssen Oncology No other potential conflicts of interest were reported.

The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysophosphatidylinositol acyltransferase (LPIAT1). Subjects presented with ID frequently accompanied by epilepsy and autistic features. LPIAT1 is a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid (AA) to lysophosphatidylinositol to produce AA-containing phosphatidylinositol. This study suggests a role for AA-containing phosphatidylinositols in the development of ID accompanied by epilepsy and autistic features., (Copyright © 2016. Published by Elsevier Inc.)