title: Single cell genomics reveals activation signatures of endogenous SCAR's networks in aneuploid human embryos and clinically intractable malignant tumors.
abstract: Somatic mutations and chromosome instability are hallmarks of genomic aberrations in cancer cells. Aneuploidies represent common manifestations of chromosome instability, which is frequently observed in human embryos and malignant solid tumors. Activation of human endogenous retroviruses (HERV)-derived loci is documented in preimplantation human embryos, hESC, and multiple types of human malignancies. It remains unknown whether the HERV activation may highlight a common molecular pathway contributing to the frequent occurrence of chromosome instability in the early stages of human embryonic development and the emergence of genomic aberrations in cancer. Single cell RNA sequencing analysis of human preimplantation embryos reveals activation of specific LTR7/HERVH loci during the transition from the oocytes to zygotes and identifies HERVH network signatures associated with the aneuploidy in human embryos. The correlation patterns' analysis links transcriptome signatures of the HERVH network activation of the in vivo matured human oocytes with gene expression profiles of clinical samples of prostate tumors supporting the existence of a cancer progression pathway from putative precursor lesions (prostatic intraepithelial neoplasia) to localized and metastatic prostate cancers. Tracking signatures of HERVH networks' activation in tumor samples from cancer patients with known long-term therapy outcomes enabled patients' stratification into sub-groups with markedly distinct likelihoods of therapy failure and death from cancer. Genome-wide analyses of human-specific genetic elements of stem cell-associated retroviruses (SCARs)-regulated networks in 12,093 clinical tumor samples across 29 cancer types revealed pan-cancer genomic signatures of clinically-lethal therapy resistant disease defined by the presence of somatic non-silent mutations (SNMs), gene-level copy number changes, and transcripts and proteins' expression of SCARs-regulated host genes. More than 73% of all cancer deaths occurred in patients whose tumors harbor the SNMs' signatures. Linear regression analysis of the cancer intractability in the United States population demonstrated that organ-specific cancer death rates are directly correlated with the percentages of patients whose tumors harbor the SNMs' signatures. Present analyses suggest that awakening of SCARs-regulated stemness networks in differentiated cells is associated with development of diverse spectrum of genomic aberrations in multiple types of clinically lethal malignant tumors contributing to emergence of therapy-resistant cancer phenotypes.
authors: Institute of Engineering in Medicine, University of California, San Diego, 9500 Gilman Dr. MC 0435, La Jolla, CA 92093-0435, USA. Electronic address: gglinskii@ucsd.edu.
authors: Gennadi V
authors: GV
authors: Glinsky
mesh_terms: D001755:Blastocyst / Q000821:virology*; D002472:Cell Transformation, Viral / Q000235:genetics*; D043171:Chromosomal Instability; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D053595:Embryonic Stem Cells / Q000821:virology*; D020077:Endogenous Retroviruses / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods*; D054884:Host-Pathogen Interactions; D006801:Humans; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D008297:Male; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy / Q000821:virology*; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000821:virology*; D010641:Phenotype; D011379:Prognosis; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics / Q000821:virology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000821:virology; D012307:Risk Factors; D020079:Terminal Repeat Sequences; D014775:Virus Activation / Q000235:genetics*
keywords: Cancer stem cells; Human embryos; Human endogenous stem cell-associated retroviruses (SCARs); Human-specific regulatory sequences; LTR7/HERVH; Therapy-resistant cancers