Initial Characterization of Canine T-cell Receptor Repertoires Using RNA-seq Data from Different Diseases and Tissues.

The dog serves as a key translational model in cancer immunotherapy. Understanding the T cell receptor (TCR) repertoire is needed for various cancer immunotherapies. Compared to humans where >300 million TCRs have been identified, <100 canine TCRs are reported.

Human basal-like breast cancer is represented by one of the two mammary tumor subtypes in dogs.

Background: About 20% of breast cancers in humans are basal-like, a subtype that is often triple-negative and difficult to treat. An effective translational model for basal-like breast cancer is currently lacking and urgently needed. To determine whether spontaneous mammary tumors in pet dogs could meet this need, we subtyped canine mammary tumors and evaluated the dog-human molecular homology at the subtype level.

Leading the pack: Best practices in comparative canine cancer genomics to inform human oncology.

Pet dogs develop spontaneous cancers at a rate estimated to be five times higher than that of humans, providing a unique opportunity to study disease biology and evaluate novel therapeutic strategies in a model system that possesses an intact immune system and mirrors key aspects of human cancer biology. Despite decades of interest, effective utilization of pet dog cancers has been hindered by a limited repertoire of necessary cellular and molecular reagents for both in vitro and in vivo studies, as well as a dearth of information regarding the genomic landscape of these cancers. Recently, many of these critical gaps have been addressed through the generation of a highly annotated canine reference genome, the creation of several tools necessary for multi-omic analysis of canine tumours, and the development of a centralized repository for key genomic and associated clinical information from canine cancer patients, the Integrated Canine Data Commons.

Shared hotspot mutations in oncogenes position dogs as an unparalleled comparative model for precision therapeutics.

Naturally occurring canine cancers have remarkable similarities to their human counterparts. To better understand these similarities, we investigated 671 client-owned dogs from 96 breeds with 23 common tumor types, including those whose mutation profile are unknown (anal sac carcinoma and neuroendocrine carcinoma) or understudied (thyroid carcinoma, soft tissue sarcoma and hepatocellular carcinoma). We discovered mutations in 50 well-established oncogenes and tumor suppressors, and compared them to those reported in human cancers.

Human basal-like breast cancer is represented by one of the two mammary tumor subtypes in dogs.

Background: About 20% of breast cancers in humans are basal-like, a subtype that is often triple negative and difficult to treat. An effective translational model for basal-like breast cancer (BLBC) is currently lacking and urgently needed. To determine if spontaneous mammary tumors in pet dogs could meet this need, we subtyped canine mammary tumors and evaluated the dog-human molecular homology at the subtype level.

A Kmer-based paired-end read assembler and genotyper for canine MHC class I genotyping.

The major histocompatibility complex class I (MHC-I) genes are highly polymorphic. MHC-I genotyping is required for determining the peptide epitopes available to an individual's T-cell repertoire. Current genotyping software tools do not work for the dog, due to very limited known canine alleles.

Canine tumor mutational burden is correlated with TP53 mutation across tumor types and breeds.

Spontaneous canine cancers are valuable but relatively understudied and underutilized models. To enhance their usage, we reanalyze whole exome and genome sequencing data published for 684 cases of >7 common tumor types and >35 breeds, with rigorous quality control and breed validation. Our results indicate that canine tumor alteration landscape is tumor type-dependent, but likely breed-independent.

A Qualitative Change in the Transcriptome Occurs after the First Cell Cycle and Coincides with Lumen Establishment during MDCKII Cystogenesis.

Madin-Darby canine kidney II (MDCKII) cells are widely used to study epithelial morphogenesis. To better understand this process, we performed time course RNA-seq analysis of MDCKII 3D cystogenesis, along with polarized 2D cells for comparison. Our study reveals a biphasic change in the transcriptome that occurs after the first cell cycle and coincides with lumen establishment.

Proteins with Evolutionarily Hypervariable Domains are Associated with Immune Response and Better Survival of Basal-like Breast Cancer Patients.

Maltase-glucoamylase (MGAM) and MGAM2 both belong to the glycoside hydrolase family 31. MGAM, a therapeutic target for type 2 diabetes, is α-1,4-glucosidase and expressed in the intestine to catalyze starch digestion. MGAM2, however, is largely uncharacterized.

SEG - A Software Program for Finding Somatic Copy Number Alterations in Whole Genome Sequencing Data of Cancer.

As next-generation sequencing technology advances and the cost decreases, whole genome sequencing (WGS) has become the preferred platform for the identification of somatic copy number alteration (CNA) events in cancer genomes. To more effectively decipher these massive sequencing data, we developed a software program named SEG, shortened from the word "segment". SEG utilizes mapped read or fragment density for CNA discovery.

Proliferative and Invasive Colorectal Tumors in Pet Dogs Provide Unique Insights into Human Colorectal Cancer.

Spontaneous tumors in pet dogs represent a valuable but undercharacterized cancer model. To better use this resource, we performed an initial global comparison between proliferative and invasive colorectal tumors from 20 canine cases, and evaluated their molecular homology to human colorectal cancer (CRC). First, proliferative canine tumors harbor overactivated WNT/β-catenin pathways and recurrent CTNNB1 (β-catenin) mutations S45F/P, D32Y and G34E.

Collaborating genomic, transcriptomic and microbiomic alterations lead to canine extreme intestinal polyposis.

Extreme intestinal polyposis in pet dogs has not yet been reported in literature. We identified a dog patient who developed numerous intestinal polyps, with the severity resembling human classic familial adenomatous polyposis (FAP), except the jejunum-ileum junction being the most polyp-dense. We investigated this dog, in comparison with 22 other dogs with spontaneous intestinal tumors but no severe polyposis, and with numerous published human cancers.

Pharmacologically targeting the myristoylation of the scaffold protein FRS2α inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression.

Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling facilitates tumor initiation and progression. Although currently approved inhibitors of FGFR kinase have shown therapeutic benefit in clinical trials, overexpression or mutations of FGFRs eventually confer drug resistance and thereby abrogate the desired activity of kinase inhibitors in many cancer types. In this study, we report that loss of myristoylation of fibroblast growth factor receptor substrate 2 (FRS2α), a scaffold protein essential for FGFR signaling, inhibits FGF/FGFR-mediated oncogenic signaling and FGF10-induced tumorigenesis.

Nucleosome positioning changes during human embryonic stem cell differentiation.

Nucleosomes are the basic unit of chromatin. Nucleosome positioning (NP) plays a key role in transcriptional regulation and other biological processes. To better understand NP we used MNase-seq to investigate changes that occur as human embryonic stem cells (hESCs) transition to nascent mesoderm and then to smooth muscle cells (SMCs).

Cell-Cycle Control of Bivalent Epigenetic Domains Regulates the Exit from Pluripotency.

Here we show that bivalent domains and chromosome architecture for bivalent genes are dynamically regulated during the cell cycle in human pluripotent cells. Central to this is the transient increase in H3K4-trimethylation at developmental genes during G1, thereby creating a "window of opportunity" for cell-fate specification. This mechanism is controlled by CDK2-dependent phosphorylation of the MLL2 (KMT2B) histone methyl-transferase, which facilitates its recruitment to developmental genes in G1.

Canine spontaneous head and neck squamous cell carcinomas represent their human counterparts at the molecular level.

Spontaneous canine head and neck squamous cell carcinoma (HNSCC) represents an excellent model of human HNSCC but is greatly understudied. To better understand and utilize this valuable resource, we performed a pilot study that represents its first genome-wide characterization by investigating 12 canine HNSCC cases, of which 9 are oral, via high density array comparative genomic hybridization and RNA-seq. The analyses reveal that these canine cancers recapitulate many molecular features of human HNSCC.

Cancer driver candidate genes AVL9, DENND5A and NUPL1 contribute to MDCK cystogenesis.

AVL9, DENND5A and NUPL1 are among the cancer driver candidate genes previously identified via dog-human comparison, and may function in epithelial cell polarity as indicated by bioinformatics analysis. To better understand their cellular functions and roles in cancer, we knocked down each gene in MDCKII cells through shRNA and performed three-dimensional culture. Compared to the control, the knockdown clones developed significantly more abnormal cysts, e.

Comprehensive characterization of the genomic alterations in human gastric cancer.

Gastric cancer is one of the most prevalent and aggressive cancers worldwide, and its molecular mechanism remains largely elusive. Here we report the genomic landscape in primary gastric adenocarcinoma of human, based on the complete genome sequences of five pairs of cancer and matching normal samples. In total, 103,464 somatic point mutations, including 407 nonsynonymous ones, were identified and the most recurrent mutations were harbored by Mucins (MUC3A and MUC12) and transcription factors (ZNF717, ZNF595 and TP53).

Molecular homology and difference between spontaneous canine mammary cancer and human breast cancer.

Spontaneously occurring canine mammary cancer represents an excellent model of human breast cancer, but is greatly understudied. To better use this valuable resource, we performed whole-genome sequencing, whole-exome sequencing, RNA-seq, and/or high-density arrays on twelve canine mammary cancer cases, including seven simple carcinomas and four complex carcinomas. Canine simple carcinomas, which histologically match human breast carcinomas, harbor extensive genomic aberrations, many of which faithfully recapitulate key features of human breast cancer.

Cell-cycle control of developmentally regulated transcription factors accounts for heterogeneity in human pluripotent cells.

Heterogeneity within pluripotent stem cell (PSC) populations is indicative of dynamic changes that occur when cells drift between different states. Although the role of metastability in PSCs is unclear, it appears to reflect heterogeneity in cell signaling. Using the Fucci cell-cycle indicator system, we show that elevated expression of developmental regulators in G1 is a major determinant of heterogeneity in human embryonic stem cells.

Frequent alteration of the tumor suppressor gene APC in sporadic canine colorectal tumors.

Sporadic canine colorectal cancers (CRCs) should make excellent models for studying the corresponding human cancers. To molecularly characterize canine CRC, we investigated exonic sequence mutations of adenomatous polyposis coli (APC), the best known tumor suppressor gene of human CRC, in 23 sporadic canine colorectal tumors, including 8 adenomas and 15 adenocarcinomas, via exon-resequencing analysis. As a comparison, we also performed the same sequencing analysis on 10 other genes, either located at human 5q22 (the same locus as APC) or 18q21 (also frequently altered in human CRC), or known to play a role in human carcinogenesis.

Transcriptional regulation of the protocadherin β cluster during Her-2 protein-induced mammary tumorigenesis results from altered N-glycan branching.

Changes in the levels of N-acetylglucosaminyltransferase V (GnT-V) can alter the function of several types of cell surface receptors and adhesion molecules by causing altered N-linked glycan branching. Using a her-2 mammary tumor mouse model, her-2 receptor signaling was down-regulated by GnT-V knock-out, resulting in a significant delay in the onset of her-2-induced mammary tumors. To identify the genes that contributed to this GnT-V regulation of early events in tumorigenesis, microarray analysis was performed using her-2 induced mammary tumors from wild-type and GnT-V-null mice.

Distinguishing between cancer driver and passenger gene alteration candidates via cross-species comparison: a pilot study.

Background: We are developing a cross-species comparison strategy to distinguish between cancer driver- and passenger gene alteration candidates, by utilizing the difference in genomic location of orthologous genes between the human and other mammals. As an initial test of this strategy, we conducted a pilot study with human colorectal cancer (CRC) and its mouse model C57BL/6J ApcMin/+, focusing on human 5q22.2 and 18q21.