Dysregulation of expression of functional genes and pathways plays critical roles in the etiology and progression of hepatocellular carcinoma (HCC). Next generation‐based RNA sequencing (RNA‐seq) offers unparalleled power to comprehensively characterize HCC at the whole transcriptome level. In this study, 17 fresh‐frozen HCC samples with paired non‐neoplastic liver tissue from Caucasian patients undergoing liver resection or transplantation were used for RNA‐seq analysis. Pairwise differential expression analysis of the RNA‐seq data was performed to identify genes, pathways, and functional terms differentially regulated in HCC versus normal tissues. At a false discovery rate (FDR) of 0.10, 13% (n = 4335) of transcripts were up‐regulated and 19% (n = 6454) of transcripts were down‐regulated in HCC versus non‐neoplastic tissue. Eighty‐five Kyoto Encyclopedia of Genes and Genomes pathways were differentially regulated (FDR, <0.10), with almost all pathways (n = 83) being up‐regulated in HCC versus non‐neoplastic tissue. Among the top up‐regulated pathways was oxidative phosphorylation (hsa00190; FDR, 1.12E‐15), which was confirmed by Database for Annotation, Visualization, and Integrated Discovery (DAVID) gene set enrichment analysis. Consistent with potential oxidative stress due to activated oxidative phosphorylation, DNA damage‐related signals (e.g., the up‐regulated hsa03420 nucleotide excision repair [FDR, 1.14E‐04] and hsa03410 base excision repair [FDR, 2.71E‐04] pathways) were observed. Among down‐regulated genes (FDR, <0.10), functional terms related to cellular structures (e.g., cell membrane [FDR, 3.05E‐21] and cell junction [FDR, 2.41E‐07], were highly enriched, suggesting compromised formation of cellular structure in HCC at the transcriptome level. Interestingly, the olfactory transduction (hsa04740; FDR, 1.53E‐07) pathway was observed to be down‐regulated in HCC versus non‐neoplastic tissue, suggesting impaired liver chemosensory functions in HCC. Our findings suggest oxidative phosphorylation and the associated DNA damage may be the major driving pathologic feature in HCC.

Transcriptomic studies have reported numerous differentially expressed genes in colorectal carcinoma (CRC) versus noncancerous tissues. Given the large number of genes identified, it is unclear which ones are the key genes that drive cancer development. To address the issue, we conducted a large-scale study of eight cohorts with thousands of tumor and nontumor samples, analyzed transcriptomic data, and identified the most miniature set of differentially expressed genes (DEGs) that can nearly perfectly describe the overall features of CRC at the genomic level. The analytical framework was built on a recently proven powerful max-linear competing risk factor model. We first analyzed six public transcriptomic datasets and identified four critical DEGs (i.e., CXCL8, PSMC2, APP, and SLC20A1) with nearly perfect (close to 100%) predictive power. The findings were further validated in a newly collected Chinese cohort and another public dataset. Among the four DEGs, PSMC2 and CXCL8 appeared to play a central role, and CXCL8 alone could serve as a biomarker for early-stage CRC. They rise as druggable and vaccinable targets for CRC. This work represents a pioneering effort to identify critical colorectal-specific genes and their interactions that have not been discovered in previous endeavors. Simple Summary: Human knowledge of cancer is still limited. There don’t exist reliable genomic biomarkers for cancer diagnosis, and truly functional and druggable genomic (gene) targets haven’t been reported. One of the main reasons is due to lack of powerful discovery tools to discover the best possible and accurate miniature set of genes to fight against the cancer war. Our research was motivated by such an urgent need, and we hope our findings can fill up gaps in the literature and medical practice. We focus on colorectal cancers in this paper.

Short telomere syndrome (STS) encompasses a broad family of genetically inherited conditions caused by various mutations in telomerase and other telomere maintenance genes, resulting in premature telomere shortening. STS involves a variety of clinical manifestations, including dyskeratosis congenita, premature achromotrichia, bone marrow failure, immunodeficiency, pulmonary fibrosis and liver disease. Liver histopathologic features in STS patients have not been well characterized. We report a 46-year-old male patient who presented for dyspnea. The patient had a complicated medical history significant for immune thrombocytopenic purpura and splenectomy, recurrent respiratory tract infections, pneumonia, primary immunodeficiency, and severe hepatopulmonary syndrome. He and his brother both developed gray hair by their late 20s. He had a long history of intermittently elevated liver enzymes starting at age 33. These clinical manifestations prompted an evaluation for a possible telomere biology disorder, which revealed the telomere length was critically short and fell at or below the first percentile for age, supporting the diagnosis. The liver biopsy showed marked portal inflammation with interface hepatitis, ductular reaction and frequent foci of lobular inflammation with focal hepatocyte dropout. Hepatocytes around the portal tracts demonstrated ballooning degeneration and occasional Mallory-Denk bodies. A trichrome stain highlighted bridging fibrosis. A literature review shows liver histology is available in only a small number of STS patients, demonstrating a variety of morphologic features. Our case and others suggest liver disease associated with STS exhibits a spectrum of histopathology. Being aware of these features is important for establishing the correct diagnosis of STS which is under recognized.

Hepatocellular adenoma (HCA) is a benign liver neoplasm that typically arises in the noncirrhotic liver. Based on molecular findings, HCA can be subclassified into the following subtypes: hepatocyte nuclear factor 1α–inactivated HCA, inflammatory HCA, β-catenin–activated HCA, sonic hedgehog-activated HCA, and unclassified HCA. Mixed β-catenin–activated inflammatory HCA may rarely occur. We report a case of HCA that was initially diagnosed as inflammatory HCA on a biopsy but finally was confirmed to be β-catenin–activated inflammatory HCA on the resection specimen. Most recent updates on molecular classification, key histologic features of each subtype, and common diagnostic pitfalls are discussed.