HGCA2.0: An RNA-Seq Based Webtool for Gene Coexpression Analysis in Homo sapiens

Genes with similar expression patterns in a set of diverse samples may be considered coexpressed. Human Gene Coexpression Analysis 2.0 (HGCA2.0) is a webtool which studies the global coexpression landscape of human genes. The website is based on the hierarchical clustering of 55,431 Homo sapiens genes based on a large-scale coexpression analysis of 3500 GTEx bulk RNA-Seq samples of healthy individuals, which were selected as the best representative samples of each tissue type. HGCA2.0 presents subclades of coexpressed genes to a gene of interest, and performs various built-in gene term enrichment analyses on the coexpressed genes, including gene ontologies, biological pathways, protein families, and diseases, while also being unique in revealing enriched transcription factors driving coexpression. HGCA2.0 has been successful in identifying not only genes with ubiquitous expression patterns, but also tissue-specific genes. Benchmarking showed that HGCA2.0 belongs to the top performing coexpression webtools, as shown by STRING analysis. HGCA2.0 creates working hypotheses for the discovery of gene partners or common biological processes that can be experimentally validated. It offers a simple and intuitive website design and user interface, as well as an API endpoint

Germline EPHB2 Receptor Variants in Familial Colorectal Cancer

Familial clustering of colorectal cancer occurs in 15–20% of cases, however recognized cancer syndromes explain only a small fraction of this disease. Thus, the genetic basis for the majority of hereditary colorectal cancer remains unknown. EPHB2 has recently been implicated as a candidate tumor suppressor gene in colorectal cancer. The aim of this study was to evaluate the contribution of EPHB2 to hereditary colorectal cancer. We screened for germline EPHB2 sequence variants in 116 population-based familial colorectal cancer cases by DNA sequencing. We then estimated the population frequencies and characterized the biological activities of the EPHB2 variants identified. Three novel nonsynonymous missense alterations were detected. Two of these variants (A438T and G787R) result in significant residue changes, while the third leads to a conservative substitution in the carboxy-terminal SAM domain (V945I). The former two variants were found once in the 116 cases, while the V945I variant was present in 2 cases. Genotyping of additional patients with colorectal cancer and control subjects revealed that A438T and G787R represent rare EPHB2 alleles. In vitro functional studies show that the G787R substitution, located in the kinase domain, causes impaired receptor kinase activity and is therefore pathogenic, whereas the A438T variant retains its receptor function and likely represents a neutral polymorphism. Tumor tissue from the G787R variant case manifested loss of heterozygosity, with loss of the wild-type allele, supporting a tumor suppressor role for EPHB2 in rare colorectal cancer cases. Rare germline EPHB2 variants may contribute to a small fraction of hereditary colorectal cancer

Cancer risks associated with germline PALB2 pathogenic variants: An international study of 524 families

PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 3 1022). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers

Regulation of growth hormone receptor gene expression during development

To improve our understanding of the potential function of the human growth hormone receptor (hGHR) during fetal development, the ontogeny of hGHR mRNA expression in human tissues was examined. In addition, portions of the hGHR gene regulatory regions were cloned and characterized.Transcription of the hGHR gene was observed in multiple tissues from as early as the first trimester of human fetal life. Two isoforms of the mRNA coding region were identified, exon 3-retained or -deleted, and it was shown that expression of these two transcripts is individual-, but not tissue-, specific. In tissues from 117 individuals (4 weeks of fetal age to 64 years postnatal), predominant expression of the exon 3-deleted isoform occurred prior to 20 weeks of fetal life, suggesting that exon 3-deleted transcripts may be developmentally regulated. A six-fold increase in hepatic hGHR mRNA was observed postnatally, while the levels in kidney and intestine showed no significant developmental change and those in lung decreased six-fold postnatally.This suggested that multiple gene promoters might be directing tissue-specific developmental changes in hGHR mRNA levels. Since heterogeneity in the 5 ' untranslated regions (5'UTR) of mRNAs can result from differential gene promoter usage, the expression patterns of three of the eight known 5'UTR variants (VI to V8, numbered according to their relative abundance in liver) were then investigated. Expression of V1, V3 and V4 was compared in fetal versus postnatal tissues, including hepatoblastomas and hepatocellular carcinomas. While V3 was detected in all tissues examined, the V1 and V4 variants were only present in normal postnatal liver specimens; they were not expressed in hepatic tumours. It was hypothesized that VI and V4 are derived by alternative splicing of a common gene transcript, while V3 synthesis is regulated by a distant and more widely transcribed gene promoter.To identify DNA sequences regulating synthesis of the V1 and V4 5 'UTR variants, portions of the 5' flanking region of the hGHR gene were cloned. Four of the 5'UTR variant sequences were precisely placed in series (5' V7-V1-V4-V8 3') on a 3.8 kb XbaI-BsaAI genomic fragment. A transcriptional start site was identified upstream of the V1 sequence and found to generate, in postnatal liver, a long 5'UTR exon containing V1, V4 and V8 sequences. Evidence for a second liver-specific transcriptional start site, located upstream of V7, was also obtained. Alternative splicing of these gene products can result in several mRNA species, including the previously isolated V1, V4, V7 and V8 mRNA isoforms. Preliminary characterization of a 4.3 kb HindIII-XbaI genomic clone has revealed that the V3 as well as V2 sequences are located in series (5' V2-V3 3' ) in a distant genomic region, and computer analysis has suggested that there are transcriptional start sites upstream of both the V2 and V3 sequences. To construct a complete and continuous physical map of the hGHR gene, a Bacterial Artificial Chromosome (BAC) recombinant clone, encompassing more than 100 kb human genomic DNA and containing both V1- and V3-variant clusters, was isolated. Future characterization of the BAC clone will produce a complete map of the hGHR gene regulatory regions.In summary, developmental changes in hGHR gene expression most likely reflect the maturation of an endocrine system but may also confer fetal-specific hGHR biological activity

REG3A/REG3B promotes acinar to ductal metaplasia through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway

Using several human and murine models, Zhang et al discover a role for the REG3A/REG3B proteins in acinar to ductal metaplasia (ADM), a precursor of pancreatic ductal adenocarcinoma (PDAC). They find that REG3B induces ADM through RAS-RAF-MEK-ERK signaling and identify EXTL3 as a REG3B receptor, providing new insights into PDAC development