Kaiso (ZBTB33) subcellular partitioning functionally links LC3A/B, the tumor microenvironment, and breast cancer survival.

The use of digital pathology for the histomorphologic profiling of pathological specimens is expanding the precision and specificity of quantitative tissue analysis at an unprecedented scale; thus, enabling the discovery of new and functionally relevant histological features of both predictive and prognostic significance. In this study, we apply quantitative automated image processing and computational methods to profile the subcellular distribution of the multi-functional transcriptional regulator, Kaiso (ZBTB33), in the tumors of a large racially diverse breast cancer cohort from a designated health disparities region in the United States. Multiplex multivariate analysis of the association of Kaiso's subcellular distribution with other breast cancer biomarkers reveals novel functional and predictive linkages between Kaiso and the autophagy-related proteins, LC3A/B, that are associated with features of the tumor immune microenvironment, survival, and race.

Enhancer Architecture and Essential Core Regulatory Circuitry of Chronic Lymphocytic Leukemia.

Enhancer profiling is a powerful approach for discovering cis-regulatory elements that define the core transcriptional regulatory circuits of normal and malignant cells. Gene control through enhancer activity is often dominated by a subset of lineage-specific transcription factors. By integrating measures of chromatin accessibility and enrichment for H3K27 acetylation, we have generated regulatory landscapes of chronic lymphocytic leukemia (CLL) samples and representative cell lines.

The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis.

Master transcription factors interact with DNA to establish cell type identity and to regulate gene expression in mammalian cells. The genome-wide map of these transcription factor binding sites has been termed the cistrome. Here we show that the androgen receptor (AR) cistrome undergoes extensive reprogramming during prostate epithelial transformation in man.

CAUSEL: an epigenome- and genome-editing pipeline for establishing function of noncoding GWAS variants.

The vast majority of disease-associated single-nucleotide polymorphisms (SNPs) mapped by genome-wide association studies (GWASs) are located in the non-protein-coding genome, but establishing the functional and mechanistic roles of these sequence variants has proven challenging. Here we describe a general pipeline in which candidate functional SNPs are first evaluated by fine mapping, epigenomic profiling, and epigenome editing, and then interrogated for causal function by using genome editing to create isogenic cell lines followed by phenotypic characterization. To validate this approach, we analyzed the 6q22.

Influence of genetic variants in type I interferon genes on melanoma survival and therapy.

Melanoma is an immunogenic tumor; however, the efficacy of immune-therapy shows large inter-individual variation with possible influence of background genetic variation. In this study we report the influence of genetic polymorphisms in the type I interferon gene cluster on chromosome 9p22 on melanoma survival. We genotyped 625 melanoma patients recruited in an oncology center in Germany for 44 polymorphisms located on chromosome 9p22 that were informative for 299 polymorphisms and spanned 15 type I interferon genes.

Integrin genes and susceptibility to human melanoma.

Integrins are transmembrane adhesion molecules that mediate cell-cell and cell-extracellular matrix attachment. Integrins regulate cell growth, proliferation, migration and apoptosis and as a consequence, can have a potential role in tumour progression and metastasis. In this study, we investigated 19 non-synonymous variants in the coding region of the human integrin genes representing 3 beta subunits and 13 alpha subunits, for their potential role in melanoma susceptibility and survival.

Germline mutations in TMEM127 confer susceptibility to pheochromocytoma.

Pheochromocytomas, which are catecholamine-secreting tumors of neural crest origin, are frequently hereditary. However, the molecular basis of the majority of these tumors is unknown. We identified the transmembrane-encoding gene TMEM127 on chromosome 2q11 as a new pheochromocytoma susceptibility gene.

A germline mutation of the KIF1B beta gene on 1p36 in a family with neural and nonneural tumors.

Recently, the KIF1B beta gene on 1p36, a region commonly deleted in neural crest cancers, was found to be a proapoptotic factor for sympathetic precursors. KIF1B beta mutations were detected in pheochromocytomas and neuroblastomas, two sympathetic lineage tumors, suggesting a role for this gene in cancer. Here, we studied five individuals from a three-generation cancer-prone family with a KIF1B beta germline variant and seven of their tumors, both of neural crest and nonneural origin.