Comprehensive analysis of cancer stemness

Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem cell-like features. Here, we provide new stemness indices for assessing the degree of oncogenic dedifferentiation. We took advantage of an innovative one-class logistic regression machine learning algorithm (OCLR) to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progenies. Using OCLR, we were able to sort TCGA tumor samples by stemness phenotype and identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of tumor microenvironment revealed the correlation of cancer stemness with immune checkpoint expression and infiltrating immune system cells not previously anticipated. We have shown the de-differentiated oncogenic phenotype increased in the metastatic tumor that further justify their more aggressive phenotype. Application of our stemness indices reveals features of intra-tumor heterogeneity in molecular profiles obtained from the single-cell analyses. Finally, the machine learning-based indices allowed for the identification of chemical compounds and novel targets for the cancer therapies aiming at tumor differentiation. Our findings provide new prognostic signatures that enable cancer biologists and oncologists to quantify the impact of tumor stemness on outcome across cancer types and may help to pave the way for progress in treatment strategies for cancer patients

Genomic Classification of Cutaneous Melanoma

We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four sub-types based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multidimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-makingclose3