Neuroendocrine prostate cancer (NEPC) can arise de novo, but much more commonly occurs as a consequence of a selective pressure from androgen deprivation therapy or androgen receptor antagonists used for prostate cancer (PCa) treatment. The process is known as neuroendocrine transdifferentiation. There is little molecular characterization of NEPCs and consequently there is no standard treatment for this kind of tumors, characterized by highly metastases rates and poor survival. For this purpose, we profiled 54 PCa samples with more than 10-years follow-up for gene and miRNA expression. We divided samples into two groups (NE-like vs. AdenoPCa), according to their clinical and molecular features. NE-like tumors were characterized by a neuroendocrine fingerprint made of known neuroendocrine markers and novel molecules, including long non-coding RNAs and components of the estrogen receptor signaling. A gene expression signature able to predict NEPC was built and tested on independently published datasets. This study identified molecular features (protein-coding, long non-coding, and microRNAs), at the time of surgery, that may anticipate the NE transformation process of prostate adenocarcinoma. Our results may contribute to improving the diagnosis and treatment of this subgroup of tumors for which traditional therapy regimens do not show beneficial effects.

Background: Triple-negative breast cancer (TNBC) is a very heterogeneous disease. Several gene expression and mutation profiling approaches were used to classify it, and all converged to the identification of distinct molecular subtypes, with some overlapping across different approaches. However, a standardised tool to routinely classify TNBC in the clinics and guide personalised treatment is lacking. We aimed at defining a specific gene signature for each of the six TNBC subtypes proposed by Lehman et al. in 2011 (basal-like 1 (BL1); basal-like 2 (BL2); mesenchymal (M); immunomodulatory (IM); mesenchymal stem-like (MSL); and luminal androgen receptor (LAR)), to be able to accurately predict them. Methods: Lehman’s TNBCtype subtyping tool was applied to RNA-sequencing data from 482 TNBC (GSE164458), and a minimal subtype-specific gene signature was defined by combining two class comparison techniques with seven attribute selection methods. Several machine learning algorithms for subtype prediction were used, and the best classifier was applied on microarray data from 72 Italian TNBC and on the TNBC subset of the BRCA-TCGA data set. Results: We identified two signatures with the 120 and 81 top up- and downregulated genes that define the six TNBC subtypes, with prediction accuracy ranging from 88.6 to 89.4%, and even improving after removal of the least important genes. Network analysis was used to identify highly interconnected genes within each subgroup. Two druggable matrix metalloproteinases were found in the BL1 and BL2 subsets, and several druggable targets were complementary to androgen receptor or aromatase in the LAR subset. Several secondary drug–target interactions were found among the upregulated genes in the M, IM and MSL subsets. Conclusions: Our study took full advantage of available TNBC data sets to stratify samples and genes into distinct subtypes, according to gene expression profiles. The development of a data mining approach to acquire a large amount of information from several data sets has allowed us to identify a well-determined minimal number of genes that may help in the recognition of TNBC subtypes. These genes, most of which have been previously found to be associated with breast cancer, have the potential to become novel diagnostic markers and/or therapeutic targets for specific TNBC subsets.

Background: In the era of risk-based prostate cancer (PCa) screening, overcoming the limitations of prostate-specific antigen (PSA) testing and stratifying men by individual risk is crucial. Our study aims to integrate anamnestic and lifestyle data with circulating biomarkers to minimize unnecessary second-level investigations (SLIs) for patients with suspected PCa, while improving the detection of clinically significant PCa (ISUP > 1). Methods: We collected plasma samples, recent clinical history, family cancer history, PSA levels, and lifestyle information from 904 men: 421 undergoing PSA testing, 421 with suspected and 62 with confirmed PCa. Univariable logistic regression was applied to identify ananmestic and lifestyle variables mostly associated with PCa. Penalized logistic regression models predictive of PCa or ISUP > 1 PCa were built both using the 814 subjects with complete information for such variables, applying a 10-fold cross validation approach, and dividing the dataset into a training (n = 445: 132 PCa, 313 non-PCa) and a test (n = 369: 147 PCa, 222 non-PCa) set. The concentration of 50 sphingolipids was analysed on the latter set of 369 subjects by mass-spectrometry, and multivariable penalized regression with 10-fold cross-validation was applied to integrate anamnestic, lifestyle, sphingolipid data. ROC-AUCs on the test sets were compared with PSA ROC-AUCs. Results: Age, cardiovascular disease (CVD), number of medications, and sedentariness were significantly associated with PCa detection and their combination with PSA improved its performance (ROC-AUC from 0.85 to 0.89). In the SLI subgroup (n = 437), adding age improved PSA predictive power (ROC-AUC from 0.60 to 0.70), but performance was still poor. Penalized regression with 10-fold cross-validation on the sphingolipid dataset identified hypertension, CVD, PSA, age, and five sphingolipids (HexCer-20, Cer-20, HexCer-24.1, GM3-24.1, DHCer-24) as key variables for accurate PCa classification (average ROC-AUC: 0.92). Cer-20 and CVD were consistently selected by models predicting ISUP > 1 PCa. In the SLI subgroup, PSA, age, CVD, SM-16, HexCer-20, HexCer-24.1, DHS1P, and DHCer-24 were selected in all 10 models (average ROC-AUC: 0.83). Conclusions: Circulating sphingolipids are promising biomarkers that, when combined with PSA, anamnestic, and lifestyle data, may enhance PCa screening precision and reduce the need for invasive, costly examinations.

Background: In the era of risk-based prostate cancer (PCa) screening, overcoming the limitations of prostate-specific antigen (PSA) testing and stratifying men by individual risk is crucial. Our study aims to integrate anamnestic and lifestyle data with circulating biomarkers to minimize unnecessary second-level investigations (SLIs) for patients with suspected PCa, while improving the detection of clinically significant PCa (ISUP>1). Methods: We collected plasma samples, recent clinical history, family cancer history, PSA levels, and lifestyle information from 904 men: 421 undergoing PSA testing, 421 with suspected and 62 with confirmed PCa. Univariable logistic regression was applied to identify ananmestic and lifestyle variables mostly associated with PCa. Penalized logistic regression models predictive of PCa or ISUP>1 PCa were built both using the 814 subjects with complete information for such variables, applying a 10-fold cross validation approach, and dividing the dataset into a training (n=445: 132 PCa, 313 non-PCa) and a test (n=369: 147 PCa, 222 non-PCa) set. The concentration of 50 sphingolipids was analysed on the latter set of 369 subjects by mass-spectrometry, and multivariable penalized regression with 10-fold cross-validation was applied to integrate anamnestic, lifestyle, sphingolipid data. ROC-AUCs on the test sets were compared with PSA ROC-AUCs. Results: Age, cardiovascular disease (CVD), number of medications, and sedentariness were significantly associated with PCa detection and their combination with PSA improved its performance (ROC-AUC from 0.85 to 0.89). In the SLI subgroup (n=437), adding age improved PSA predictive power (ROC-AUC from 0.60 to 0.70), but performance was still poor. Penalized regression with 10-fold cross-validation on the sphingolipid dataset identified hypertension, CVD, PSA, age, and five sphingolipids (HexCer-20, Cer-20, HexCer-24.1, GM3-24.1, DHCer-24) as key variables for accurate PCa classification (average ROC-AUC: 0.92). Cer-20 and CVD were consistently selected by models predicting ISUP>1 PCa. In the SLI subgroup, PSA, age, CVD, SM-16, HexCer-20, HexCer-24.1, DHS1P, and DHCer-24 were selected in all 10 models (average ROC-AUC: 0.83). Conclusions: Circulating sphingolipids are promising biomarkers that, when combined with PSA, anamnestic, and lifestyle data, may enhance PCa screening precision and reduce the need for invasive, costly examinations.