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Background: Gene expression profiling has distinguished sporadic breast tumour classes with genetic and clinical differences. Less is known about the molecular classification of familial breast tumours, which are generally considered to be less heterogeneous. Here, we describe molecular signatures that define BRCA1 subclasses depending on the expression of the gene encoding for oestrogen receptor, ESR1.Methods: For this purpose, we have used the Oncochip v2, a cancer-related cDNA microarray to analyze 14 BRCA1-associated breast tumours.Results: Signatures were found to be molecularly associated with different biological processes and transcriptional regulatory programs. The signature of ESR1-positive tumours was mainly linked to cell proliferation and regulated by ER, whereas the signature of ESR1-negative tumours was mainly linked to the immune response and possibly regulated by transcription factors of the REL/NFkappaB family. These signatures were then verified in an independent series of familial and sporadic breast tumours, which revealed a possible prognostic value for each subclass. Over-expression of immune response genes seems to be a common feature of ER-negative sporadic and familial breast cancer and may be associated with good prognosis. Interestingly, the ESR1-negative tumours were substratified into two groups presenting slight differences in the magnitude of the expression of immune response transcripts and REL/NFkappaB transcription factors, which could be dependent on the type of BRCA1 germline mutation.Conclusion: This study reveals the molecular complexity of BRCA1 breast tumours, which are found to display similarities to sporadic tumours, and suggests possible prognostic implications. [ABSTRACT FROM AUTHOR]

Background: There is no effective therapy for patients with malignant pleural mesothelioma (MPM) who progressed to platinum-based chemotherapy and immunotherapy., Methods: We aimed to investigate the antitumor activity of CDK4/6 inhibitors using in vitro and in vivo preclinical models of MPM., Results: Based on publicly available transcriptomic data of MPM, patients with CDK4 or CDK6 overexpression had shorter overall survival. Treatment with abemaciclib or palbociclib at 100 nM significantly decreased cell proliferation in all cell models evaluated. Both CDK4/6 inhibitors significantly induced G1 cell cycle arrest, thereby increasing cell senescence and increased the expression of interferon signalling pathway and tumour antigen presentation process in culture models of MPM. In vivo preclinical studies showed that palbociclib significantly reduced tumour growth and prolonged overall survival using distinct xenograft models of MPM implanted in athymic mice., Conclusions: Treatment of MPM with CDK4/6 inhibitors decreased cell proliferation, mainly by promoting cell cycle arrest at G1 and by induction of cell senescence. Our preclinical studies provide evidence for evaluating CDK4/6 inhibitors in the clinic for the treatment of MPM., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Genome-wide association studies on colorectal cancer have identified more than 60 susceptibility loci, but for most of them there is no clear knowledge of functionality or the underlying gene responsible for the risk modification. Expression quantitative trail loci (eQTL) may provide functional information for such single nucleotide polymorphisms (SNPs)., Methods: We have performed detailed eQTL analysis specific for colon tissue on a series of 97 colon tumours, their paired adjacent normal mucosa and 47 colon mucosa samples donated by healthy individuals. R package MatrixEQTL was used to search for genome-wide cis-eQTL and trans-eQTL fitting linear models adjusted for age, gender and tissue type to rank transformed expression data., Results: The cis-eQTL analyses has revealed 29,073 SNP-gene associations with permutation-adjusted P-values < 0.01. These correspond to 363 unique genes. The trans-eQTL analysis identified 10,665 significant SNP-gene associations, most of them in the same chromosome, further than 1 Mb of the gene. We provide a web tool to search for specific SNPs or genes. The tool calculates Pearson or Spearman correlation, and allows to select tissue type for analysis. Data and plots can be exported., Conclusions: This resource should be useful to prioritise SNPs for further functional studies and to identify relevant genes behind identified loci.

Background: Somatic copy number aberrations (CNAs) are common acquired changes in cancer cells having an important role in the progression of colon cancer (colorectal cancer, CRC). This study aimed to perform a characterisation of CNA and their impact in gene expression., Methods: Copy number aberrations were inferred from SNP array data in a series of 99 CRC. Copy number aberration events were calculated and used to assess the association between copy number dosage, clinical and molecular characteristics of the tumours, and gene expression changes. All analyses were adjusted for the quantity of stroma in each sample, which was inferred from gene expression data., Results: High heterogeneity among samples was observed; the proportion of altered genome ranged between 0.04 and 26.6%. Recurrent CNA regions with gains were frequent in chromosomes 7p, 8q, 13q, and 20, whereas 8p, 17p, and 18 cumulated losses. A significant positive correlation was observed between the number of somatic mutations and total CNA (Spearman's r=0.42, P=0.006). Approximately 37% of genes located in CNA regions changed their level of expression and the average partial correlation (adjusted for stromal content) with copy number was 0.54 (interquartile range 0.20 to 0.81). Altered genes showed enrichment in pathways relevant for CRC. Tumours classified as CMS2 and CMS4 by the consensus molecular subtyping showed higher frequency of CNA. Losses of one small region in 1p36.33, with gene CDK11B, were associated with poor prognosis. More than 66% of the recurrent CNA were validated in the The Cancer Genome Atlas (TCGA) data when analysed with the same procedure. Furthermore, 79% of the genes with altered expression in our data were validated in the TCGA., Conclusions: Although CNA are frequent events in microsatellite stable CRC, few focal recurrent regions were found. These aberrations have strong effects on gene expression and contribute to deregulate relevant cancer pathways. Owing to the diploid nature of stromal cells, it is important to consider the purity of tumour samples to accurately calculate CNA events in CRC.