Biology subjects

Dienstmann, R.

Publications and source records attributed to Dienstmann, R..

6 recordsLinked to original sources

bioRxiv2024

Evaluation of homologous recombination repair status in metastatic prostate cancer by next-generation sequencing and functional tissue-based immunofluorescence assays

PurposeMetastatic prostate cancer (mPC) is enriched for homologous recombination repair (HRR) gene alterations; these biomarkers have prognostic and predictive value. Next-generation sequencing (NGS) allows for patient stratification based on these biomarkers, but widespread clinical implementation is still limited. Moreover, not all mutations in HRR genes result in functional HRR loss in the tumor. We investigated the correlation between genomic and functional loss of HRR, using NGS and an optimized RAD51 immunofluorescence (RAD51-IF) assay in mPC clinical biopsies. Experimental designObservational study including patients with stage IV prostate cancer. Biopsies from either primary tumor or metastatic biopsies underwent NGS (targeted sequencing and/or whole-exome sequencing), and RAD51-IF. Clinical data was extracted from electronic patient records. Results219 biopsies from 187 patients were acquired, including primary (151/219) and metastatic (68/219) tumor biopsies collected either in the metastatic hormone- sensitive (169/219) or castration-resistant (50/219) setting. NGS (181 biopsies from 157 patients) showed frequent genomic alterations in TP53 (40%), AR (15%), PTEN (14%), MYC (10%), BRCA2 (9%), ATM (8%) and BRCA1 (2%). Tissue for RAD51 IF was available for 206 samples; of those, 140/206 (68%) were evaluable for RAD51- IF. Based on a previously defined threshold of 10% RAD51-positive cells, 21% samples had RAD51-low results compatible with HRR deficiency (HRD). Sample matched RAD51-IF and genomics data were obtained for 128 biopsies (117 patients): RAD51-IF had a high sensitivity (68%) and specificity (85%) to identify cases with BRCA1/2 alterations. Additionally, the RAD51-IF assay was able to identify restoration of HRR function in selected cases with BRCA2 reversion mutations or BRCA1 expression. ConclusionsRAD51-IF is feasible in routine clinical samples from mPC patients and associates strongly with clinically relevant HRR gene alterations.

cancer biology↗

bioRxiv2020

Maintaining oxidized H3 in heterochromatin is required for the oncogenic capacity of triple-negative breast cancer cells

The histone modification of H3 oxidized at lysine 4 (H3K4ox) is catalyzed by lysyl oxidase-like 2 (LOXL2) and is enriched in heterochromatin in triple-negative breast cancer (TNBC) cells. Although H3K4ox has been linked to the maintenance of compacted chromatin, the molecular mechanism underlying this maintenance is unknown. Here we show that H3K4ox is read by the CRL4B complex, leading to the ubiquitination of histone H2A through the E3 ligase RBX1. Finally, interactions between RUVBL1/2 and LOXL2 are involved in the incorporation of the histone variant H2A.Z, which plays an essential role in the mechanism controlling the dynamics of oxidized H3. Maintenance of H3K4ox in chromatin is essential for heterochromatin properties, and disruption of any of the members involved in this pathway blocks the oncogenic properties of TNBC cells.

cancer biology↗

bioRxiv2020

RBMS1 suppresses colon cancer metastasis through targeted stabilization of its mRNA regulon

Broad dysregulation of gene expression control is a hallmark of cancer progression. Identifying the underlying master regulators that drive pathological gene expression is a key challenge in precision oncology. Here, we have developed a network analytical framework, named PRADA, that identifies oncogenic RNA-binding proteins through the systematic detection of coordinated changes in their target regulons. Application of this approach to data collected from clinical samples, patient-derived xenografts, and cell line models of colon cancer metastasis revealed the RNA-binding protein RBMS1 as a suppressor of colon cancer progression. We observed that silencing RBMS1 results in increased metastatic capacity in xenograft mouse models, and that restoring its expression blunts metastatic liver colonization. We have found that RBMS1 functions as a post-transcriptional regulator of RNA stability by directly binding and stabilizing ~80 target mRNAs. Measurements in more than 180 clinical samples as well as survival analyses in publicly available datasets, have shown that RBMS1 silencing and the subsequent downregulation of its targets are strongly associated with disease progression and poor survival in colon cancer patients. Together, our findings establish a role for RBMS1 as a previously unknown regulator of RNA stability and as a suppressor of colon cancer metastasis with clinical utility for risk stratification of patients. SignificanceBy applying a new analytical approach to transcriptomic data from clinical samples and models of colon cancer progression, we have uncovered RBMS1 as a suppressor of metastasis and as a post-transcriptional regulator of RNA stability. Notably, RBMS1 silencing and downregulation of its targets are negatively associated with patient survival.

systems biology↗

bioRxiv2018

A harmonized meta-knowledgebase of clinical interpretations of cancer genomic variants

Precision oncology relies on the accurate discovery and interpretation of genomic variants to enable individualized diagnosis, prognosis, and therapy selection. We found that knowledgebases containing clinical interpretations of somatic cancer variants are highly disparate in interpretation content, structure, and supporting primary literature, impeding consensus when evaluating variants and their relevance in a clinical setting. With the cooperation of experts of the Global Alliance for Genomics and Health (GA4GH) and six prominent cancer variant knowledgebases, we developed a framework for aggregating and harmonizing variant interpretations to produce a meta-knowledgebase of 12,856 aggregate interpretations covering 3,437 unique variants in 415 genes, 357 diseases, and 791 drugs. We demonstrated large gains in overlap between resources across variants, diseases, and drugs as a result of this harmonization. We subsequently demonstrated improved matching between a patient cohort and harmonized interpretations of potential clinical significance, observing an increase from an average of 33% per individual knowledgebase to 56% in aggregate. Our analyses illuminate the need for open, interoperable sharing of variant interpretation data. We also provide an open and freely available web interface (search.cancervariants.org) for exploring the harmonized interpretations from these six knowledgebases.

bioinformatics↗

bioRxiv2017

Cancer Genome Interpreter Annotates The Biological And Clinical Relevance Of Tumor Alterations

While tumor genome sequencing has become widely available in clinical and research settings, the interpretation of tumor somatic variants remains an important bottleneck. Most of the alterations observed in tumors, including those in well-known cancer genes, are of uncertain significance. Moreover, the information on tumor genomic alterations shaping the response to existing therapies is fragmented across the literature and several specialized resources. Here we present the Cancer Genome Interpreter (http://www.cancergenomeinterpreter.org), an open access tool that we have implemented to annotate genomic alterations and interpret their possible role in tumorigenesis and in the response to anti-cancer therapies.

cancer biology↗

bioRxiv2016

Genomic determinants of protein abundance variation in colorectal cancer cells

Assessing the extent to which genomic alterations compromise the integrity of the proteome is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labelling and tribrid mass spectrometry to characterize the proteomic landscapes of 50 colorectal cancer cell lines and to decipher the relationships between genomic and proteomic variation. The robust quantification of 12,000 proteins and 27,000 phosphopeptides revealed how protein symbiosis translates to a co-variome which is subjected to a hierarchical order and exposes the collateral effects of somatic mutations on protein complexes. Targeted depletion of key chromatin modifiers confirmed the transmission of variation and the directionality as characteristics of protein interactions. Protein level variation was leveraged to build drug response predictive models towards a better understanding of pharmacoproteomic interactions in colorectal cancer. Overall, we provide a deep integrative view of the molecular structure underlying the variation of colorectal cancer cells.\n\nHighlightsO_LIThe cancer cell functional \"co-variome\" is a strong attribute of the proteome.\nC_LIO_LIMutations can have a direct impact on protein levels of chromatin modifiers.\nC_LIO_LITransmission of genomic variation is a characteristic of protein interactions.\nC_LIO_LIPharmacoproteomic models are strong predictors of response to DNA damaging agents.\nC_LI\n\nAbbreviations

systems biology↗