Publications by authors named "Rameen Beroukhim"

To dissect variant-function relationships in the KRAS oncoprotein, we performed deep mutational scanning (DMS) screens for both wild-type and KRAS mutant alleles. We defined the spectrum of oncogenic potential for nearly all possible variants, identifying several novel transforming alleles and elucidating a model to describe the frequency of mutations in human cancer as a function of transforming potential, mutational probability, and tissue-specific mutational signatures. Biochemical and structural analyses of variants identified in a KRAS second-site suppressor DMS screen revealed that attenuation of oncogenic KRAS can be mediated by protein instability and conformational rigidity, resulting in reduced binding affinity to effector proteins, such as RAF and PI3-kinases, or reduced SOS-mediated nucleotide exchange activity.

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Unlabelled: We investigated the effectiveness of navtemadlin (KRT-232) in treating recurrent glioblastoma. A surgical window-of-opportunity trial ( NCT03107780 ) was conducted on 21 patients to determine achievable drug concentrations within tumor tissue and examine mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact.

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  • A study examined how molecular features, clinical metrics, and treatment affect the overall survival of glioma patients amidst recent changes in classification and care standards.
  • The research involved analyzing 4,400 gliomas from various sources, finding that 27.2% had updated molecular classifications that differed from their initial diagnoses; survival rates varied significantly between different patient groups.
  • The study identified key prognostic factors for different glioma types and created survival prediction tools based on age, molecular features, and treatment, aiming to enhance understanding and research on gliomas.
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Reducing disparities is vital for equitable access to precision treatments in cancer. Socioenvironmental factors are a major driver of disparities, but differences in genetic variation likely also contribute. The impact of genetic ancestry on prioritization of cancer targets in drug discovery pipelines has not been systematically explored due to the absence of pre-clinical data at the appropriate scale.

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Purpose: Adverse clinical events cause significant morbidity in patients with GBM (GBM). We examined whether genomic alterations were associated with AE (AE) in patients with GBM.

Experimental Design: We identified adults with histologically confirmed IDH-wild-type GBM with targeted next-generation sequencing (OncoPanel) at Dana Farber Cancer Institute from 2013 to 2019.

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  • Glioblastoma (GBM) is a challenging brain cancer with poor outcomes, and understanding its tumor microenvironment could improve treatment effectiveness.
  • The study adapts stereotactic biopsies to gather multi-omics data from GBM patients, revealing detailed insights into the tumor and immune response.
  • Results indicate that stereotactic needle biopsies can provide high-quality samples for comprehensive analysis, aiding in monitoring treatment responses and furthering research.
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  • Pediatric high-grade gliomas (pHGG) are really tough brain tumors that usually can't be cured and often have mutations in a gene called histone H3.3.
  • These mutations cause problems with how genes work and can make the brain cells unstable.
  • Researchers found that a DNA repair enzyme called PNKP helps the cancer cells survive, which could be a new way to create treatments specifically for these mutated cells.
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Although several recent studies have characterized structural variants (SVs) in germline and cancer genomes, the features of SVs in these different contexts have not been directly compared. We examined similarities and differences between 2 million germline and 115 thousand tumor SVs from a cohort of 963 patients from The Cancer Genome Atlas (TCGA). We found significant differences in features related to their genomic sequences and localization that suggest differences between SV-generating processes and selective pressures.

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Double-strand break (DSB) repair is associated with a 1000-fold increase in mutations compared to normal replication of the same sequences. In budding yeast, repair of an HO endonuclease-induced DSB at the α locus can be repaired by using a homologous, heterochromatic donor harboring a transcriptionally silenced gene, resulting in a (Ura) repair product where is expressed. Repair-associated mutations can be selected by resistance to 5-fluoroorotic acid (FOA).

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Purpose: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design.

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  • Aneuploidies are changes in the number of chromosomes in cancer cells and are very common.
  • Scientists created a tool called BISCUT to find specific areas in the genome that help cancer cells survive or grow faster.
  • The study discovered important genes related to cancer, including one called WRN, and showed that these chromosome changes are influenced by how much they help or hurt the cells.
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Purpose: Anaplastic lymphoma kinase (ALK) aberrations have been identified in pediatric-type infant gliomas, but their occurrence across age groups, functional effects, and treatment response has not been broadly established.

Experimental Design: We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric, and 10 congenital) with in vitro and in vivo validation of aberrations.

Results: ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years).

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Collateral lethality occurs when loss of a gene/protein renders cancer cells dependent on its remaining paralog. Combining genome-scale CRISPR/Cas9 loss-of-function screens with RNA sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase vaccinia-related kinase 1 (VRK1) for their survival in vivo. VRK1 dependency was inversely correlated with expression of its paralog VRK2.

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Motivation: Somatic copy-number alterations (SCNAs) play an important role in cancer development. Systematic noise in sequencing and array data present a significant challenge to the inference of SCNAs for cancer genome analyses. As part of The Cancer Genome Atlas, the Broad Institute Genome Characterization Center developed the Tangent normalization method to generate copy-number profiles using data from single-nucleotide polymorphism (SNP) arrays and whole-exome sequencing (WES) technologies for over 10 000 pairs of tumors and matched normal samples.

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  • The study explores how prostate cancer evolves genetically due to treatments aimed at blocking androgen receptor (AR) signaling, highlighting the need for a deeper understanding of structural changes in the cancer genome.
  • Researchers analyzed 674 prostate cancer samples (531 localized and 143 metastatic) through whole genome and transcriptome sequencing to identify significant genetic alterations and structural variations.
  • They found unique genetic patterns in different stages of the disease, distinguishing 9 subclasses of metastatic castration-resistant prostate cancer (mCRPC) which relate to specific genetic traits and clinical outcomes, offering insights for potential targeted therapies.
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Differential mRNA expression between ancestry groups can be explained by both genetic and environmental factors. We outline a computational workflow to determine the extent to which germline genetic variation explains cancer-specific molecular differences across ancestry groups. Using multi-omics datasets from The Cancer Genome Atlas (TCGA), we enumerate ancestry-informative markers colocalized with cancer-type-specific expression quantitative trait loci (e-QTLs) at ancestry-associated genes.

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Aims: Dysembryoplastic neuroepithelial tumour (DNT) is a glioneuronal tumour that is challenging to diagnose, with a wide spectrum of histological features. Three histopathological patterns have been described: specific DNTs (both the simple form and the complex form) comprising the specific glioneuronal element, and also the non-specific/diffuse form which lacks it, and has unclear phenotype-genotype correlations with numerous differential diagnoses.

Methods: We used targeted methods (immunohistochemistry, fluorescence in situ hybridisation and targeted sequencing) and large-scale genomic methodologies including DNA methylation profiling to perform an integrative analysis to better characterise a large retrospective cohort of 82 DNTs, enriched for tumours that showed progression on imaging.

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