High tumor amplification burden is associated with mutations in the pan-cancer setting.

Next-generation sequencing data is fundamentally changing the clinical management of patients with cancer. The most frequent genomic alterations in malignancy are mutations and amplifications, with a subset of tumors having multiple amplifications - "amplificators". We sought to understand the molecular correlates of high tumor amplification burden in a pan-cancer context.

Variable Mutation Expression in Human Cancers: A "Hide-and-Seek" Mechanism Linked to Differential MHC-I Presentation Dynamics.

Not all genomic mutations are expressed at the transcript/protein level, which may explain variation in cancer development, prognosis, and treatment response/resistance. In this study, our aim was to describe the prevalence of somatic mutation loss of expression ('variant silencing') in a large collection of human samples, and the potential impact of such variant silencing on tumor immunogenicity. Whole-exome mutation description and tumor-normal paired mRNA expression data originating from 636 unique patients diagnosed with 21 distinct tumor types (all solid tumors) were retrieved from The Cancer Genome Atlas (TCGA).

Therapeutic implications of cancer gene amplifications without mRNA overexpression: silence may not be golden.

Amplifications of oncogenic genes are often considered actionable. However, not all patients respond. Questions have therefore arisen regarding the degree to which amplifications, especially non-focal ones, mediate overexpression.

BRAF hot spot mutation in thyroid carcinomas: first Moroccan experience from a single-institution retrospective study.

Background: The incidence of thyroid cancer is increasing worldwide at an alarming rate. BRAF mutation is described to be associated with a worse prognostic of thyroid carcinomas, as well as extrathyroidal invasion and increased mortality.

Objective: To our knowledge, there are no reported studies neither from Morocco nor from other Maghreb countries regarding the prevalence of BRAF mutation in thyroid carcinomas.

High prevalence of clonal hematopoiesis-type genomic abnormalities in cell-free DNA in invasive gliomas after treatment.

Plasma cell-free DNA (cfDNA) is emerging as an important diagnostic tool in cancer. However, cfDNA alterations may differ from those in tissue and sometimes may reflect processes unrelated to the cancer, including clonal hematopoiesis (CH). We examined plasma cfDNA, tested by next-generation sequencing (NGS), for characterized alterations (excluding variants of unknown significance) in 135 patients with invasive glioma.

Real-world data from a molecular tumor board demonstrates improved outcomes with a precision N-of-One strategy.

Next-generation sequencing (NGS) can identify novel cancer targets. However, interpreting the molecular findings and accessing drugs/clinical trials is challenging. Furthermore, many tumors show resistance to monotherapies.

Machine learning model to predict oncologic outcomes for drugs in randomized clinical trials.

Predicting oncologic outcome is challenging due to the diversity of cancer histologies and the complex network of underlying biological factors. In this study, we determine whether machine learning (ML) can extract meaningful associations between oncologic outcome and clinical trial, drug-related biomarker and molecular profile information. We analyzed therapeutic clinical trials corresponding to 1102 oncologic outcomes from 104 758 cancer patients with advanced colorectal adenocarcinoma, pancreatic adenocarcinoma, melanoma and nonsmall-cell lung cancer.

Angiosarcoma heterogeneity and potential therapeutic vulnerability to immune checkpoint blockade: insights from genomic sequencing.

Background: Angiosarcoma is an aggressive tumor. Recent case series describe exceptional responses to checkpoint blockade in this disease.

Methods: Herein, we explored the genomic correlates of 48 angiosarcomas from the Angiosarcoma Project (12,499 variants analyzed in 6603 genes; whole-exome sequencing) versus 10,106 pan-cancer tumors in The Cancer Genome Atlas including 235 sarcomas but no angiosarcoma.

Role of ultraviolet mutational signature versus tumor mutation burden in predicting response to immunotherapy.

Hydrophobic neoantigens are more immunogenic because they are better presented by the major histocompatibility complex and better recognized by T cells. Tumor cells can evade the immune response by expressing checkpoints such as programmed death ligand 1. Checkpoint blockade reactivates immune recognition and can be effective in diseases such as melanoma, which harbors a high tumor mutational burden (TMB).

New therapeutic approaches to overcoming resistant EGFR exon 20 alterations.

EGFR exon 20 alterations are rare events seen mainly in non-small cell lung cancer (NSCLC). They include EGFR T790 and C797S mutations (associated with secondary resistance to classic EGFR tyrosine kinase inhibitors (TKIs)), and EGFR exon 20 in-frame insertions (associated with resistance to first- and second-generation EGFR TKIs). In silico modeling of structural changes in aberrant proteins has informed selection of compounds with potential clinical activity: poziotinib (whose smaller size permits access to the restricted kinase pocket created by EGFR and ERBB2 exon 20 insertions); cetuximab (an antibody that attenuates dimerization caused by EGFR exon 20 insertions), and TAK-788 (another EGFR/ERBB2 TKI).

The Crossroads of Precision Medicine and Therapeutic Decision-Making: Use of an Analytical Computational Platform to Predict Response to Cancer Treatments.

Metastatic cancer is a medical challenge that has been historically resistant to treatments. One area of leverage in cancer care is the development of molecularly-driven combination therapies, offering the possibility to overcome resistance. The selection of optimized treatments based on the complex molecular features of a patient's tumor may be rendered easier by using a computer-assisted program.

Mutated is a marker of increased expression: analysis of 7,525 pan-cancer tissues.

Anti-angiogenic therapies are an important class of anti-cancer treatment drugs. However, their efficacy is limited to certain tumors and would benefit from identifying a biomarker predictive of therapeutic response. (tumor protein p53) is a tumor suppressor gene frequently mutated in cancer and implicated in cell-cycle regulation, apoptosis, and angiogenesis.

APOBEC-related mutagenesis and neo-peptide hydrophobicity: implications for response to immunotherapy.

Tumor-associated neo-antigens are mutated peptides that allow the immune system to recognize the affected cell as foreign. Cells carrying excessive mutation load often develop mechanisms of tolerance. PD-L1/PD-1 checkpoint immunotherapy is a highly promising approach to overcome these protective signals and induce tumor shrinkage.

Analysis of Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics.

Purpose: Fusions that involve neurotrophic-tropomyosin receptor kinase () genes are known drivers of oncogenesis. Therapies that target these ultra-rare, constitutionally active fusions have been remarkably effective. Herein, we analyze the prevalence of the full array of alterations-fusions, mutations, copy number alterations, and increased transcript expression-in diverse adult and pediatric tumor types to understand the landscape of aberrations in cancer.

Prevalence of PDL1 Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors.

Importance: Copy number alterations in programmed cell death ligand 1 (PDL1 or CD274), programmed cell death 1 ligand 2 (PDCD1LG2 or PDL2), and Janus kinase 2 (JAK2) genes (chromosome 9p24.1) characterize Hodgkin lymphoma, resulting in high response rates to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade. The prevalence and utility of PDL1 amplification as a response biomarker to PD-1/PD-L1 blockade are unknown in other tumors.

Elucidation of Drug Combination Synergy in Treatment of Pancreatic Ductal Adenocarcinoma.

Background/aim: Advances in therapies targeting proteins and pathways affected by genetic alterations has raised the possibility of personalized cancer treatments.

Materials And Methods: The efficacy of targeting molecular aberrations was determined in the pancreatic ductal adenocarcinoma (PDAC) cell line, CAPAN2. Two mutations were targeted, KRAS (p.

Genomic landscape of advanced basal cell carcinoma: Implications for precision treatment with targeted and immune therapies.

Metastatic basal cell cancer (BCC) is an ultra-rare malignancy with no approved therapies beyond Hedgehog inhibitors. We characterized the genomics, tumor mutational burden (TMB), and anti-PD-1 therapy responses in patients with locally advanced or metastatic BCC. Overall, 2,039 diverse cancer samples that had undergone comprehensive genomic profiling (CGP) were reviewed.

BRAF mutation as a novel driver of eosinophilic cystitis.

Eosinophilic cystitis is a rare manifestation of hypereosinophilia and a cause of morbidity, including dysuria and hematuria. Although some cases can be attributed to infection or allergy, most cases are assessed to be idiopathic and treated with corticosteroids. However, hypereosinophilia can also be due to actionable clonal molecular alterations in the haematopoietic cells, similar to other myeloproliferative neoplasms.

High expression of PD-1 ligands is associated with mutational signature and APOBEC3 alterations.

Immunotherapy with checkpoint inhibitors, such as antibodies blocking the programmed cell-death receptor-1 (PD-1), has resulted in remarkable responses in patients having traditionally refractory cancers. Although response to PD-1 inhibitors correlates with PD-1 ligand (PD-L1 or PD-L2) expression, PD-1 ligand positivity represents only a part of the predictive model necessary for selecting patients predisposed to respond to immunotherapy. We used all genomic, transcriptomic, proteomic and phenotypic data related to 8,475 pan-cancer samples available in The Cancer Genome Atlas (TCGA) and conducted a logistic regression analysis based on a large set of variables, such as microsatellite instability (MSI-H), mismatch repair (MMR) alterations, polymerase δ () and polymerase ε () mutations, activation-induced/apolipoprotein-B editing cytidine deaminases (AID/APOBEC) alterations, lymphocyte markers and mutation burden estimates to determine independent factors that associate with PD-1 ligand overexpression.

Concordance between HER-2 status determined by qPCR in Fine Needle Aspiration Cytology (FNAC) samples compared with IHC and FISH in Core Needle Biopsy (CNB) or surgical specimens in breast cancer patients.

Determining the status of HER2-neu amplification and overexpression in breast cancer is crucial for prognosis but mostly for treatment purposes. Standard techniques include the determination of IHC in combination with in situ hybridization techniques to confirm a HER2-neu amplification in case of IHC2+ using either a core-needle biopsy or a surgical specimen. qPCR has been also demonstrated to be able to determine HER2 status, mostly in core biopsies or in surgical specimens.

RET mutation and increased angiogenesis in medullary thyroid carcinomas.

Advanced medullary thyroid cancers (MTCs) are now being treated with drugs that inhibit receptor tyrosine kinases, many of which involved in angiogenesis. Response rates vary widely, and toxic effects are common, so treatment should be reserved for MTCs likely to be responsive to these drugs. RET mutations are common in MTCs, but it is unclear how they influence the microvascularization of these tumors.

Circulating Cell-Free Tumor DNA Analysis of 50 Genes by Next-Generation Sequencing in the Prospective MOSCATO Trial.

Purpose: Liquid biopsies based on circulating cell-free DNA (cfDNA) analysis are described as surrogate samples for molecular analysis. We evaluated the concordance between tumor DNA (tDNA) and cfDNA analysis on a large cohort of patients with advanced or metastatic solid tumor, eligible for phase I trial and with good performance status, enrolled in MOSCATO 01 trial (clinical trial NCT01566019).

Experimental Design: Blood samples were collected at inclusion and cfDNA was extracted from plasma for 334 patients.

Epigenetic-related gene expression profile in medullary thyroid cancer revealed the overexpression of the histone methyltransferases EZH2 and SMYD3 in aggressive tumours.

Epigenetic control of gene expression plays a major influence in the development and progression of many cancer types. Aim of the present study was to investigate the expression of epigenetic regulators in a large cohort of medullary thyroid carcinomas (MTC), correlating the data with the clinical outcome and mutational status of the patients. Taqman Low Density Arrays (TLDAs) were used to analyze expression levels of several genes involved in the epigenetic control of transcription in a series of 54 MTCs.

Genomes in the clinic: the Gustave Roussy Cancer Center experience.

The extensive molecular characterization of tumors with high throughput technologies has led to the segmentation of different tumors into very small molecularly defined subgroups. Many ongoing clinical trials are conducted only when specific molecular alterations are identified in tumor samples. In this review, we will describe the implementation of genome analysis in the clinical setting as it has expanded over the last four years in our Precision Medicine Program.

Overexpression of genes involved in miRNA biogenesis in medullary thyroid carcinomas with RET mutation.

Abnormal expression of non-coding micro RNA (miRNA) has been described in medullary thyroid carcinoma (MTC). Expression of genes encoding factors involved in miRNA biogenesis results often deregulated in human cancer and correlates with aggressive clinical behavior. In this study, expression of four genes involved in miRNA biogenesis (DICER, DROSHA, DCGR8, and XPO5) was investigated in 54 specimens of MTC.