Multi-omics profiling of longitudinal samples reveals early genomic changes in follicular lymphoma.

Follicular lymphoma (FL) is the most common indolent type of B-cell non-Hodgkin lymphoma. Advances in treatment have improved overall survival, but early relapse or transformation to aggressive disease is associated with inferior outcome. To identify early genetic events and track tumor clonal evolution, we performed multi-omics analysis of 94 longitudinal biopsies from 44 FL patients; 22 with transformation (tFL) and 22 with relapse without transformation (nFL).

Chromosomal instability and a deregulated cell cycle are intrinsic features of high-risk gastrointestinal stromal tumours with a metastatic potential.

Patients with localised, high-risk gastrointestinal stromal tumours (GIST) benefit from adjuvant imatinib treatment. Still, approximately 40% of patients relapse within 3 years after adjuvant therapy and the clinical and histopathological features currently used for risk classification cannot precisely predict poor outcomes after standard treatment. This study aimed to identify genomic and transcriptomic profiles that could be associated with disease relapse and thus a more aggressive phenotype.

Comprehensive interrogation of gene lists from genome-scale cancer screens with oncoEnrichR.

Genome-scale screening experiments in cancer produce long lists of candidate genes that require extensive interpretation for biological insight and prioritization for follow-up studies. Interrogation of gene lists frequently represents a significant and time-consuming undertaking, in which experimental biologists typically combine results from a variety of bioinformatics resources in an attempt to portray and understand cancer relevance. As a means to simplify and strengthen the support for this endeavor, we have developed oncoEnrichR, a flexible bioinformatics tool that allows cancer researchers to comprehensively interrogate a given gene list along multiple facets of cancer relevance.

screenwerk: a modular tool for the design and analysis of drug combination screens.

Motivation: There is a rapidly growing interest in high-throughput drug combination screening to identify synergizing drug interactions for treatment of various maladies, such as cancer and infectious disease. This creates the need for pipelines that can be used to design such screens, perform quality control on the data and generate data files that can be analyzed by synergy-finding bioinformatics applications.

Results: screenwerk is an open-source, end-to-end modular tool available as an R-package for the design and analysis of drug combination screens.

Mutational analysis and protein profiling predict drug sensitivity in multiple myeloma cell lines.

Introduction: Multiple myeloma (MM) is a heterogeneous disease where cancer-driver mutations and aberrant signaling may lead to disease progression and drug resistance. Drug responses vary greatly, and there is an unmet need for biomarkers that can guide precision cancer medicine in this disease.

Methods: To identify potential predictors of drug sensitivity, we applied integrated data from drug sensitivity screening, mutational analysis and functional signaling pathway profiling in 9 cell line models of MM.

Genetic Characterization in High-Risk Individuals from a Low-Resource City of Peru.

Background: Genetic testing for hereditary cancers is inconsistently applied within the healthcare systems in Latin America. In Peru, the prevalence and spectrum of cancer-predisposing germline variants is thus poorly characterized. Purpose: To determine the spectrum and prevalence of cancer-predisposing germline variants and variants of uncertain significance (VUS) in high-risk individuals located in a Peruvian low-resource setting city.

The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics.

During autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The contributions of specific lipids, such as cholesterol, to the membranes that form the autophagosome, remain to be fully characterized. Here, we demonstrate that short term cholesterol depletion leads to a rapid induction of autophagy and a corresponding increase in autophagy initiation events.

Strategies to inhibit FGFR4 V550L-driven rhabdomyosarcoma.

Background: Rhabdomyosarcoma (RMS) is a paediatric cancer driven either by fusion proteins (e.g., PAX3-FOXO1) or by mutations in key signalling molecules (e.

Clonal evolution in primary breast cancers under sequential epirubicin and docetaxel monotherapy.

Background: Subclonal evolution during primary breast cancer treatment is largely unexplored. We aimed to assess the dynamic changes in subclonal composition of treatment-naïve breast cancers during neoadjuvant chemotherapy.

Methods: We performed whole exome sequencing of tumor biopsies collected before, at therapy switch, and after treatment with sequential epirubicin and docetaxel monotherapy in 51 out of 109 patients with primary breast cancer, who were included in a prospectively registered, neoadjuvant single-arm phase II trial.

Cancer Predisposition Sequencing Reporter (CPSR): A flexible variant report engine for high-throughput germline screening in cancer.

The value of high-throughput germline genetic testing is increasingly recognized in clinical cancer care. Disease-associated germline variants in cancer patients are important for risk management and surveillance, surgical decisions and can also have major implications for treatment strategies since many are in DNA repair genes. With the increasing availability of high-throughput DNA sequencing in cancer clinics and research, there is thus a need to provide clinically oriented sequencing reports for germline variants and their potential therapeutic relevance on a per-patient basis.

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in and : A Prospective Lynch Syndrome Database Study.

Background: Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance.

Combining a Universal Telomerase Based Cancer Vaccine With Ipilimumab in Patients With Metastatic Melanoma - Five-Year Follow Up of a Phase I/IIa Trial.

Background: Ipilimumab improves survival for patients with metastatic malignant melanoma. Combining a therapeutic cancer vaccine with ipilimumab may increase efficacy by providing enhanced anti-tumor immune responses. UV1 consists of three synthetic long peptides from human telomerase reverse transcriptase (hTERT).

The Quandary of DNA-Based Treatment Assessment in De Novo Metastatic Prostate Cancer in the Era of Precision Oncology.

Guidelines for genetic testing have been established for multiple tumor types, frequently indicating the most confident molecularly targeted treatment options. However, considering the often-complex presentation of individual cancer patients, in addition to the combinatorial complexity and inherent uncertainties of molecular findings, deriving optimal treatment strategies frequently becomes very challenging. Here, we report a comprehensive analysis of a 68-year-old male with metastatic prostate cancer, encompassing pathology and MRI findings, transcriptomic results, and key genomics findings from whole-exome sequencing, both somatic aberrations and germline variants.

Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Purpose: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages.

Results: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively.

Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Dysregulation of MITF Leads to Transformation in MC1R-Defective Melanocytes.

The MC1R/cAMP/MITF pathway is a key determinant for growth, differentiation, and survival of melanocytes and melanoma. MITF-M is the melanocyte-specific isoform of Microphthalmia-associated Transcription Factor (MITF) in human melanoma. Here we use two melanocyte cell lines to show that forced expression of hemagglutinin (HA) -tagged MITF-M through lentiviral transduction represents an oncogenic insult leading to consistent cell transformation of the immortalized melanocyte cell line Hermes 4C, being a melanocortin-1 receptor (MC1R) compound heterozygote, while not causing transformation of the MC1R wild type cell line Hermes 3C.

Mutational dynamics and immune evasion in diffuse large B-cell lymphoma explored in a relapse-enriched patient series.

Diagnostic and relapse diffuse large B-cell lymphoma (DLBCL) biopsies reveal increased mutational burden/loss of heterozygosity in . Serially sampled tumor biopsies provide insight into therapeutic targets and evolutionary divergence in relapsed/refractory DLBCL.

Molecularly matched therapy in the context of sensitivity, resistance, and safety; patient outcomes in end-stage cancer - the MetAction study.

In precision cancer medicine, the challenge is to prioritize DNA driver events, account for resistance markers, and procure sufficient information for treatment that maintains patient safety. The MetAction project, exploring how tumor molecular vulnerabilities predict therapy response, first established the required workflow for DNA sequencing and data interpretation (2014-2015). Here, we employed it to identify molecularly matched therapy and recorded outcome in end-stage cancer (2016-2019).

Results of multigene panel testing in familial cancer cases without genetic cause demonstrated by single gene testing.

We have surveyed 191 prospectively sampled familial cancer patients with no previously detected pathogenic variant in the BRCA1/2, PTEN, TP53 or DNA mismatch repair genes. In all, 138 breast cancer (BC) cases, 34 colorectal cancer (CRC) and 19 multiple early-onset cancers were included. A panel of 44 cancer-predisposing genes identified 5% (9/191) pathogenic or likely pathogenic variants and 87 variants of uncertain significance (VUS).

Survival by colon cancer stage and screening interval in Lynch syndrome: a prospective Lynch syndrome database report.

Background: We previously reported that in pathogenic mismatch repair () variant carriers, the incidence of colorectal cancer (CRC) was not reduced when colonoscopy was undertaken more frequently than once every 3 years, and that CRC stage and interval since last colonoscopy were not correlated.

Methods: The Prospective Lynch Syndrome Database (PLSD) that records outcomes of surveillance was examined to determine survival after colon cancer in relation to the time since previous colonoscopy and pathological stage. Only variants scored by the InSiGHT variant database as class 4 or 5 (clinically actionable) were included in the analysis.