CRCINA inaugural symposium: A meeting on tumor and immune ecosystems.

The CRCINA inaugural symposium, a meeting on tumor and immune ecosystems, took place in the vibrant and picturesque city of Nantes. The meeting gathered world-renowned experts in cancer biology and immunology. It showcased the most advanced science on mechanisms driving cellular heterogeneity, plasticity, and signaling in normal and cancer cellular ecosystems, which contribute to cancer development, progression, and therapeutic resistance.

Mechanisms of resistance to bispecific T-cell engagers in multiple myeloma and their clinical implications.

Bispecific T-cell engagers (TCEs) are revolutionizing patient care in multiple myeloma (MM). These monoclonal antibodies, that redirect T cells against cancer cells, are now approved for the treatment of triple-class exposed relapsed/refractory MM (RRMM). They are currently tested in earlier lines of the disease, including in first line.

Preneoplastic liver colonization by 11p15.5 altered mosaic cells in young children with hepatoblastoma.

Pediatric liver tumors are very rare tumors with the most common diagnosis being hepatoblastoma. While hepatoblastomas are predominantly sporadic, around 15% of cases develop as part of predisposition syndromes such as Beckwith-Wiedemann (11p15.5 locus altered).

Acquired resistance to a GPRC5D-directed T-cell engager in multiple myeloma is mediated by genetic or epigenetic target inactivation.

Bispecific antibodies targeting GPRC5D demonstrated promising efficacy in multiple myeloma, but acquired resistance usually occurs within a few months. Using a single-nucleus multi-omic strategy in three patients from the MYRACLE cohort (ClinicalTrials.gov registration: NCT03807128 ), we identified two resistance mechanisms, by bi-allelic genetic inactivation of GPRC5D or by long-range epigenetic silencing of its promoter and enhancer regions.

Discovering cryptic splice mutations in cancers via a deep neural network framework.

Somatic mutations can disrupt splicing regulatory elements and have dramatic effects on cancer genes, yet the functional consequences of mutations located in extended splice regions is difficult to predict. Here, we use a deep neural network (SpliceAI) to characterize the landscape of splice-altering mutations in cancer. In our in-house series of 401 liver cancers, SpliceAI uncovers 1244 cryptic splice mutations, located outside essential splice sites, that validate at a high rate (66%) in matched RNA-seq data.

Using Facebook advertising data to describe the socio-economic situation of Syrian refugees in Lebanon.

While the fighting in the Syrian civil war has mostly stopped, an estimated 5.6 million Syrians remain living in neighboring countries. Of these, an estimated 1.

Accurate intercensal estimates of energy access to track Sustainable Development Goal 7.

Unlabelled: Intercensal estimates of access to electricity and clean cooking fuels at policy planning microregions in a country are essential for understanding their evolution and tracking progress towards Sustainable Development Goals (SDG) 7. Surveys are prohibitively expensive to get such intercensal microestimates. Existing works, mainly, focus on electrification rates, make predictions at the coarse spatial granularity, and generalize poorly to intercensal periods.

Hepatocellular Carcinoma in Mongolia Delineates Unique Molecular Traits and a Mutational Signature Associated with Environmental Agents.

Purpose: Mongolia has the world's highest incidence of hepatocellular carcinoma (HCC), with ∼100 cases/100,000 inhabitants, although the reasons for this have not been thoroughly delineated.

Experimental Design: We performed a molecular characterization of Mongolian (n = 192) compared with Western (n = 187) HCCs by RNA sequencing and whole-exome sequencing to unveil distinct genomic and transcriptomic features associated with environmental factors in this population.

Results: Mongolian patients were younger, with higher female prevalence, and with predominantly HBV-HDV coinfection etiology.

Bi-allelic hydroxymethylbilane synthase inactivation defines a homogenous clinico-molecular subtype of hepatocellular carcinoma.

Background & Aims: Acute intermittent porphyria (AIP), caused by heterozygous germline mutations of the heme synthesis pathway enzyme HMBS (hydroxymethylbilane synthase), confers a high risk of hepatocellular carcinoma (HCC) development. Yet, the role of HMBS in liver tumorigenesis remains unclear.

Methods: Herein, we explore HMBS alterations in a large series of 758 HCC cases, including 4 patients with AIP.

H3K27me3 conditions chemotolerance in triple-negative breast cancer.

The persistence of cancer cells resistant to therapy remains a major clinical challenge. In triple-negative breast cancer, resistance to chemotherapy results in the highest recurrence risk among breast cancer subtypes. The drug-tolerant state seems largely defined by nongenetic features, but the underlying mechanisms are poorly understood.

Structure, Dynamics, and Impact of Replication Stress-Induced Structural Variants in Hepatocellular Carcinoma.

Unlabelled: Oncogene activation leads to replication stress and promotes genomic instability. Here we combine optical mapping and whole-genome sequencing (WGS) to explore in depth the nature of structural variants (SV) induced by replication stress in cyclin-activated hepatocellular carcinomas (CCN-HCC). In addition to classical tandem duplications, CCN-HCC displayed frequent intra-chromosomal and interchromosomal templated insertion cycles (TIC), likely resulting from template switching events.

Detection of acquired TERT amplification in addition to predisposing p53 and Rb pathways alterations in EGFR-mutant lung adenocarcinomas transformed into small-cell lung cancers.

Introduction: Among the different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) reported in EGFR-mutated lung adenocarcinoma (EGFR-LUAD) patients, histological transformation into small cell carcinoma (SCLC) occurs in 3-14% of resistant cases, regardless of the generation of EGFR-TKI. In recent studies, bi-allelic inactivation of TP53 and RB1 has been identified in a vast majority of transformed SCLCs. However, the molecular mechanisms driving this histologic transformation remain largely unknown, mainly due to the rarity of samples.

Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study.

Background: Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma.

Methods: We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20-92 years recruited between Oct 22, 1993, and March 12, 2017.

Comprehensive characterization of viral integrations and genomic aberrations in HBV-infected intrahepatic cholangiocarcinomas.

Background And Aims: Despite the epidemiological association between intrahepatic cholangiocarcinoma (iCCA) and HBV infection, little is known about the relevant oncogenic effects. We sought to identify the landscape and mechanism of HBV integration, along with the genomic architecture of HBV-infected iCCA (HBV-iCCA) tumors.

Approach And Results: We profiled a cohort of 108 HBV-iCCAs using whole-genome sequencing, deep sequencing, and RNA sequencing, together with preconstructed data sets of HBV-infected HCC (HBV-HCC; n = 167) and combined hepatocellular cholangiocarcinoma (HBV-cHCC/CCA; n = 59), and conventional (n = 154) and fluke-related iCCAs (n = 16).

Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma.

Background: Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples.

Loss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate.

Succinate dehydrogenase is a key enzyme in the tricarboxylic acid cycle and the electron transport chain. All four subunits of succinate dehydrogenase are tumor suppressor genes predisposing to paraganglioma, but only mutations in the SDHB subunit are associated with increased risk of metastasis. Here we generated an knockout chromaffin cell line and compared it with deficient cells.

Analyzing the Effect of Time in Migration Measurement Using Georeferenced Digital Trace Data.

Georeferenced digital trace data offer unprecedented flexibility in migration estimation. Because of their high temporal granularity, many migration estimates can be generated from the same data set by changing the definition parameters. Yet despite the growing application of digital trace data to migration research, strategies for taking advantage of their temporal granularity remain largely underdeveloped.

DNA Methylation Signatures Reveal the Diversity of Processes Remodeling Hepatocellular Carcinoma Methylomes.

Background And Aims: DNA methylation patterns are highly rearranged in HCCs. However, diverse sources of variation are intermingled in cancer methylomes, precluding the precise characterization of underlying molecular mechanisms. We developed a computational framework (methylation signature analysis with independent component analysis [MethICA]) leveraging independent component analysis to disentangle the diverse processes contributing to DNA methylation changes in tumors.