Association of clonal hematopoiesis and mosaic chromosomal alterations with solid malignancy incidence and mortality.

Background: Understanding the impact of clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) on solid tumor risk and mortality can shed light on novel cancer pathways.

Methods: The authors analyzed whole genome sequencing data from the Trans-Omics for Precision Medicine Women's Health Initiative study (n = 10,866). They investigated the presence of CHIP and mCA and their association with the development and mortality of breast, lung, and colorectal cancers.

Vaccinia Virus: Mechanisms Supporting Immune Evasion and Successful Long-Term Protective Immunity.

Vaccinia virus is the most successful vaccine in human history and functions as a protective vaccine against smallpox and monkeypox, highlighting the importance of ongoing research into vaccinia due to its genetic similarity to other emergent poxviruses. Moreover, vaccinia's ability to accommodate large genetic insertions makes it promising for vaccine development and potential therapeutic applications, such as oncolytic agents. Thus, understanding how superior immunity is generated by vaccinia is crucial for designing other effective and safe vaccine strategies.

Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate.

Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels.

Circulating Tumor DNA Enables Sensitive Detection of Actionable Gene Fusions and Rearrangements Across Cancer Types.

Purpose: Genomic rearrangements can generate potent oncogenic drivers or disrupt tumor suppressor genes. This study examines the landscape of fusions and rearrangements detected by liquid biopsy (LBx) of circulating tumor DNA (ctDNA) across different cancer types.

Experimental Design: LBx from 53,842 patients with 66 solid tumor types were profiled using FoundationOneLiquid CDx, a hybrid-capture sequencing platform that queries 324 cancer-related genes.

Anti-EGFR Antibodies in the Management of Advanced Colorectal Cancer.

Colorectal cancer is the third most common cancer worldwide, and incidence is rising in younger individuals. Anti-EGFR antibodies, including cetuximab and panitumumab, have been incorporated into standard-of-care practice for patients with advanced disease. Herein, we review the molecular characteristics of these agents and the trials that lead to their approvals.

Endoglin, a Novel Biomarker and Therapeutical Target to Prevent Malignant Peripheral Nerve Sheath Tumor Growth and Metastasis.

Purpose: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGFβ coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs.

Distinct cAMP Signaling Microdomains Differentially Regulate Melanosomal pH and Pigmentation.

cAMP signaling is a well-established regulator of melanin synthesis. Two distinct cAMP signaling pathways-the transmembrane adenylyl cyclase pathway, activated primarily by the MC1R, and the soluble adenylyl cyclase (sAC) pathway-affect melanin synthesis. The sAC pathway affects melanin synthesis by regulating melanosomal pH, and the MC1R pathway affects melanin synthesis by regulating gene expression and post-translational modifications.

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point.

Soluble adenylyl cyclase contributes to imiquimod-mediated inflammation and is a potential therapeutic target in psoriasis.

Cyclic AMP (cAMP) has a key role in psoriasis pathogenesis, as indicated by the therapeutic efficacy of phosphodiesterase inhibitors that prevent the degradation of cAMP. However, whether soluble adenylate cyclase (sAC) (encoded by the ADCY10 gene), which is an important source for cAMP, is involved in Th17 cell-mediated inflammation or could be an alternative therapeutic target in psoriasis is unknown. We have utilized the imiquimod model of murine psoriasiform dermatitis to address this question.

Identification of Novel Genetic Markers for the Risk of Spinal Pathologies: A Genome-Wide Association Study of 2 Biobanks.

Background: Identifying genetic risk factors for spinal disorders may lead to knowledge regarding underlying molecular mechanisms and the development of new treatments.

Methods: Cases of lumbar spondylolisthesis, spinal stenosis, degenerative disc disease, and pseudarthrosis after spinal fusion were identified from the UK Biobank. Controls were patients without the diagnosis.

T cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control.

Antigen-specific CD8 T cell accumulation in tumors is a prerequisite for effective immunotherapy, and yet the mechanisms of lymphocyte transit are not well defined. Here we show that tumor-associated lymphatic vessels control T cell exit from tumors via the chemokine CXCL12, and intratumoral antigen encounter tunes CXCR4 expression by effector CD8 T cells. Only high-affinity antigen downregulates CXCR4 and upregulates the CXCL12 decoy receptor, ACKR3, thereby reducing CXCL12 sensitivity and promoting T cell retention.

Types of Liquid Biopsies: Understanding the Different Lenses Through Which They Can Detect Cancer.

This commentary remarks on the recently published article by Gouda et al on developing mutation-agnostic liquid biopsy, emphasizing the different types of liquid biopsies that are available to detect cancer.

A systematic review and meta-analysis of germline BRCA mutations in pancreatic cancer patients identifies global and racial disparities in access to genetic testing.

Background: Germline BRCA1 and BRCA2 mutations (gBRCAm) can inform pancreatic cancer (PC) risk and treatment but most of the available information is derived from white patients. The ethnic and geographic variability of gBRCAm prevalence and of germline BRCA (gBRCA) testing uptake in PC globally is largely unknown.

Materials And Methods: We carried out a systematic review and prevalence meta-analysis of gBRCA testing and gBRCAm prevalence in PC patients stratified by ethnicity.

Analysis of Circulating Tumor DNA to Predict Risk of Recurrence in Patients With Esophageal and Gastric Cancers.

Purpose: Circulating tumor DNA (ctDNA) analyses allow for postoperative risk stratification in patients with curatively treated colon and breast cancers. Use of ctDNA in esophagogastric cancers (EGC) is less characterized and could identify high-risk patients who have been treated with curative intent.

Methods: In this retrospective analysis of real-world data, ctDNA levels were analyzed in the preoperative, postoperative, and surveillance settings in patients with EGC using a personalized multiplex polymerase chain reaction-based next-generation sequencing assay.

Genetic features and therapeutic relevance of emergent circulating tumor DNA alterations in refractory non-colorectal gastrointestinal cancers.

Acquired resistance to systemic treatments is inevitable in most cancers, but the genetic basis for this in many cancer types has remained elusive due to constraints in obtaining tissue specimens longitudinally. In the management of gastrointestinal cancers, molecular profiling is conventionally performed at a single time point, although serial evaluations may yield biological insights that inform treatment decisions. We characterize genetic changes in serial liquid biopsies which provide real-time snapshots of tumor genetics and heterogeneity in refractory non-colorectal gastrointestinal cancers, and determine the clinical utility of repeat circulating tumor DNA (ctDNA) testing.

The yin/yang balance of the MHC-selfimmunopeptidome.

The MHC- immunopeptidome of professional antigen presenting cells is a cognate ligand for the TCRs expressed on both conventional and thymic-derived natural regulatory T cells. In regulatory T cells, the TCR signaling associated with MHC-peptide recognition induces antigen specific as well as bystander immunosuppression. On the other hand, TCR activation of conventional T cells is associated with protective immunity.

Peptide Receptor Radionuclide Therapy in Merkel Cell Carcinoma: A Comprehensive Review.

Merkel cell carcinoma is a rare, aggressive skin malignancy, also known as neuroendocrine carcinoma of the skin, with high rates of recurrence and distant metastasis. In refractory metastatic Merkel cell carcinoma (mMCC), besides immunotherapy, chemotherapy, and radiation, peptide receptor radionuclide therapy (PRRT) may be a viable option since this type of tumor can express somatostatin receptors. We performed a comprehensive review of the literature to evaluate the efficacy of PRRT in mMCC patients.

Using Circulating Tumor DNA in Colorectal Cancer: Current and Evolving Practices.

There exists a tremendous opportunity in identifying and determining the appropriate predictive and prognostic biomarker(s) for risk stratification of patients with colorectal cancers (CRCs). Circulating tumor DNA (ctDNA) has emerged as a promising prognostic and possibly predictive biomarker in the personalized management of patients with CRCs. The disease is particularly suited to a liquid biopsy-based approach since there is a great deal of shedding of circulating tumor fragments (cells, DNA, methylation markers, etc).

Unmet Needs in Oncology Clinical Research and Treatment in Africa: Focus on Ghana.

Cancer incidence is increasing worldwide and is a major cause of mortality. The relative magnitude of the increase is remarkably high in low human development index (HDI; 95%) and medium HDI (64%) countries. On the African continent, a corresponding increase in cancer burden is predicted, particularly for sub-Saharan Africa.