Global funding for cancer research between 2016 and 2020: a content analysis of public and philanthropic investments.

BACKGROUND: Cancer is a leading cause of disease burden globally, with more than 19·3 million cases and 10 million deaths recorded in 2020. Research is crucial to understanding the determinants of cancer and the effects of interventions, and to improving outcomes. We aimed to analyse global patterns of public and philanthropic investment in cancer research. METHODS: In this content analysis, we searched the UberResearch Dimensions database and Cancer Research UK data for human cancer research funding awards from public and philanthropic funders between Jan 1, 2016, and Dec 31, 2020. Included award types were project and programme grants, fellowships, pump priming, and pilot projects. Awards focused on operational delivery of cancer care were excluded. Awards were categorised by cancer type, cross-cutting research theme, and research phase. Funding amount was compared with global burden of specific cancers, measured by disability-adjusted life-years, years lived with disability, and mortality using data from the Global Burden of Disease study. FINDINGS: We identified 66 388 awards with total investment of about US$24·5 billion in 2016-20. Investment decreased year-on-year, with the largest drop observed between 2019 and 2020. Pre-clinical research received 73·5% of the funding across the 5 years ($18 billion), phase 1-4 clinical trials received 7·4% ($1·8 billion), public health research received 9·4% ($2·3 billion), and cross-disciplinary research received 5·0% ($1·2 billion). General cancer research received the largest investment ($7·1 billion, 29·2% of the total funding). The most highly funded cancer types were breast cancer ($2·7 billion [11·2%]), haematological cancer ($2·3 billion [9·4%]), and brain cancer ($1·3 billion [5·5%]). Analysis by cross-cutting theme revealed that 41·2% of investment ($9·6 billion) went to cancer biology research, 19·6% ($4·6 billion) to drug treatment research, and 12·1% ($2·8 billion) to immuno-oncology. 1·4% of the total funding ($0·3 billion) was spent on surgery research, 2·8% ($0·7 billion) was spent on radiotherapy research, and 0·5% ($0·1 billion) was spent on global health studies. INTERPRETATION: Cancer research funding must be aligned with the global burden of cancer with more equitable funding for cancer research in low-income and middle-income countries (which account for 80% of cancer burden), both to support research relevant to these settings, and build research capacity within these countries. There is an urgent need to prioritise investment in surgery and radiotherapy research given their primacy in the treatment of many solid tumours. FUNDING: None.

The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications.

Splenic marginal zone lymphoma (SMZL) is a rare, predominantly indolent B-cell lymphoma constituting fewer than 2% of lymphoid neoplasms. However, around 30% of patients have a shorter survival despite currently available treatments and the prognosis is especially poor for the 5-15% of cases that transform to a large cell lymphoma. Mounting evidence suggests that the molecular pathogenesis of SMZL is critically shaped by microenvironmental triggering and cell-intrinsic aberrations. Immunogenetic investigations have revealed biases in the immunoglobulin gene repertoire, indicating a role of antigen selection. Furthermore, cytogenetic studies have identified recurrent chromosomal abnormalities such as deletion of the long arm of chromosome 7, though specific disease-associated genes remain elusive. Our knowledge of SMZL's mutational landscape, based on a limited number of cases, has identified recurring mutations in KLF2, NOTCH2, and TP53, as well as genes clustering within vital B-cell differentiation pathways. These mutations can be clustered within patient subgroups with different patterns of chromosomal lesions, immunogenetic features, transcriptional signatures, immune microenvironments, and clinical outcomes. Regarding SMZL epigenetics, initial DNA methylation profiling has unveiled epigenetically distinct patient subgroups, including one characterized by elevated expression of Polycomb repressor complex 2 (PRC2) components. Furthermore, it has also demonstrated that patients with evidence of high historical cell division, inferred from methylation data, exhibit inferior treatment-free survival. This review provides an overview of our current understanding of SMZL's molecular basis and its implications for patient outcomes. Additionally, it addresses existing knowledge gaps, proposes future research directions, and discusses how a comprehensive molecular understanding of the disease will lead to improved management and treatment choices for patients.

Targeted Genetic Sequencing Analysis of 223 Cases of Pseudomyxoma Peritonei Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Shows Survival Related to GNAS and KRAS Status.

BACKGROUND AND AIM: Pseudomyxoma peritonei (PMP) is an unusual condition with unique behaviour caused by a mucinous neoplasm, usually arising from the appendix. The aim of this study was to evaluate the prevalence of genomic alterations in clinical specimens of PMP using a targeted assay and correlate the findings with clinical, pathological and outcome data. Sequencing data from 223 patients were analysed. RESULTS: The median follow-up interval was 48 months. The primary neoplasm was appendiceal in 216 patients, ovarian in 4, urachal in 2 and renal in one. We confirmed common mutations in GNAS and KRAS (42% each) with significant co-occurrence of variants in these genes. TP53 mutations were found in 8%. Other mutations were rare but included novel mutations in BAP1 and ERBB4. Of 17 patients with acellular peritoneal mucin, 6 (35%) were positive for DNA mutations. The non-appendiceal cases generally showed a similar mutational landscape to the appendiceal lesions with GNAS and KRAS commonly mutated, although one urachal lesion showed multi-hit TP53 mutation without variants in either GNAS or KRAS. Survival was significantly associated with the grade of the primary neoplasm, the grade of the peritoneal disease, the completeness of cytoreduction score and with mutation in either GNAS, KRAS or both. The hazard ratio (HR) associated with mutation in GNAS and/or KRAS was 1.87 (p = 0.004). CONCLUSIONS: Survival outcome was more closely associated with the grade of the peritoneal disease than with the grade of the primary neoplasm. Our findings support the developing concept that mutational analysis may provide prognostic information in patients with PMP.

The Genomics of Hairy Cell Leukaemia and Splenic Diffuse Red Pulp Lymphoma.

Classical hairy cell leukaemia (HCLc), its variant form (HCLv), and splenic diffuse red pulp lymphoma (SDRPL) constitute a subset of relatively indolent B cell tumours, with low incidence rates of high-grade transformations, which primarily involve the spleen and bone marrow and are usually associated with circulating tumour cells characterised by villous or irregular cytoplasmic borders. The primary aim of this review is to summarise their cytogenetic, genomic, immunogenetic, and epigenetic features, with a particular focus on the clonal BRAFV600E mutation, present in most cases currently diagnosed with HCLc. We then reflect on their cell of origin and pathogenesis as well as present the clinical implications of improved biological understanding, extending from diagnosis to prognosis assessment and therapy response.