Citations

Abstract Background Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease. Methods We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables. Results Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control). Conclusions In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome.

The clinical and largely unpredictable heterogeneity of phenotypes in patients with mitochondrial disorders demonstrates the ongoing challenges in the understanding of this semi-autonomous organelle in biology and disease. Previously, we used the gene-breaking transposon to create 1200 transgenic zebrafish strains tagging protein-coding genes (Ichino et al., 2020), including the lrpprc locus. Here, we present and characterize a new genetic revertible animal model that recapitulates components of Leigh Syndrome French Canadian Type (LSFC), a mitochondrial disorder that includes diagnostic liver dysfunction. LSFC is caused by allelic variations in the LRPPRC gene, involved in mitochondrial mRNA polyadenylation and translation. lrpprc zebrafish homozygous mutants displayed biochemical and mitochondrial phenotypes similar to clinical manifestations observed in patients, including dysfunction in lipid homeostasis. We were able to rescue these phenotypes in the disease model using a liver-specific genetic model therapy, functionally demonstrating a previously under-recognized critical role for the liver in the pathophysiology of this disease.

Abstract Diffuse gliomas are aggressive brain tumors that lack effective therapies. Despite advances in the molecular characterization of gliomas, targeted treatments have failed to improve patient outcomes to date. Here, we employed a functional genomics approach to rapidly identify therapeutic vulnerabilities and provide a strategy to individualize patient treatment. Our process combined comprehensive genomic and transcriptomic tumor profiling, custom algorithms and visualization software for data integration, and preclinical 3-dimensional ex vivo models (mcancers) for drug screening to assess response to therapeutic agents targeting specific molecular alterations. A total of 32 cases, including 5 oligodendrogliomas (1 primary and 4 recurrent), 5 astrocytomas (1 primary and 4 recurrent), and 22 glioblastomas (5 primary and 17 recurrent), were included in the study. Immunohistochemistry and integrated genomics confirmed that mcancers maintain key molecular alterations, including mutations, chromosomal rearrangements and focal amplifications, cellularity, and heterogeneity, faithfully recapitulating the original tumor. A total of 119 single drugs and 183 combinations were tested, including a panel of 26-brain penetrant targeted agents (18 single drugs and 8 combinations) that was curated to target common glioma oncogenic pathways and was tested across all cases. A strong correlation was observed between therapeutic vulnerabilities of glioma mcancers to targeted agents (EGFR, MET, PDGFR, HDAC inhibitors, etc.) and clinical experience. Single agent activity of panel compounds in the ex vivo setting was generally poor, with only 35% mCancers exhibiting > 70% growth inhibition at Cmax. In contrast, combination strategies, especially ones including epigenetic drugs, were significantly more effective (affecting 22 out of 32 mCancers), underscoring the molecular complexity of gliomas and the need for clinical trials testing combination treatments. Our data identified a number of novel combination treatments with significant efficacy across glioma subtypes and molecular profiles, suggesting that our functional genomics pipeline can guide treatment selection and inform clinical trial enrollment for gliomas.

Abstract Glioblastoma (GBM) is the most aggressive adult brain tumor with no effective therapy. Despite advances on its molecular characterization, targeted therapeutics remain out of reach. This lack-of-progress is largely attributed to molecular and spatial heterogeneity and absence of clinically applicable models to guide patient care. Moreover, as standard surgical resection is aimed at contrast-enhancing (CE) tumor, the molecular landscape and treatment response of the remaining non-contrast enhancing (nCE) component is largely unknown despite its active role in tumor progression and local recurrence. Here, we aimed to identify the functional impact of tumor heterogeneity and to explore therapeutic vulnerabilities of both CE and nCE components. Four tumor regions (two CE and two nCE) from each of five GBM patients were collected under neuronavigation. The resulting tissue was subjected to generation of 3D tumor models (a brain tumor initiating-enriched cell line and a spheroid-based mcancer model) with comparable success in both CE and nCE samples. A panel of 25 brain penetrant drugs (alone and in combination) targeting GBM drivers (i.e. RTK/Ras/PI3K, RB/cell cycle, p53/apoptosis, DNA damage repair, transcription addiction) was developed and used to test for therapeutic vulnerabilities. From each tumor region, 4.5 ± 3.7 (average ± SD) different targeting strategies were identified exhibiting at least 70% growth inhibition at Cmax. Drug response heterogeneity was relatively rare, varied among cases, and was independent of tumor enhancement status. To our knowledge, this is the first study to systemically assess treatment response from both CE and nCE patient-derived GBM models. Ongoing studies include comprehensive genome and transcriptome profiling and pathway analysis from these different tumor regions. We postulate that interrogation of molecular landscapes and vulnerability profiles of both CE and nCE tumor regions, will enable us to personalize and prioritize effective targeted interventions for GBM treatment.

Abstract Overall Survival estimates from diagnosis are valuable for guiding treatment, but do not consider the years already survived. Conditional survival (CS) provides dynamic survival predictions over time. This study was conducted to estimate CS at 1–8 years from diagnosis and the impact of baseline prognostic factors on CS in multiple myeloma (MM) patients. This is a retrospective study including 2556 MM patients diagnosed between 2004–2019. CS (t|s) was defined as the probability of surviving t years given survival of s years. Median age was 64 years. Median follow-up was 6.2 years and median overall survival from diagnosis was 7.5 years. The 5-year CS estimates at s = 0, 1, 2, 3, and 5 years were 0.64, 0.61, 0.61, 0.61, and 0.58, respectively. On multivariate analysis, age ≥ 65 and proteasome inhibitor + immunomodulatory-based induction were associated with decreased survival and increased survival, respectively, retained at 5 years. The adverse impact of 1q gain/amplification, high-risk IgH translocation, and ISS-3 was significant at 1 and 3 years but not 5 years. Chromosome 17 abnormality was associated with decreased survival only at 1 year. Among MM patients, 5-year CS was stable at 1–5 years from diagnosis. The prognostic impact of high-risk cytogenetic factors decreased with additional years survived.