Chimeric antigen receptor T (CART) cell therapy has revolutionized the treatment of relapsed/refractory B cell malignancies in recent years. Despite high initial response rates, durable response rates are low, and CART cell efficacy in solid tumors is very modest. Additionally, the overall success of CART cell therapy is limited by toxicities such as cytokine release syndrome and neurotoxicity. Decades of advancement in genome sequencing technology and bioinformatics have given us a better understanding of how cancer develops and evolves following treatments. This has resulted in a better understanding of patient response to cancer treatment on a molecular level. Resistance to CART cell therapy can be mediated by the cancer cells, the tumor microenvironment, or the patient’s T cells. In this review, we will outline lessons learned from multi-omics studies (1) to identify biomarkers of response or toxicity to CART cell therapy or (2) to develop biomarker-guided therapeutic interventions to overcome these limitations.
Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoma comprising less than 2% of lymphoid neoplasms. Approximately 70% of patients have a progressive disease requiring treatment and up to 30% of patients relapse or transform to diffuse large B-cell lymphoma. Whilst research over the last decade has transformed our understanding of many B-cell tumours, it is only beginning to shed light on the molecular pathogenesis of SMZL. Expansive immunogenetic investigations have shown biases in the immunoglobulin gene repertoire with distinct patterns of somatic hypermutation, suggesting a pathogenic role for antigen selection. In parallel cytogenetic studies have found a number of recurrent chromosomal lesions, in particular a deletion of the long arm of chromosome 7, though causative genes have not been identified. Our understanding of the mutational landscape of SMZL is built on a limited number of index cases, but has highlighted recurrent mutations in KLF2, NOTCH2 and TP53, and a spectrum of genes that cluster within biological pathways of importance in B-cell differentiation. While preliminary DNA methylation profiling has shown epigenetically distinct patient sub-groups, including a group defined by elevated expression of polycomb repressor complex 2 components. This review will provide an overview of our current understanding of the molecular basis of SMZL, and how this information impacts patient outcomes. Furthermore, we will outline; (1) the knowledge gaps that still exist; (2) a potential future research direction; and (3) how a detailed molecular understanding of the disease will ultimately provide patients with improved management and treatment choices.
Aim: High-risk pedigrees (HRPs) are a powerful design to map highly penetrant risk genes. We previously described Shared Genomic Segment (SGS) analysis, a mapping method for single large extended pedigrees that also addresses genetic heterogeneity inherent in complex diseases. SGS identifies shared segregating chromosomal regions that may inherit in only a subset of cases. However, single large pedigrees that are individually powerful (at least 15 meioses between studied cases) are scarce. Here, we expand the SGS strategy to incorporate evidence from two extended HRPs by identifying the same segregating risk locus in both pedigrees and allowing for some relaxation in the size of each HRP.
Methods: Duo-SGS is a procedure to combine single-pedigree SGS evidence. It implements statistically rigorous duo-pedigree thresholding to determine genome-wide significance levels that account for optimization across pedigree pairs. Single-pedigree SGS identifies optimal segments shared by case subsets at each locus across the genome, with nominal significance assessed empirically. Duo-SGS combines the statistical evidence for SGS segments at the same genomic location in two pedigrees using Fisher’s method. One pedigree is paired with all others and the best duo-SGS evidence at each locus across the genome is established. Genome-wide significance thresholds are determined through distribution-fitting and the Theory of Large Deviations. We applied the duo-SGS strategy to eleven extended, myeloma HRPs.
Results: We identified one genome-wide significant region at 18q21.33 (0.85 Mb, P = 7.3 × 10-9) which contains one gene, CDH20. Thirteen regions were genome-wide suggestive: 1q42.2, 2p16.1, 3p25.2, 5q21.3, 5q31.1, 6q16.1, 6q26, 7q11.23, 12q24.31, 13q13.3, 18p11.22, 18q22.3 and 19p13.12.
Conclusion: Our results provide novel risk loci with segregating evidence from multiple HRPs and offer compelling targets and specific segment carriers to focus a future search for functional variants involved in inherited risk formyeloma.
Neurofibromatosis type 1 (NF1) is a complex autosomal dominant neurocutaneous disorder with a variable phenotype involving multiple body systems. It is due to a mutation in the NF1 gene, which results in the production of abnormal neurofibromin protein. According to the National Institutes of Health diagnostic criteria, hyperpigmented skin markings or café-au-lait macules (CALMs), axillary freckling, Lisch nodules, and neurofibromas are characteristic NF1 features. A milder phenotype, apparently manifesting with only pigmentary skin changes, has recently been associated with the c.2970_2972 in-frame deletion. Although neurological findings, including epilepsy and neurocognitive deficits, have been frequently described as a part of the classic NF1 form, they have not been properly characterized in this milder variant. We report for the first time the case of a patient harboring the c.2970_2972del of the NF1 gene and presenting with CALMs, idiopathic generalized epilepsy, and transient brain MRI alterations (so-called “unidentified bright objects”).
Aim: Mental illness comprises a group of heterogeneous conditions attributable to a complex interplay between hereditary and environmental components. Acting at the interface between environmental stimuli and their genomic actions, nuclear receptors (NRs) appear uniquely suited to facilitate gene-environment interactions in the context of mental health. Genetic disruptions to the NR transcriptomic complex (NTC) give rise to neuropsychiatric pathologies, and epidemiological risks involving a steroid response are among the most replicated in psychiatry. Importantly, pharmacological targeting of NR-mediated signaling is clinically effective in the treatment of psychiatric disorders. Here, we systematically interrogated large-scale deposited data to provide a comprehensive evaluation of the genomic NTC risk burden in mental illness.
Methods: Utilizing data from large, recent genome-, exome-, and methylome-wide association studies on psychiatric disorders, we assessed the representation of NTC genes among top associated loci and tested the gene set associations for NTC and NR target genes using GWAS summary statistics. Through data mining and transcriptomic profiling of NR-mediated signaling in the diseased and healthy human brain, we categorized psychiatry-relevant NTC gene networks.
Results: We found that NTC genes are significantly overrepresented in genome-, methylome-, and exome-wide associated loci and that the NTC, as well as NR target gene sets, is overall associated with mental illness. Accordingly, we identified transcriptomic NTC signatures in patient brain samples. In line with a key role for orchestrated NR-mediated signaling in the developing brain, particularly NTC co-expression networks with prenatal peak expression are enriched with differentially methylated, sex-biased, and psychiatry-associated risk variants.
Conclusion: Here, we provide multilevel evidence that supports genomic NR-mediated signaling as a common and core molecular mechanism in mental illness, and we highlight specific NR-signaling pathways with putative diagnostic and pharmacological intervention potential in psychiatry.
Aim: Here, we aim to evaluate the chemopreventive efficacy of kava root extracts (KRE) in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and investigate potential molecular targets of kavalactones, the main components of kava.
Methods: TRAMP mice were administrated with KRE formulated food for different periods of time, and then the incidences of high-grade prostatic intraepithelial neoplasia (HG-PIN) and adenocarcinomas and tumor burdens were compared between vehicle control and KRE food fed groups. In addition, the inhibitory effect of the KRE and kavalactones on monoamine oxidase A (MAO-A) and lysine-specific demethylase 1 (LSD1) enzyme activities were examined by commercially available inhibitor screening kits. Histone H3 lysine 9 dimethylation was also evaluated in prostate cancer cells and tumor tissues using Western blotting analysis.
Results: Dietary feeding of 0.3% and 0.6% KRE to TRAMP mice from ages of 6 weeks to 12 weeks inhibited HG-PIN by 43.5% and 59.7%, respectively, and prostate adenocarcinoma by 53.5% and 66.4%, respectively. In addition, 0.6% KRE fed TRAMP mice from ages of 6 weeks to 24 weeks exhibited a significant reduction of genitourinary weight (a surrogate of tumor burden) by 54.5% and reduced body weight gain. Furthermore, the KRE and kavalactones showed a significant inhibition of LSD1 and MAO-A enzyme activities.
Conclusion: Our results suggest that consumption of kava products through diet can delay prostate cancer development and progression and that kavalactones may be a new structure model for developing a potent dual inhibitor of LSD1 and MAO-A.
Prostate cancer (PCa) remains a disease of high incidence, but orphan of a specific screening program. For this reason, non-invasive techniques capable to predict PCa in patients with high specificity and sensitivity are still an urgent need. One of the major goals is to improve the PCa diagnosis and the identification of patients who benefit from tissue biopsies. Another need is the necessity to have novel biomarkers to better stratify the risk of patients with PCa to predict the aggressiveness of the tumor and the overall survival. Liquid biopsy can be an important non-invasive tool to stratify PCa at the molecular level to improve diagnosis and prognosis, and, possibly, to develop screening programs and follow-up. With this review, we are reporting the lastest update of aberrant methylation detection on circulating tumor DNA as a tool to improve prostate cancer diagnosis and prognosis.
Aim: We here assessed the impact of B-cell receptor stereotypy on progression-free survival (PFS) and overall survival in patients from the HOVON 68 trial.
Methods: Based on IGHV mutational analyses from participating centers in Sweden, Norway, Finland, Denmark, Poland, and the Netherlands, B-cell receptor stereotyped subsets were assigned using the ARResT/AssignSubsets software. Analysis for recurrent mutations was performed by next-generation sequencing by a 454-base platform. All other clinical data were extracted from the HOVON database by November 2016.
Results: In total, 178 out of 192 patients with sequences available were technically suitable for analysis. Thirty-eight patients (21%) were assigned to one of the 19 major subsets: Subset #2 (n = 12, 6.7%), Subset #8 (n = 7, 3.9%), Subset #6 (n = 6, 3.4%), and Subset #1 (n = 5, 2.8%). Other subsets found were: Subsets #3, #5, #31, and #64B. By November 2016, a PFS event had occurred for 150 patients (84%) and 79 patients (44%) had died. The median follow-up time for patients still alive was 78.9 months. Patients with UM-IGHV belonging to Subset #2 had significantly longer PFS than UM-IGHV 3-21-utilizing non-Subset #2 patients [UM-IGHV Subset #2 median PFS 61.3 months (n = 8) vs. UM-IGHV 3-21 non-Subset #2 median PFS 22.3 months (n = 6), P = 0.01]. Overall, no significant differences in PFS between groups were found for patients with M-IGHV.
Conclusion: In the HOVON 68 trial. Subset #2 patients had a good treatment outcome comparable to the outcome for non-high-risk patients with chronic lymphocytic leukemia following fludarabine-cyclophosphamide-rituximab-based treatment.
Aim: Chronic lymphocytic leukemia (CLL) has been shown to cluster in families. First-degree relatives of individuals with CLL have an ~8 fold increased risk of developing the malignancy. Strong heritability suggests pedigree studies will have good power to localize pathogenic genes. However, CLL is relatively rare and heterogeneous, complicating ascertainment and analyses. Our goal was to identify CLL risk loci using unique resources available in Utah and methods to address intra-familial heterogeneity.
Methods: We identified a six-generation high-risk CLL pedigree using the Utah Population Database. This pedigree contains 24 CLL cases connected by a common ancestor. We ascertained and genotyped eight CLL cases using a high-density SNP array, and then performed shared genomic segment (SGS) analysis - a method designed for extended high-risk pedigrees that accounts for heterogeneity.
Results: We identified a genome-wide significant region (P = 1.9 × 10-7, LOD-equivalent 5.6) at 2q22.1. The 0.9 Mb region was inherited through 26 meioses and shared by seven of the eight genotyped cases. It sits within a ~6.25 Mb locus identified in a previous linkage study of 206 small CLL families. Our narrow region intersects two genes, including CXCR4 which is highly expressed in CLL cells and implicated in maintenance and progression.
Conclusion: SGS analysis of an extended high-risk CLL pedigree identified the most significant evidence to-date for a 0.9 Mb CLL disease locus at 2q22.1, harboring CXCR4. This discovery contributes to a growing literature implicating CXCR4 in inherited risk to CLL. Investigation of the segregating haplotype in the pedigree will be valuable for elucidating risk variant(s).
Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.
Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.
Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10-6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL (P = 1.0) or MZL (P = 0.91). For F3, we observed an association with CLL
Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.