Publications
Addressing Indigenous rights and interests in genetic resources has become increasingly challenging in an open science environment that promotes unrestricted access to genomic data. Although Indigenous experiences with genetic research have been shaped by a series of negative interactions, there is increasing recognition that equitable benefits can only be realized through greater participation of Indigenous communities. Issues of trust, accountability and equity underpin Indigenous critiques of genetic research and the sharing of genomic data. This Perspectives article highlights identified issues for Indigenous communities around the sharing of genomic data and suggests principles and actions that genomic researchers can adopt to recognize community rights and interests in data.
Presence or absence of gene fusions is one of the most important diagnostic markers in many cancer types. Consequently, fusion detection methods using various genomics data types, such as RNA sequencing (RNA-seq) are valuable tools for research and clinical applications. While information-rich RNA-seq data have proven to be instrumental in discovery of a number of hallmark fusion events, bioinformatics tools to detect fusions still have room for improvement. Here, we present Fusion-Bloom, a fusion detection method that leverages recent developments in de novo transcriptome assembly and assembly-based structural variant calling technologies (RNA-Bloom and PAVFinder, respectively). We benchmarked Fusion-Bloom against the performance of five other state-of-the-art fusion detection tools using multiple datasets. Overall, we observed Fusion-Bloom to display a good balance between detection sensitivity and specificity. We expect the tool to find applications in translational research and clinical genomics pipelines.
Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (TPDS). BAP1 TPDS is associated with an increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma, and several other cancer subtypes. Here, we report a germline nonsense BAP1 variant (c.850G>T, p.Glu284Ter) in a patient with bladder cancer and a strong family history of malignancy. Concurrently, we identified a somatic frameshift BAP1 variant, and as expected, immunostaining validated the loss of BAP1 protein in patient-derived tumor specimens. Together, these data provide strong evidence of pathogenicity in this case. With the addition of bladder cancer to the tumor types reported with germline BAP1 mutations, our understanding of the BAP1 TPDS continues to evolve, and may affect future screening and surveillance guidelines.
Familial aggregation of lymphoid cancers and immune-related disorders suggests a role for genetic susceptibility; however, few studies examine environmental factors. According to the hygiene hypothesis, adult-onset-immune-related diseases may be a consequence of reduced childhood infectious exposures and aberrant immune development. In a cohort of 196 multiple-case lymphoid cancer families, we analyzed environmental factors related to the hygiene hypothesis.
Very few people live to eighty-five years and older (the 'oldest old'), and even fewer live to this age without developing chronic diseases. It is important to understand the relationship, if any, of modifiable factors such as diet on healthy aging. However, there are few studies of diet among healthy oldest old, especially in North American populations. We aimed to characterize dietary patterns among 'super-seniors' (SS) within the Canadian Healthy Aging Study.
Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder named for its characteristic hair-like cytoplasmic projections from the malignant cells. HCL is classified as an indolent lymphoproliferative neoplasm, representing ~2% of all leukemias with ~1240 new cases diagnosed annually in the US; median age-at-onset is 55 years [1]. It affects males more than females (4:1), and whites more than African-Americans [1]. Although familial and sporadic HCL exhibit similar clinical features, no characteristic germline genetic variation has been found. Familial HCL is rare with fewer than 20 families reported in the literature. Thirteen of the 15 reported pedigrees had two affected individuals; the remaining two pedigrees harbored three, including the family reported here [2,3,4,5]. Investigators have speculated that HCL may be an HLA-linked disorder but, in aggregate, the data are inconclusive [3,4,5]. The discovery that a somatic BRAF mutation (V600E) was nearly universal in HCL (but absent in other B-cell neoplasms) provided major insight into disease biology, identifying a critical therapeutic target [6], but no germline genetic susceptibility variants have been identified. In this study we applied high-throughput sequencing technology to four multiplex HCL pedigrees, seeking to identify shared germline variants conferring HCL susceptibility. In addition, we used CRISPR/Cas9-based genome editing to introduce CASP9 p.H237P, one of the variants shared by all four affected members of the largest pedigree, into a model cell line, followed by measurements of cellular caspase-9 activity and apoptotic response.
Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00–1.17, p = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01–1.31, p = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes.
A high organic content CE‐MS/MS (HOCE‐MS/MS) method was developed for the proteomic analysis of envelope proteins extracted from spinach leaves. Separation was performed in a 1‐m long hydroxypropyl cellulose coated capillary, using 8% (v/v) formic acid in 70% (v/v) methanol and 22% water as the BGE. A flow‐through microvial interface was used to couple the CE system with an Orbitrap Fusion Lumos mass spectrometer, and field‐amplified sample stacking was used to improve the concentration sensitivity. Using this optimized method, 3579 peptides and 1141 proteins were identified using the Proteome Discoverer software with a 1% false discovery rate at the protein level. Relative to conventional aqueous CE, HOCE‐MS did a better job of discovering hydrophobic peptides and provided more peptide and protein identifications. Relative to nano‐LC‐MS, it achieved comparable peptide and protein identification performance and detected peptides not identified by LC‐MS: of the full set of peptides identified using the two techniques, 19% were identified only using HOCE‐MS. It also outperformed nano‐LC‐MS with respect to the detection of low molecular weight peptides.