Biology subjects

Rustad, E. H.

Publications and source records attributed to Rustad, E. H..

4 recordsLinked to original sources

bioRxiv2021

Public T-cell epitopes shared among SARS-CoV-2 variants are presented on prevalent HLA class I alleles

T-cell epitopes with broad population coverage may form the basis for a new generation of SARS-CoV-2 vaccines. However, published studies on immunoprevalence are limited by small test cohorts, low frequencies of antigen-specific cells and lack of data correlating eluted HLA ligands with T-cell responsiveness. As the protective role of pre-existing cross-reactivity to homologous peptides is unclear, we aimed to identify SARS-CoV-2-specific minimal epitopes recognized by CD8 T-cells among 48 peptides eluted from prevalent HLA alleles, and an additional 84 predicted binders, in a large cohort of convalescents (n=83) and pre-pandemic control samples (n=19). We identified nine conserved SARS-CoV-2-specific epitopes restricted by four of the most prevalent HLA class I alleles in the Norwegian study cohort, to which responding CD8 T cells were detected in 70-100% of convalescents expressing the relevant HLA allele. Only two of these were derived from the Spike protein, included in current vaccines. We found a strong correlation between immunoprevalence and immunodominance. Thus, the CD8 T-cell response to SARS-CoV-2 is more focused than previously believed. Using a new algorithm, we predict that a vaccine including these epitopes could induce a T-cell response in 83% of Caucasians.

immunology↗

bioRxiv2020

Copy number signatures predict chromothripsis and associate with poor clinical outcomes in patients with newly diagnosed multiple myeloma

Chromothripsis is detectable in 20-30% of newly diagnosed multiple myeloma (NDMM) patients and is emerging as a new independent adverse prognostic factor. In this study, we interrogate 752 NDMM patients using whole genome sequencing (WGS) to study the relationship of copy number (CN) signatures to chromothripsis and show they are highly associated. CN signatures are highly predictive of the presence of chromothripsis (AUC=0.90) and can be used to identify its adverse prognostic impact. The ability of CN signatures to predict the presence of chromothripsis was confirmed in a validation series of WGS comprised of 235 hematological cancers (AUC=0.97) and an independent series of 34 NDMM (AUC=0.87). We show that CN signatures can also be derived from whole exome data (WES) and using 677 cases from the same series of NDMM, we were able to predict both the presence of chromothripsis (AUC=0.82) and its adverse prognostic impact. CN signatures constitute a flexible tool to identify the presence of chromothripsis and is applicable to WES and WGS data.

genomics↗

bioRxiv2020

Accelerated single cell seeding in relapsed multiple myeloma

The malignant progression of multiple myeloma is characterized by the seeding of cancer cells in different anatomic sites followed by their clonal expansion. It has been demonstrated that this spatial evolution at varying anatomic sites is characterized by genomic heterogeneity. However, it is unclear whether each anatomic site at relapse reflects the expansion of pre-existing but previously undetected disease or secondary seeding from other sites. Furthermore, genomic evolution over time at spatially distinct sites of disease has not been investigated in a systematic manner. To address this, we interrogated 25 samples, by whole genome sequencing, collected at autopsy from 4 patients with relapsed multiple myeloma and demonstrated that each site had a unique evolutionary trajectory characterized by distinct single and complex structural variants and copy number changes. By analyzing the landscape of mutational signatures at these sites and for an additional set of 125 published whole exomes collected from 51 patients, we demonstrate the profound mutagenic effect of melphalan and platinum in relapsed multiple myeloma. Chemotherapy-related mutagenic processes are known to introduce hundreds of unique mutations in each surviving cancer cell. These mutations can be detectable by bulk sequencing only in cases of clonal expansion of a single cancer cell bearing the mutational signature linked to chemotherapy exposure thus representing a unique single-cell genomic barcode linked to a discrete time window in each patients life. We leveraged this concept to show that multiple myeloma systemic seeding is accelerated at clinical relapse and appears to be driven by the survival and subsequent expansion of a single myeloma cell following treatment with high dose melphalan therapy and autologous stem cell transplant.

cancer biology↗

bioRxiv2019

Revealing the impact of recurrent and rare structural variants in multiple myeloma

The landscape of structural variants (SVs) in multiple myeloma remains poorly understood. Here, we performed comprehensive classification and analysis of SVs in multiple myeloma, interrogating a large cohort of 762 patients with whole genome and RNA sequencing. We identified 100 SV hotspots involving 31 new candidate driver genes, including drug targets BCMA (TNFRSF17) and SLAMF7. Complex SVs, including chromothripsis and templated insertions, were present in 61 % of patients and frequently resulted in the simultaneous acquisition of multiple drivers. After accounting for all recurrent events, 63 % of SVs remained unexplained. Intriguingly, these rare SVs were associated with up to 7-fold enrichment for outlier gene expression, indicating that many rare driver SVs remain unrecognized and are likely important in the biology of individual tumors.

genomics↗