arcasHLA: high-resolution HLA typing from RNAseq

Orenbuch, Rose; Filip, Ioan; Comito, Devon; Shaman, Jeffrey; Pe’er, Itsik; Rabadán, Raúl

doi:10.1093/bioinformatics/btz474

Cited by 145 publications

(134 citation statements)

References 40 publications

Supporting

Mentioning

114

Contrasting

Order By: Relevance

“…Using this database, current RNA-seq based methods can determine the identity of HLA alleles present in an individual with 4 to 6-digit resolution. However, even the most advanced methods like arcasHLA 18 have a 10% error-rate for the identification of some HLA genes and, importantly, cannot determine new HLA alleles absent from the database they use. Reliable HLA typing therefore still requires dedicated DNA-based approaches.…”

Section: Allele-resolved Isoform Sequences Enable High Resolution Hlamentioning

confidence: 99%

“…Currently, HLA-typing is performed in clinical laboratories by amplifying the genomic DNA encoding these genes and sequencing these amplicons with short read sequencers 1 . This is required because even though all of these genes are expressed by immune cells in the blood and are therefore captured by RNA-seq, even sophisticated computational tools relying on complex workflows and statistically rigorous frameworks struggle to process RNA-seq data and provide reliable allelic identities 6,18 . Further, these tools rely on databases of known HLA allele sequences which prevents them for identifying so far unknown HLA alleles.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Complete characterization of the human immune cell transcriptome using accurate full-length cDNA sequencing

Cole

Byrne

Adams

et al. 2019

Preprint

View full text Add to dashboard Cite

ABSTRACTThe human immune system relies on highly complex and diverse transcripts and the proteins they encode. These include transcripts for Human Leukocyte Antigen (HLA) class I and II receptors which are essential for self/non-self discrimination by the immune system as well as transcripts encoding B cell and T cell receptors (BCR and TCR) which recognize, bind, and help eliminate foreign antigens.HLA genes are highly diverse within the human population with each individual possessing two of thousands of different alleles in each of the 9 major HLA genes. Determining which combination of alleles an individual possesses for each HLA gene (high-resolution HLA-typing) is essential to establish donor-recipient compatibility in organ and bone-marrow transplantations. BCR and TCR genes in turn are generated by recombining a diverse set of gene segments on the DNA level in each maturing B and T cell, respectively. This process generates adaptive immune receptor repertoires (AIRR) of composed of unique transcripts expressed by each B and T cells. These repertoires carry a vast amount of health relevant information. Both short-read RNA-seq based HLA-typing1 and adaptive immune receptor repertoire sequencing2–5 currently rely heavily on our incomplete knowledge of the genetic diversity at HLA6 and BCR/TCR loci7,8.Here we used our nanopore sequencing based Rolling Circle toConcatemeric Consensus (R2C2) protocol9 to generate over 10,000,000 full-length cDNA sequences at a median accuracy of 97.9%. We used this dataset to demonstrate that deep and accurate full-length cDNA sequencing can - in addition to providing isoform-level transcriptome analysis for over 9,000 loci - be used to generate accurate sequences of HLA alleles for HLA allele typing and discovery as well as detailed AIRR data for the analysis of the adaptive immune system without requiring specific knowledge of the diversity at HLA and BCR/TCR loci.

show abstract

Section: Allele-resolved Isoform Sequences Enable High Resolution Hlamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Complete characterization of the human immune cell transcriptome using accurate full-length cDNA sequencing

Cole

Byrne

Adams

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Moreover, RNA-seq is capable of revealing other types of neoantigen sources, such as gene fusion [ 44 , 45 ], alternative splicing isoforms and RNA editing events [ 46 ]. In the absence of clinical HLA (human leukocyte antigen) typing data, RNA-seq can be an additional source for in silico typing to improve the confidence of WES-based HLA determination [ 47 ]. High-confidence somatic mutation data that were identified based on WES and RNA-seq are commonly used in the isolation and ranking (or prioritization) of mutated peptide sequences aiming to detect peptides with the highest probability of being bound to the MHC and presented on the cell surface for TCR recognition [ 48 , 49 ].…”

Section: Introductionmentioning

confidence: 99%

Main Strategies for the Identification of Neoantigens

Gopanenko

Кособокова

Косоруков

2020

Cancers

View full text Add to dashboard Cite

Genetic instability of tumors leads to the appearance of numerous tumor-specific somatic mutations that could potentially result in the production of mutated peptides that are presented on the cell surface by the MHC molecules. Peptides of this kind are commonly called neoantigens. Their presence on the cell surface specifically distinguishes tumors from healthy tissues. This feature makes neoantigens a promising target for immunotherapy. The rapid evolution of high-throughput genomics and proteomics makes it possible to implement these techniques in clinical practice. In particular, they provide useful tools for the investigation of neoantigens. The most valuable genomic approach to this problem is whole-exome sequencing coupled with RNA-seq. High-throughput mass-spectrometry is another option for direct identification of MHC-bound peptides, which is capable of revealing the entire MHC-bound peptidome. Finally, structure-based predictions could significantly improve the understanding of physicochemical and structural features that affect the immunogenicity of peptides. The development of pipelines combining such tools could improve the accuracy of the peptide selection process and decrease the required time. Here we present a review of the main existing approaches to investigating the neoantigens and suggest a possible ideal pipeline that takes into account all modern trends in the context of neoantigen discovery.

show abstract

“…In the present study, we aimed to systematically characterize HLA-I ASE loss across tumor types using a novel, accurate allele-specific quantification method ( Figure 1a) that builds upon previously established high-resolution HLA genotyping protocols from RNA-seq 17,18 . In light of ubiquitous HLA-I aberrant expression in cancer, we hypothesized that HLA-I ASE loss may constitute a universal immune escape mechanism with significant clinical impact, particularly in the context of immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

HLA allele-specific expression loss in tumors can shorten survival and hinder immunotherapy

Filip

Orenbuch

Zhao

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Efficient presentation of aberrant peptide fragments by the human leukocyte antigen class I (HLA-I) genes is necessary for immune detection and killing of cancer cells. Patient HLA-I genotypes are known to impact the efficacy of cancer immunotherapy, and the somatic loss of HLA-I heterozygosity has been established as a factor in immune evasion. While global deregulated expression of HLA-I has been reported in different tumor types, the role of HLA-I allele-specific expression loss - that is, the preferential RNA expression loss of specific HLA-I alleles - has not been fully characterized in cancer. In the present study, we quantified HLA-I allele-specific expression (ASE) across eleven TCGA tumor types using a novel method from input RNA and whole-exome sequencing data. Allele-specific loss in at least one of the three HLA-I genes (ASE loss) was pervasive and associated to worse overall survival across tumor types, including pancreatic adenocarcinomas, prostate carcinomas and glioblastomas, among others. In particular, our analysis shows that detection of neoantigens with binding affinity to the specific HLA-I genes subject to ASE loss was a top prognostic indicator of overall survival. Additionally, we found that ASE loss hindered immunotherapy in retrospective analyses. Together, these results highlight the prevalence of HLA-I ASE loss - a previously uncharacterized phenomenon in cancer - and provide initial evidence of its clinical significance in cancer prognosis and immunotherapy treatment.

show abstract

arcasHLA: high-resolution HLA typing from RNAseq

Cited by 145 publications

References 40 publications

Complete characterization of the human immune cell transcriptome using accurate full-length cDNA sequencing

Complete characterization of the human immune cell transcriptome using accurate full-length cDNA sequencing

Main Strategies for the Identification of Neoantigens

HLA allele-specific expression loss in tumors can shorten survival and hinder immunotherapy

Contact Info

Product

Resources

About