Derivation of HLA types from shotgun sequence datasets

Warren, René L.; Choe, Gina; Freeman, Douglas J; Castellarin, Mauro; Munro, Sarah A.; Moore, Richard A.; Holt, Robert A.

doi:10.1186/gm396

Cited by 165 publications

(161 citation statements)

References 28 publications

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“…Previous studies have explored the potential immunogenicity of tumor mutations (Segal et al 2008;Warren and Holt 2010;Khalili et al 2012), but these have been hampered by small sample size and the inability to specify autologous HLA restriction. Recently, we described a method of HLA calling from RNA-seq data that shows high sensitivity and specificity (Warren et al 2012). Here, we have obtained matched tumor mutational profiles and HLA-A genotypes from TCGA subjects and used these data to predict patient-specific mutational epitope profiles.…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

“…RNA-seq BAM files for each of the 1069 subjects were downloaded from CGhub and used directly as input for HLAminer (Warren et al 2012). HLAminer was run with default values, in parallel on a computer cluster.…”

Section: Hla Predictionsmentioning

confidence: 99%

“…These were the only tumor sites with complete and nonembargoed data at the time of this study. The RNA-seq data were first processed using HLAminer (Warren et al 2012) to predict, at four-digit resolution, the two HLA-A alleles carried by each subject. Data from 515 patients with unambiguous HLA-A calls were processed further.…”

Section: Summary Of Available Datamentioning

confidence: 99%

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Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival

et al. 2014

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Somatic missense mutations can initiate tumorogenesis and, conversely, anti-tumor cytotoxic T cell (CTL) responses. Tumor genome analysis has revealed extreme heterogeneity among tumor missense mutation profiles, but their relevance to tumor immunology and patient outcomes has awaited comprehensive evaluation. Here, for 515 patients from six tumor sites, we used RNA-seq data from The Cancer Genome Atlas to identify mutations that are predicted to be immunogenic in that they yielded mutational epitopes presented by the MHC proteins encoded by each patient’s autologous HLA-A alleles. Mutational epitopes were associated with increased patient survival. Moreover, the corresponding tumors had higher CTL content, inferred from CD8A gene expression, and elevated expression of the CTL exhaustion markers PDCD1 and CTLA4. Mutational epitopes were very scarce in tumors without evidence of CTL infiltration. These findings suggest that the abundance of predicted immunogenic mutations may be useful for identifying patients likely to benefit from checkpoint blockade and related immunotherapies.

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Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

Section: Hla Predictionsmentioning

confidence: 99%

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Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival

et al. 2014

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“…Ground truth HLA allele types were obtained from each dataset's original publications (11,(15)(16)(17).…”

Section: Methodsmentioning

confidence: 99%

“…Because most of the gold-standard HLA types we used for benchmarking are based on core exons of the HLA genes (15)(16)(17), the benchmarking procedure considered four-digit types with the same core exon sequences as "consistent" types. This fraction ranged from 0 to 1.9% of alleles in the benchmarking datasets.…”

Section: Significancementioning

confidence: 99%

Fast and accurate HLA typing from short-read next-generation sequence data with xHLA

Xie¹,

Yeo²,

Wong³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

124

100

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The HLA gene complex on human chromosome 6 is one of the most polymorphic regions in the human genome and contributes in large part to the diversity of the immune system. Accurate typing of HLA genes with short-read sequencing data has historically been difficult due to the sequence similarity between the polymorphic alleles. Here, we introduce an algorithm, xHLA, that iteratively refines the mapping results at the amino acid level to achieve 99-100% four-digit typing accuracy for both class I and II HLA genes, taking only ∼3 min to process a 30× whole-genome BAM file on a desktop computer.MHC | autoimmune diseases | transplantation

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The loss of neoantigens is an important reason for immune escape in multiple myeloma patients with high intratumor heterogeneity

Wang,

Xu,

Lan

et al. 2023

Cancer Medicine

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ObjectivesIntratumor heterogeneity (ITH) is an important factor for clinical outcomes in patients with multiple myeloma (MM). High ITH has been proven to be a key reason for tumor immune escape and treatment resistance. Neoantigens are thought to be associated with ITH, but the specific correlation and functional basis for this remains unclear.MethodsWe study this question through the whole‐exome sequencing (WES) data from 43 high ITH newly diagnosed MM patients in our center. Mutant allele tumor heterogeneity (MATH) was conducted to quantify ITH. The cutoff value for high intratumor heterogeneity was determined by comparing MATH of different kinds of tumors. NeoPredPipe was performed to predict neoantigens and binding affinity.ResultsCompared to other tumors, MM has a relatively low tumor mutation burden but a high ITH. Patients with high MATH had significantly shorter progression‐free survival times than those with low MATH (p = 0.001). In high ITH samples, there is a decrease in strong‐binding neoantigens (p = 0.019). The loss of strong‐binding neoantigens is a key factor for insensitivity to therapy (p = 0.015). Loss of heterozygosity in HLA was not observed. In addition, patients with fewer neoantigens loss had higher rates of disease remission (p = 0.047). CD8 + T cells (p = 0.012) and NK cells (p = 0.011) decreased significantly in patients with high neoantigens loss rate. A prediction model based on neoantigens was built to evaluate the strength of immune escape.ConclusionThe loss of strong‐binding neoantigens explains why tumors with high ITH have a higher degree of immune escape and may be feasible for deciding the clinical treatment of MM.

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Derivation of HLA types from shotgun sequence datasets

Cited by 165 publications

References 28 publications

Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival

Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival

Fast and accurate HLA typing from short-read next-generation sequence data with xHLA

The loss of neoantigens is an important reason for immune escape in multiple myeloma patients with high intratumor heterogeneity

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