Abstract
Human leukocyte antigen (HLA) genes provide useful information on the relationship between cancer and the immune system. Despite the ease of obtaining these data through next-generation sequencing methods, interpretation of these relationships remains challenging owing to the complexity of HLA genes. To resolve this issue, we developed a Bayesian method, ALPHLARD-NT, to identify HLA germline and somatic mutations as well as HLA genotypes from whole-exome sequencing (WES) and whole-genome sequencing (WGS) data. ALPHLARD-NT showed 99.2% accuracy for WGS-based HLA genotyping and detected five HLA somatic mutations in 25 colon cancer cases. In addition, ALPHLARD-NT identified 88 HLA somatic mutations, including recurrent mutations and a novel HLA-B type, from WES data of 343 colon adenocarcinoma cases. These results demonstrate the potential of ALPHLARD-NT for conducting an accurate analysis of HLA genes even from low-coverage data sets. This method can become an essential tool for comprehensive analyses of HLA genes from WES and WGS data, helping to advance understanding of immune regulation in cancer as well as providing guidance for novel immunotherapy strategies.
Highlights
Human leukocyte antigen (HLA) genes are essential components of the immune system, which present peptides to immune cells to facilitate recognition of nonself antigens
We developed a Bayesian method, ALPHLARD-NT, to identify HLA germline and somatic mutations as well as HLA genotypes from whole-exome sequencing (WES) and whole-genome sequencing (WGS) data
We first evaluated the accuracy of this method for HLA genotyping from a WGS data set
Summary
Human leukocyte antigen (HLA) genes are essential components of the immune system, which present peptides to immune cells to facilitate recognition of nonself antigens. New methods for HLA genotyping have been developed more recently with advances in molecular techniques, including whole-exome sequencing (WES), whole-genome sequencing (WGS), and RNA sequencing (Boegel et al, 2012; Warren et al, 2012; Kim and Pourmand 2013; Liu et al, 2013; Bai et al, 2014; Szolek et al, 2014; Nariai et al, 2015; Shukla et al, 2015; Dilthey et al, 2016; Xie et al, 2017; Hayashi et al, 2018; Lee and Kingsford, 2018) With these methods, information of both somatic mutations and HLA genotypes can be obtained from the entire sequence, which can facilitate investigations on the relationship between cancer and the immune system. The low coverage of WGS data makes it challenging to detect HLA germline and somatic mutations
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