POLYSOLVER

Overview

POLYSOLVER (POLYmorphic loci SOLVER) is a computational tool for HLA class I typing and somatic HLA mutation calling from whole-exome sequencing data. It infers patient-specific HLA-A, HLA-B, and HLA-C alleles from tumor/normal sequence reads, then detects somatic mutations within those polymorphic loci — a task that is challenging because standard mutation callers assume diploid non-repetitive reference regions.

Used by

• Giannakis et al. 2016 — CRC neoantigen-survival study: Applied to 619 CRC tumor/normal WES pairs (Illumina HiSeq 2000, SureSelect v.2; mean 90× coverage) to type HLA class I alleles and call somatic HLA mutations; 66/619 (11%) samples carried HLA mutations (96 total); mutated alleles were enriched for neoantigen-binding residues and for somatic hits in TIL-high tumors (chi-squared p = 1.2e-22), consistent with immune-escape selection PMID:27149842.
• Used to detect HLA mutations from exome data in 412 BLCA tumors; HLA mutations detected in 4.6% (19/412), enriched in the high-APOBEC/high-burden MSig1 cluster (p=0.039) PMID:28988769

Notes

• HLA loci are highly polymorphic; standard read mappers frequently misalign reads, making somatic variant calling unreliable without HLA-aware tools.
• Shukla et al. (2015, Nature Biotechnology) developed and validated POLYSOLVER; cited in multiple TCGA pan-cancer studies.
• In Giannakis et al., class II HLA loci were not analyzed — a stated limitation.
• Somatic HLA mutations detected by POLYSOLVER may represent immune-escape events under positive selection from tumor-infiltrating lymphocytes.

Sources

• Shukla SA et al. (2015) Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes. Nature Biotechnology 33:1152–1158.
• PMID:27149842

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