What question did this study set out to answer?

The aim is to compare PCR-free whole-genome sequencing with exome sequencing to improve the detection of somatic driver mutations in cancer.

April 5, 2026

Abstract 1990: Pan-cancer PCR-free whole-genome sequencing refines the somatic driver landscape beyond exome sequencing alone.

Puntos clave

The aim is to compare PCR-free whole-genome sequencing with exome sequencing to improve the detection of somatic driver mutations in cancer.
Analyzed matched tumor-normal PCR-free whole-genome sequencing data from over 8,000 TCGA cases.
Applied a unified pipeline for single nucleotide variant (SNV) and indel detection with stringent filtering.
Focused on the concordance of mutations between whole-genome sequencing and exome sequencing.
Examined coverage and sequence context of mutations, especially in GC-rich and duplicated regions.
PCR-free WGS identified significantly more high-confidence coding mutations compared to WES.
Notable improvements were observed in GC-rich exons and regions typically challenging to capture.
Pathogenic variants in key cancer genes like TP53, FOXA1, and EGFR were identified, enhancing genotype-phenotype knowledge.
An indel mutation in BAP1's 5'UTR was uncovered that WES missed, indicating its potential clinical relevance.

Resumen

Abstract Background: The initial TCGA exome sequencing project established a foundational catalog of somatic mutations. However, capture biases and limited coverage in GC-rich and repetitive regions may have obscured bona fide driver events and introduced systematic “blind spots” in the landscape of protein-coding genes. Leveraging high-depth, PCR-free whole-genome sequencing (WGS), we revisited the somatic mutation landscape in multiple tumor types to enhance driver discovery by improving sensitivity in GC-rich regions and reducing artifact-driven false positives. Methods: We analyzed matched tumor–normal PCR-free WGS data from 8,000 TCGA cases across several cancer types with existing previously published somatic mutation calls from whole exome sequencing (WES) data, applying a unified best-practice pipeline for SNV/indel detection and stringent post-calling filters. We focused on (i) concordance between WGS and exome across coding regions, (ii) coverage, allele fraction, and local sequence context (GC content, segmental duplications) of discordant sites, and (iii) recurrence and positional clustering of variants in established cancer genes. Results: PCR-free WGS identified substantially more high-confidence coding mutations than WES, with the greatest gains in GC-rich exons and difficult-to-capture loci. This increased sensitivity uncovered additional pathogenic or likely pathogenic variants in canonical drivers, including TP53 and FOXA1 in breast cancer, EGFR in glioblastoma, and BAP1 in uveal melanoma (UVM), thereby strengthening known genotype–phenotype associations. In UVM, we observed an indel in the BAP1 5′UTR/promoter region that was systematically missed by WES but supported by robust read evidence in WGS data, nominating an expanded spectrum of BAP1-disrupting events with potential regulatory and clinical relevance. Conversely, we found a subset of WES-only calls localized to segmental duplications or low-support sites, consistent with technical artifacts. Integrated re-annotation of discordant calls thus both eliminates spurious events and reveals underappreciated driver mutations and mechanisms. Conclusions: Our systematic comparison demonstrates that PCR-free WGS can refine the somatic mutation and driver landscape beyond exome-based catalogs, particularly in GC-rich and regulatory regions. These results advocate for re-interrogation of previously profiled tumor types with contemporary WGS to achieve a more complete and accurate map of cancer-driving alterations. Citation Format: Gengchao Wang, David I Heiman, Vasuki Narasimha Swamy, Chip Stewart, Xavi Loinaz, Ron Solan, Chunyang Bao, David Lehotzky, Brian P Danysh, Luis Antonio Corchete Sanchez, Zachary Everton, Sam Wiseman, Antonia Kowalewski, Samantha Van Seters, Saveliy Belkin, Haruna Tomono, Andrew D Cherniack, Ryul Kim, Gang-Hee Lee, Won-Chul Lee, Hansol Park, Rebecca Jang, Young Seok Ju, Gad Getz, Esther Rheinbay. Pan-cancer PCR-free whole-genome sequencing refines the somatic driver landscape beyond exome sequencing alone abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1990.

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