Whole-genome sequencing (WGS)

Overview

Unbiased short-read sequencing of the entire tumor (and matched normal) genome, used in the corpus for structural variant detection, mutational signature analysis at non-coding sites, evolutionary timing, and microbiome read mining.

Used by

  • PMID:35927489 — 177 WGS samples in the CLL-map cohort; identified 681 SV breakpoints in 141 patients (~4.8/patient), BCL2 translocations predominantly in M-CLL via aberrant V(D)J, and a recurrent 37-Mb chr14 deletion disrupting ZFP36L1 (and DICER1, TRAF3) in U-CLL via class-switch recombination. Supported mutational signature analysis (canonical AID SBS84 enriched in U-CLL clustered mutations; non-canonical AID SBS85 enriched in M-CLL, p=1.6×10^-9; plus SBS18) PMID:35927489.
  • PMID:36723991 — WGS on FACS-purified Hodgkin and Reed Sternberg cells from 25 cHL patients with matched intratumoral T cells as germline; established the first comprehensive WGS landscape of cHL, with median post-artifact-removal mutational burden of 5,279 SBS+indels per genome (range 1,880–18,883), prevalent APOBEC mutagenesis (SBS2/SBS13), AID off-target activity, chromothripsis, and timing of WGD as a late event PMID:36723991.
  • PMID:37202560 — tumor WGS in the AC-ICAM colon cancer atlas, used for microbiome read mining alongside 16S rRNA sequencing PMID:37202560.
  • PMID:37730754 — shallow WGS used for CNV assessment from 62 plasma samples (10 patients) in the longitudinal ctDNA arm of the rhabdomyosarcoma progression/relapse study PMID:37730754.
  • PMID:38117484 — WGS on a subset of 64 glioma patients in the GLASS International consortium; integrated with 450K/EPIC methylation arrays and RNA-seq PMID:38117484.
  • PMID:38412093 — WGS on 9 of 141 characterized anaplastic thyroid carcinoma regions (the remaining 132 underwent WES) PMID:38412093.
  • PMID:38488813 — WGS at 30X on 44 prostate cancer PDX models; paired with targeted sequencing (T200.1 panel) and RNA-seq for integrative multi-platform molecular characterization PMID:38488813.
  • PMID:39305899 — WGS (BWA-MEM2, MuSE, Mutect2, SomaticSniper, Strelka2, Battenberg/ASCAT) on a subset of the UCLA sarcoma biobank (194 specimens from 126 patients); used alongside DFCI-ONCOPANEL-3 targeted DNA and bulk RNA-seq to characterize 24 bone and soft-tissue sarcoma subtypes; enabled CNV analysis including whole-genome duplications in intra-patient heterogeneity studies and functional-vs-genomic concordance analyses PMID:39305899.
  • Low-pass WGS (5x) applied to 51 primary and 102 metastatic breast cancer specimens in AURORA cohort; 11 DNA segments more frequently amplified in metastases (q<0.05), including MYC and MDM4 regions PMID:36585450
  • Applied to primary tumors from 2 MEC patients (Patient 1: 29x tumor/25x normal; Patient 2: 22x tumor/15x normal; GRCh37/hg19); revealed >30-way biallelic chromoplexy event in MEC1 and double-minute ELK4 amplification in MEC2 PMID:36577525
  • Applied to 40 treatment-naive HGSOC tumor-normal pairs; mutational signature inference classified tumours into HRD-Dup (n=16), HRD-Del (n=6), and FBI (n=14) subtypes PMID:36517593
  • Applied to 14 NHL cases (DLBCL and FL) with matched tumor/normal pairs in the BCGSC study; identified 109 recurrently mutated genes including KMT2D and MEF2B as major histone-modifier drivers PMID:21796119
  • Two HNSCC tumors underwent whole-genome sequencing at 31x mean coverage in the Broad HNSCC study, complementing whole-exome sequencing of 74 tumors PMID:21798893
  • WGS applied to 65 breast tumors (BCCRC) to characterize structural rearrangements and somatic mutation landscapes PMID:22495314
  • WGS of 25 melanoma tumors used to identify PREX2 recurrent mutations and characterize KIT/BRAF alteration patterns PMID:22622578
  • WGS used in HCC genomic studies to identify TERT promoter mutations, CTNNB1, and TP53 alterations PMID:22634756
  • Used for WGS of 103 breast cancer tumors in the Broad cohort (brca_broad), enabling structural variant and fusion discovery including MAGI3-AKT3 PMID:22722202
  • Used for WGS of 37 medulloblastoma tumors in the PCGP cohort (mbl_pcgp), identifying KDM6A, DDX3X, and SMARCA4 as driver genes PMID:22722829
  • 97 of 276 TCGA colorectal carcinoma pairs analyzed by low-pass whole-genome sequencing (~3-4X coverage) for structural variant detection alongside WES PMID:22810696
  • 39 of 125 pediatric medulloblastoma pairs (ICGC) analyzed by deep whole-genome sequencing at 35-fold mean coverage; identified tetraploidy as frequent early event in Group 3 and 4 tumors and described first medulloblastoma fusion genes PMID:22832583
  • Applied alongside WES in Genentech colorectal cohort to detect structural variants including RSPO2/RSPO3 fusions PMID:22895193
  • Applied to SCLC tumors in CLCGP study (29 cases) to detect structural rearrangements and copy number alterations in TP53/RB1-null tumors PMID:22941188
  • Used in JHU SCLC study (36 tumors) to complement WES and characterise copy number landscape including SOX2/MYCL amplifications PMID:22941189
  • Applied to subset of TCGA LUSC tumors (178-tumor cohort) to detect structural variants alongside WES-based somatic mutation calling PMID:22960745
  • Applied in Broad LUAD WES study (183 tumors) to characterise structural variation and somatic copy number alterations PMID:22980975
  • WGS of 87 neuroblastoma tumor/normal pairs from the Broad cohort; detected structural variants including MYCN amplifications and ALK rearrangements PMID:23334666
  • WGS of 7 ETP-ALL tumor/normal pairs at St. Jude; revealed complex structural rearrangements in FLT3, JAK1/2, and cytokine receptor genes PMID:23334668
  • Whole-genome sequencing (~49× tumor / 30× germline; 101 bp paired reads) on 16 esophageal adenocarcinoma pairs; rearrangements called by dRanger yielded 2,952 candidate events; no recurrent fusions found PMID:23525077
  • Whole-genome sequencing (mean 61× tumor / 34× normal; Illumina GAIIx paired-end 101 bp) on 57 prostate tumor/normal pairs; identified 5,596 somatic rearrangements by dRanger and characterized chromoplexy chains in 88% of tumors PMID:23622249
  • Whole-genome sequencing (mean 30.54× coverage) on 50 AML tumor/normal-skin pairs in TCGA AML study; VAF-based clonal architecture analysis showed >50% of tumors had ≥1 subclone PMID:23634996
  • Applied in 5 of 60 ACC tumor/normal pairs (Illumina HiSeq 2000, mean coverage 37x) for structural variant detection using CREST; complemented whole-exome sequencing for comprehensive somatic alteration characterization PMID:23685749
  • Applied to 96 pediatric pilocytic astrocytoma tumor/blood pairs (Illumina HiSeq2000, BWA + samtools + Picard, hg19); mean somatic mutation rate <0.1/Mb; PINDEL, CREST, and DELLY used for SV detection revealing KIAA1549:BRAF fusions and novel BRAF/NTRK2 fusions PMID:23817572
  • Applied to 42 deep-coverage GBM tumor/normal pairs; detected 238 high-confidence somatic rearrangements including EGFR intragenic events and one case of chromothripsis; identified TERT promoter mutations in 84% PMID:24120142
  • Applied at fourfold mean haploid coverage in 99 BLCA tumors; WGS mate-pair reads confirmed FGFR3-TACC3 fusion junctions detected by RNA-seq PMID:24121792
  • Applied to 4 MCL tumor/normal pairs; detected ~3,700 somatic mutations per tumor (1.2/Mb) and identified kataegis foci in 3/4 cases around the t(11;14) breakpoint and Ig loci PMID:24145436
  • Paired tumor/normal whole-genome sequencing on Illumina (hg19, BWA alignment) for 28 metastatic neuroendocrine neoplasms in the BC Cancer POG program; combined with RNA-seq in an integrated WGTA approach that identified actionable alterations in 24/28 patients PMID:24326773.
  • Applied to 26 of 203 multiple myeloma tumor/normal pairs at ~30× average depth; all 26 samples harbored structural variants; enabled identification of SVs and complemented WES-based mutation calling PMID:24434212
  • Applied to 44 rhabdomyosarcoma tumor/normal pairs on Complete Genomics platform at mean 105× depth with 97% genome coverage; identified 553 somatic SVs affecting 419 genes and established the PAX-fusion-positive vs PAX-fusion-negative RMS classification PMID:24436047
  • Low-pass paired-end WGS (6–8× coverage) of 114 bladder carcinoma tumors; identified 3 in-frame FGFR3-TACC3 fusions and 4 ERBB2 rearrangements with different fusion partners; average 22 genomic rearrangements per sample PMID:24476821
  • Referenced in HCC genomic landscape review as part of next-generation sequencing approaches that identified novel HCC driver genes including TERT, ARID1A, ARID2, RPS6KA3, PIK3CA, IRF2, NFE2L2, and KEAP1 PMID:24735922
  • Germline WGS cited as the sequencing approach used for identifying candidate FNHGC predisposition variants in CDH1-negative families, including DOT1L, INSR, FBXO24, and CTNND1 PMID:24816255
  • Low-pass WGS (1-3x coverage) from 100-250 ng input DNA (KAPA LTP / Illumina HiSeq 2000) applied to four FFPE prostate needle biopsies; CNA profiles concordant with high-resolution aCGH, enabling pre-treatment CNA burden assessment PMID:25024180
  • Low-pass WGS (<6x coverage) on 107 tumor/germline pairs from the TCGA gastric adenocarcinoma cohort (stad_tcga_pub) to detect structural rearrangements, including CLDN18-ARHGAP26 and CLDN18-ARHGAP6 interchromosomal fusions PMID:25079317
  • Low-pass WGS on 93 of 230 lung adenocarcinomas (luad_tcga_pub) identified an average of 36 gene-gene/gene-inter-gene rearrangements per tumor; chromothripsis detected in 6/93 (6%); ALK, ROS1, RET fusions detected exclusively in transversion-low tumors PMID:25079552
  • Used to sequence 50 ChRCC tumors (60× tumor / 30× normal) in the TCGA ChRCC project, enabling detection of structural rearrangements at the TERT promoter and kataegis events via Meerkat. PMID:25155756
  • Applied to four CRC primary/metastasis trios (median 87× tumor, 50× normal) at the New York Genome Center to validate MSK-IMPACT findings; confirmed all panel-level calls and revealed genome-wide discordance in heterogeneous cases. PMID:25164765
  • Used in Ewing sarcoma WGS of 112 tumors with matched germline on Illumina HiSeq2000 (median 35× tumor depth); BWA alignment to GRCh37-lite; identified STAG2 (17%), TP53 (7%), and EZH2 as significantly mutated genes PMID:25223734
  • WGS at median 45.1× depth on 47 tumor/xenograft/normal DNA samples from 15 breast cancer PDX series; used to identify somatic SNVs (4.3–27.7×10³ per genome) and SVs driving clonal selection at engraftment PMID:25470049
  • Applied to 3 primary-tumor regions plus 2 matched lymph-node metastases each from 2 gastric adenocarcinoma patients (Pt1: 4,082 nonsilent mutations; Pt2: 287); phylogenetic analysis revealed divergence among primary regions with metastases sharing a common clonal ancestor PMID:25583476
  • High-coverage WGS performed on 29 HNSC tumors as part of TCGA profiling; identified 62 structural aberrations per tumor on average, no recurrent ALK/ROS/RET fusions, and FGFR3-TACC3 fusions in 2 HPV(+) tumors PMID:25631445
  • Deep WGS on 38 melanoma samples plus low-pass WGS on 119 samples enabled identification of structural rearrangements and complex chromothripsis events (ShatterSeek) enriched in Triple-WT subtype. PMID:26091043
  • Whole-genome sequencing used to characterize structural variants and mutational signatures in breast cancer PMID:26168399
  • Whole-genome sequencing used to identify somatic mutations and structural rearrangements in colorectal cancer PMID:26343386
  • Performed on 56 neuroblastomas (39 high-risk, 17 low-risk) with matched normal controls (Illumina HiSeq 2000, 2x100 nt PE, aligned to hg19 with BWA); identified recurrent 5p15.33 breakpoint cluster upstream of TERT in 12/39 (31%) high-risk tumors; average 13.3 non-synonymous mutations per genome PMID:26466568
  • Low-pass WGS on 100 pairs and high-pass on 19 primary prostate adenocarcinomas (TCGA); used to characterize structural variants and mutational burden (median 0.94 mutations/Mb) complementing the primary WES platform PMID:26544944.
  • Used via Complete Genomics cPAL platform (NCBI Build 37) on 21 salivary adenoid cystic carcinoma test-set tumors; enabled discovery of novel MYBL1-NFIB fusions from t(8;9) translocations and diverse MYBL1 rearrangements PMID:26631609.
  • Applied to 14 primary uveal melanoma samples with matched germline; BWA alignment to GRCh37, SAMtools/bcftools variant calling, Janda SV calling, and binocular CNV segmentation; enabled discovery of PLCB4 p.D630Y hotspot and BRCA-like mutational signature in 79% of samples PMID:26683228.
  • Used for alignment to GRCh37-lite in 15 matched primary/recurrent medulloblastoma pairs with germline controls plus 18 pairs without germline (46 total samples); demonstrated <12% shared somatic SNVs/indels between primary and recurrent tumors PMID:26760213.
  • WGS used for telomere-length analysis and TERT-promoter mutation detection in a subset of diffuse gliomas from the TCGA pan-glioma cohort; ATRX-mutant gliomas showed significantly longer telomeres than TERTp-mutant samples (ALT mechanism) PMID:26824661
  • WGS on Illumina HiSeq 2500 (100 bp paired-end) of 20 ACC tumors and primagrafts with reads aligned to hg19 by BWA; rearrangements called with dRanger and BreakPointer; identified MYB super-enhancer hijacking mechanism PMID:26829750
  • WGS of 25 ACC tumor/normal pairs (mean coverage 65.2× tumor / 38.1× normal) on Illumina HiSeq; identified 253 chromosomal rearrangements including 5 novel NFIB fusion partners and Rho-GTPase pathway disruption in 44% of tumors PMID:26862087
  • Whole-genome sequencing data from the BCC/SCC corpus (EGAD0000101525) used as a reference baseline for skin cancer mutation burdens (cSCC mean 50 substitutions/Mb, BCC mean 65 substitutions/Mb) in the NB-UVB surveillance model. PMID:26950094
  • Applied to 40 MRT tumor/normal pairs (median tumor content 88.0%); identified near-universal SMARCB1 biallelic inactivation (39/40 cases), quiet overall genomes (median 612.5 SNVs/case, 0.231 mutations/Mb), and Chr22 as the dominant structural variation locus (9/15 recurrent CNA loci, 22/26 verified gene fusions). PMID:26977886
  • Whole-genome sequencing cited as reference methodology for comprehensive mutation detection in AML; the primary AMLSG study used a targeted 111-gene panel, with WGS noted as context for driver-gene discovery PMID:27276561
  • Whole-genome sequencing used alongside WES and targeted NGS in studies of germline susceptibility and somatic driver characterization in young-onset NSCLC PMID:27346245
  • WGS on N=32 B-ALL cases to identify IGH-DUX4 rearrangements and characterize the genomic landscape of the DUX4/ERG B-ALL subtype. PMID:27776115
  • Low-pass (6–8×) whole-genome sequencing performed on 51 oesophageal cancers as part of the TCGA esophageal/stomach multi-platform study to characterize structural variants PMID:28052061.
  • Performed whole-genome sequencing to comprehensively catalog structural variants and mutational signatures PMID:28373299
  • Used whole-genome sequencing to detect structural variants and mutational signatures in pediatric cancers PMID:28445112
  • Used in the ICGC cholangiocarcinoma cohort (n=71 tumor/normal pairs, average 64.2× depth on Illumina HiSeq X10/2500/2000) to define four etiology-driven molecular subtypes of CCA PMID:28667006
  • Applied across 390 medulloblastoma tumor/normal pairs (200 new + 190 previously published) to map driver events in all four consensus subgroups; identified hotspot KBTBD4 insertions, PRDM6 enhancer-hijacking, and 24 mutational signatures PMID:28726821
  • Applied to 136 of 412 BLCA tumors for deep structural variant and mutation clonality analysis (supplementing WES) PMID:28988769
  • Applied to 37 of 206 TCGA sarcomas to complement WES and characterize structural variants and whole-genome doubling across 6 histologies PMID:29100075
  • Used in the TCGA MC3 project for orthogonal validation of WES-derived somatic calls on 1,059 samples (median 126 validation sites/sample); also used to validate RNA-seq-based fusions via discordant read pairs PMID:29596782
  • Applied to AALE chr_3p-deleted clones (MiSeq low-coverage) processed with HMMCopy and IchorCNA for subclonal copy number, alongside karyotyping to confirm 3p hemizygosity PMID:29622463

Notes

  • Small WGS cohorts in some corpus papers (e.g., n=25 in cHL, 177 in CLL) are repeatedly cited as a limitation for SV and rare-variant inference PMID:35927489 PMID:36723991.
  • HRS-cell WGS in cHL required whole-genome amplification, introducing palindromic SBS artifacts that had to be computationally removed PMID:36723991.

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