title: High-depth sequencing of over 750 genes supports linear progression of primary tumors and metastases in most patients with liver-limited metastatic colorectal cancer.
abstract: BACKGROUND
  Colorectal cancer with metastases limited to the liver (liver-limited mCRC) is a distinct clinical subset characterized by possible cure with surgery. We performed high-depth sequencing of over 750 cancer-associated genes and copy number profiling in matched primary, metastasis and normal tissues to characterize genomic progression in 18 patients with liver-limited mCRC.
  
  
  RESULTS
  High depth Illumina sequencing and use of three different variant callers enable comprehensive and accurate identification of somatic variants down to 2.5% variant allele frequency. We identify a median of 11 somatic single nucleotide variants (SNVs) per tumor. Across patients, a median of 79.3% of somatic SNVs present in the primary are present in the metastasis and 81.7% of all alterations present in the metastasis are present in the primary. Private alterations are found at lower allele frequencies; a different mutational signature characterized shared and private variants, suggesting distinct mutational processes. Using B-allele frequencies of heterozygous germline SNPs and copy number profiling, we find that broad regions of allelic imbalance and focal copy number changes, respectively, are generally shared between the primary tumor and metastasis.
  
  
  CONCLUSIONS
  Our analyses point to high genomic concordance of primary tumor and metastasis, with a thick common trunk and smaller genomic branches in general support of the linear progression model in most patients with liver-limited mCRC. More extensive studies are warranted to further characterize genomic progression in this important clinical population.
authors: Iain Beehuat
authors: IB
authors: Tan
authors: Simeen
authors: S
authors: Malik
authors: Kalpana
authors: K
authors: Ramnarayanan
authors: John R
authors: JR
authors: McPherson
authors: Dan Liang
authors: DL
authors: Ho
authors: Yuka
authors: Y
authors: Suzuki
authors: Sarah Boonhsui
authors: SB
authors: Ng
authors: Su
authors: S
authors: Yan
authors: Kiat Hon
authors: KH
authors: Lim
authors: Dennis
authors: D
authors: Koh
authors: Chew Min
authors: CM
authors: Hoe
authors: Chung Yip
authors: CY
authors: Chan
authors: Rachel
authors: R
authors: Ten
authors: Brian Kp
authors: BK
authors: Goh
authors: Alexander Yf
authors: AY
authors: Chung
authors: Joanna
authors: J
authors: Tan
authors: Cheryl Xueli
authors: CX
authors: Chan
authors: Su Ting
authors: ST
authors: Tay
authors: Lezhava
authors: L
authors: Alexander
authors: Niranjan
authors: N
authors: Nagarajan
authors: Axel M
authors: AM
authors: Hillmer
authors: Choon Leong
authors: CL
authors: Tang
authors: Clarinda
authors: C
authors: Chua
authors: Bin Tean
authors: BT
authors: Teh
authors: Steve
authors: S
authors: Rozen
authors: Patrick
authors: P
authors: Tan
mesh_terms: D000465:Algorithms; D000483:Alleles; D022981:Allelic Imbalance / Q000235:genetics; D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019295:Computational Biology; D018450:Disease Progression; D005787:Gene Frequency / Q000235:genetics; D052138:Genes, Neoplasm; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009378:Neoplasms, Multiple Primary / Q000235:genetics