title: Hotspot mutation panel testing reveals clonal evolution in a study of 265 paired primary and metastatic tumors.
abstract: OBJECTIVE
  We used a clinical next-generation sequencing (NGS) hotspot mutation panel to investigate clonal evolution in paired primary and metastatic tumors.
  
  
  METHODS
  A total of 265 primary and metastatic tumor pairs were sequenced using a 46-gene cancer mutation panel capable of detecting one or more single-nucleotide variants as well as small insertions/deletions. Mutations were tabulated together with tumor type and percentage, mutational variant frequency, time interval between onset of primary tumor and metastasis, and neoadjuvant therapy status.
  
  
  RESULTS
  Of note, 227 of 265 (85.7%) tumor metastasis pairs showed identical mutation calls. Of the tumor pairs with identical mutation calls, 160 (60.4%) possessed defining somatic mutation signatures and 67 (25.3%) did not exhibit any somatic mutations. There were 38 (14.3%) cases that showed at least one novel mutation call between the primary and metastasis. Metastases were almost two times more likely to show novel mutations (n = 20, 7.5%) than primary tumors (n = 12, 4.5%). TP53 was the most common additionally mutated gene in metastatic lesions, followed by PIK3CA and SMAD4. PIK3CA mutations were more often associated with metastasis in colon carcinoma samples.
  
  
  CONCLUSIONS
  Clinical NGS hotspot panels can be useful in analyzing clonal evolution within tumors as well as in determining subclonal mutations that can expand in future metastases. PIK3CA, SMAD4, and TP53 are most often involved in clonal divergence, providing potential targets that may help guide the clinical management of tumor progression or metastases.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rashmi S
authors.initials: RS
authors.lastname: Goswami
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Keyur P
authors.initials: KP
authors.lastname: Patel
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rajesh R
authors.initials: RR
authors.lastname: Singh
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: E Scott
authors.initials: ES
authors.lastname: Kopetz
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ricardo H
authors.initials: RH
authors.lastname: Alvarez
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kausar J
authors.initials: KJ
authors.lastname: Jabbar
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sinchita
authors.initials: S
authors.lastname: Roy-Chowdhuri
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. mark.routbort@mdanderson.org.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Routbort
mesh_terms: D058534:Class I Phosphatidylinositol 3-Kinases; D060965:Clonal Evolution / Q000235:genetics*; D004252:DNA Mutational Analysis; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051901:Smad4 Protein / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C497796:SMAD4 protein, human; D051901:Smad4 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human