title: Microsatellite Alterations With Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis.
abstract: OBJECTIVE
  Molecular events that lead to recurrence and/or metastasis after curative treatment of patients with colorectal cancers (CRCs) are poorly understood. Patients with stage II or III primary CRC with elevated microsatellite alterations at selected tetranucleotide repeats and low levels of microsatellite instability (E/L) are more likely to have disease recurrence after treatment. Hypoxia and/or inflammation not only promote metastasis, but also induce elevated microsatellite alterations at selected tetranucleotide repeats by causing deficiency of MSH3 in the cancer cell nucleus. We aimed to identify genetic alterations associated with metastasis of primary colorectal tumors to liver and to determine their effects on survival.
  
  
  METHODS
  We obtained 4 sets of primary colorectal tumors and matched liver metastases from hospitals in Korea and Japan. Intragenic microsatellites with large repeats at 141 loci were examined for frame-shift mutations and/or loss of heterozygosity (LOH) as possible consequences of MSH3 deficiency. Highly altered loci were examined for association with E/L in liver metastases. We analyzed data from 156 of the patients with stage II or III primary colorectal tumors to determine outcomes and whether altered loci were associated with E/L.
  
  
  RESULTS
  LOH at several loci at chromosome 9p24.2 (9p24.2-LOH) was associated with E/L in liver metastases (odds ratio = 10.5; 95% confidence interval: 2.69-40.80; P = .0007). We found no significant difference in the frequency of E/L, 9p24.2-LOH, mutations in KRAS or BRAF, or the combination of E/L and 9p24.2-LOH, between primary colorectal tumors and their matched metastases. Patients with stage II or III colorectal tumors with E/L and 9p24.2-LOH had increased survival after CRC recurrence (hazard ratio = 0.25; 95% CI: 0.12-0.50; P = .0001), compared with patients without with E/L and 9p24.2-LOH. E/L with 9p24.2-LOH appeared to be an independent prognostic factor for overall survival of patients with stage III CRC (hazard ratio = 0.06; 95% CI: 0.01-0.57; P = .01).
  
  
  CONCLUSIONS
  E/L with 9p24-LOH appears to be a biomarker for less aggressive metastasis from stage III primary colorectal tumors.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas. Electronic address: mkoi@med.Umich.edu.
authors.forename: Minoru
authors.initials: M
authors.lastname: Koi
authors.affiliation: Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
authors.forename: Melissa
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Department of Pathology, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Chan
authors.initials: C
authors.lastname: Choi
authors.affiliation: Department of Surgery, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Hyeong-Rok
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Surgery, Toho University Faculty of Medicine, Tokyo, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Koike
authors.affiliation: Department of Molecular Immunology, Toho University Faculty of Medicine, Tokyo, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Hemmi
authors.affiliation: Department of Gastroenterological Surgery and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagasaka
authors.affiliation: Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas; Department of Gastrointestinal and Pediatric Surgery, Graduate School of Medicine Mie University, Mie, Japan.
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Okugawa
authors.affiliation: Department of Gastrointestinal and Pediatric Surgery, Graduate School of Medicine Mie University, Mie, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Toiyama
authors.affiliation: Department of Gastrointestinal and Pediatric Surgery, Graduate School of Medicine Mie University, Mie, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Kitajima
authors.affiliation: Department of Gastrointestinal and Pediatric Surgery, Graduate School of Medicine Mie University, Mie, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Imaoka
authors.affiliation: Department of Gastrointestinal and Pediatric Surgery, Graduate School of Medicine Mie University, Mie, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kusunoki
authors.affiliation: Department of Biostatistics School of Public Health, University of Michigan, Ann Arbor, Michigan.
authors.forename: Yin-Hsiu
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Biostatistics School of Public Health, University of Michigan, Ann Arbor, Michigan.
authors.forename: Bhramar
authors.initials: B
authors.lastname: Mukherjee
authors.affiliation: Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas. Electronic address: RickBo@BaylorHealth.edu.
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. Electronic address: jcarethe@med.umich.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Carethers
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D016009:Chi-Square Distribution; D002869:Chromosome Aberrations; D002899:Chromosomes, Human, Pair 9; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary* / Q000601:surgery; D016015:Logistic Models; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D016017:Odds Ratio; D010641:Phenotype; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D056910:Republic of Korea; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Colon Cancer; Microsatellite Instability; Progression; Recurrence