title: c-MYC Copy-Number Gain Is an Independent Prognostic Factor in Patients with Colorectal Cancer.
abstract: BACKGROUND
  The aim of this study was to determine the incidence and clinicopathological significance of c-MYC gene copy-number (GCN) gain in patients with primary colorectal cancer (CRC).
  
  
  METHODS
  The c-MYC GCN was investigated in 367 consecutive CRC patients (cohort 1) by using dual-color silver in situ hybridization. Additionally, to evaluate regional heterogeneity, we examined CRC tissue from 3 sites including the primary cancer, distant metastasis, and lymph-node metastasis in 152 advanced CRC patients (cohort 2). KRAS exons 2 and 3 were investigated for mutations.
  
  
  RESULTS
  In cohort 1, c-MYC gene amplification, defined by a c-MYC:centromere of chromosome 8 ratio ≥ 2.0, was detected in 31 (8.4%) of 367 patients. A c-MYC GCN gain, defined by ≥ 4.0 c-MYC copies/nucleus, was found in 63 (17.2%) patients and was associated with poor prognosis (P = 0.015). Multivariate Cox regression analysis showed that the hazard ratio for c-MYC GCN gain was 2.35 (95% confidence interval, 1.453-3.802; P < 0.001). In a subgroup of stage II-III CRC patients, c-MYC GCN gain was significantly associated with poor prognosis by univariate (P = 0.034) and multivariate (P = 0.040) analyses. c-MYC protein overexpression was observed in 201 (54.8%) out of 367 patients and weakly correlated with c-MYC GCN gain (ρ, 0.211). In cohort 2, the c-MYC genetic status was heterogenous in advanced CRC patients. Discordance between GCN gain in the primary tumor and either distant or lymph-node metastasis was 25.7% and 30.4%, respectively. A similar frequency for c-MYC GCN gain and amplification was observed in CRC patients with both wild-type and mutated KRAS.
  
  
  CONCLUSIONS
  c-MYC GCN gain was an independent factor for poor prognosis in consecutive CRC patients and in the stage II-III subgroup. Our findings indicate that the status of c-MYC may be helpful in predicting the patients' outcome and for managing CRC patients.
authors.affiliation: Department of Pathology, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea.
authors.forename: Kyu Sang
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yoonjin
authors.initials: Y
authors.lastname: Kwak
authors.affiliation: Department of Pathology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Kyung Han
authors.initials: KH
authors.lastname: Nam
authors.affiliation: Department of Surgery, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea.
authors.forename: Duck-Woo
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Surgery, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea.
authors.forename: Sung-Bum
authors.initials: SB
authors.lastname: Kang
authors.affiliation: Department of Pathology, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea; Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Gheeyoung
authors.initials: G
authors.lastname: Choe
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea.
authors.forename: Hye Seung
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D016271:Proto-Oncogene Proteins c-myc