Genomic copy‐number alterations of MYC and FHIT genes are associated with survival in esophageal squamous‐cell carcinoma

Esophageal squamous‐cell carcinoma (ESCC) is one of the most common cancers and is associated with a poor prognosis. Studies are warranted on the clinical relevance of its genomic copy‐number alterations (CNA) as prognosticators for ESCC. In the present study, we first screened recurrent CNA by array‐based comparative genomic hybridization using an in‐house focused bacterial artificial chromosome‐based array for 108 loci in 45 ESCC specimens. We detected 14 regions showing recurrent (>20%) CNA (4 losses and 10 gains) by array‐based comparative genomic hybridization in the first cohort. Among them, loss of 3p14.2 and gain of 8q24.21 for the FHIT and MYC genes, respectively, and the accumulation of those two CNA (higher FM‐CNA scores) were significantly associated with a worse overall survival (OS) in the first cohort (P = 0.0273, P = 0.0356 and P = 0.0089, respectively). In the independent validation cohort of 92 resected ESCC cases, loss of FHIT, gain of MYC and higher FM‐CNA scores determined by a quantitative genomic PCR‐based copy‐number analysis were associated with a worse OS (P = 0.0011, P = 0.0104 and P = 0.0008, respectively) and disease‐free survival (P = 0.0038, P = 0.0132 and P = 0.0021, respectively). In addition, the Cox model showed the presence of either CNA to be an independent prognosticator for OS and disease‐free survival in the validation cohort (P = 0.0120 and P = 0.0255, respectively). These results suggest that CNA of MYC and FHIT are poor prognostic markers, and risk stratification based on the copy‐number status of those genes is useful to select the optimal treatment strategy in resected ESCC patients. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02329.x, 2012)

[1]  Q. Zhan,et al.  Genomic alterations with impact on survival in esophageal squamous cell carcinoma identified by array comparative genomic hybridization , 2011, Genes, chromosomes & cancer.

[2]  J. Yokota,et al.  MYC Amplification as a Prognostic Marker of Early-Stage Lung Adenocarcinoma Identified by Whole Genome Copy Number Analysis , 2010, Clinical Cancer Research.

[3]  Derek Y. Chiang,et al.  The landscape of somatic copy-number alteration across human cancers , 2010, Nature.

[4]  J. Luketich,et al.  Esophageal cancer: an update. , 2010, International journal of surgery.

[5]  M. Stratton,et al.  A census of amplified and overexpressed human cancer genes , 2010, Nature Reviews Cancer.

[6]  J. Inazawa,et al.  Identification of PAK4 as a putative target gene for amplification within 19q13.12‐q13.2 in oral squamous‐cell carcinoma , 2009, Cancer science.

[7]  J. Inazawa,et al.  Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. , 2009, Carcinogenesis.

[8]  Mef Nilbert,et al.  Prognostic Impact of Array-based Genomic Profiles in Esophageal Squamous Cell Cancer , 2008, BMC Cancer.

[9]  X. Wang,et al.  DNA methylation and loss of protein expression in esophageal squamous cell carcinogenesis of high-risk area. , 2007, Journal of experimental & clinical cancer research : CR.

[10]  Lan-Jun Zhang,et al.  Negative implication of C-MYC as an amplification target in esophageal cancer. , 2006, Cancer genetics and cytogenetics.

[11]  A. Ohtsu.  Chemoradiotherapy for esophageal cancer: current status and perspectives , 2004, International Journal of Clinical Oncology.

[12]  J. Inazawa,et al.  Comparative genomic hybridization (CGH)‐arrays pave the way for identification of novel cancer‐related genes , 2004, Cancer science.

[13]  K. Chin,et al.  Frequent Silencing of Low Density Lipoprotein Receptor-Related Protein 1B (LRP1B) Expression by Genetic and Epigenetic Mechanisms in Esophageal Squamous Cell Carcinoma , 2004, Cancer Research.

[14]  S. Law,et al.  Chromosomal aberrations in esophageal squamous cell carcinoma among Chinese: gain of 12p predicts poor prognosis after surgery. , 2004, Human pathology.

[15]  T. Hubbard,et al.  A census of human cancer genes , 2004, Nature Reviews Cancer.

[16]  C. Croce,et al.  Allele loss and promoter hypermethylation of VHL, RAR-beta, RASSF1A, and FHIT tumor suppressor genes on chromosome 3p in esophageal squamous cell carcinoma. , 2003, Cancer research.

[17]  B. Klump,et al.  C-myc gene amplification in different stages of oesophageal squamous cell carcinoma: prognostic value in relation to treatment modality. , 2003, Anticancer research.

[18]  Akira Masuda,et al.  Chromosome instability in human lung cancers: possible underlying mechanisms and potential consequences in the pathogenesis , 2002, Oncogene.

[19]  Xin Zhao,et al.  Detection of multiple gene hypermethylation in the development of esophageal squamous cell carcinoma. , 2002, Carcinogenesis.

[20]  M. Oka,et al.  Gain of 5p15 detected by comparative genomic hybridization as an independent marker of poor prognosis in patients with esophageal squamous cell carcinoma. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[21]  M. Oka,et al.  Gain of 5 p 15 Detected by Comparative Genomic Hybridization as an Independent Marker of Poor Prognosis in Patients with Esophageal Squamous Cell Carcinoma 1 , 2002 .

[22]  Chi-Hung Lin,et al.  Comparative genomic hybridization of esophageal squamous cell carcinoma , 2001, Cancer.

[23]  F. Sato,et al.  Loss of fragile histidine triad gene expression is associated with progression of esophageal squamous cell carcinoma, but not with the patient's prognosis and smoking history , 2000, Cancer.

[24]  C. Croce,et al.  Altered expression of Fhit in carcinoma and precarcinomatous lesions of the esophagus. , 2000, Cancer research.

[25]  T. Littlewood,et al.  Action of Myc in vivo - proliferation and apoptosis. , 2000, Current opinion in genetics & development.

[26]  E. Prochownik,et al.  MYC oncogenes and human neoplastic disease , 1999, Oncogene.

[27]  K. Kinzler,et al.  Genetic instabilities in human cancers , 1998, Nature.

[28]  J. Roder,et al.  Ratio of invaded to removed lymph nodes as a predictor of survival in squamous cell carcinoma of the oesophagus , 1994, The British journal of surgery.

[29]  A. Goddard,et al.  Chromosome aberrations and cancer. , 1991, Science.

[30]  A. Knudson.  Hereditary cancer, oncogenes, and antioncogenes. , 1985, Cancer research.