title: Molecular profile and copy number analysis of sporadic colorectal cancer in Taiwan.
abstract: BACKGROUND
  Colorectal cancer (CRC) is a major health concern worldwide, and recently becomes the most common cancer in Asia. The case collection of this study is one of the largest sets of CRC in Asia, and serves as representative data for investigating genomic differences between ethnic populations. We took comprehensive and high-resolution approaches to compare the clinicopathologic and genomic profiles of microsatellite instability (MSI) vs. microsatellite stability (MSS) in Taiwanese sporadic CRCs.
  
  
  METHODS
  1,173 CRC tumors were collected from the Taiwan population, and sequencing-based microsatellite typing assay was used to determine MSI and MSS. Genome-wide SNP array was used to detect CN alterations in 16 MSI-H and 13 MSS CRCs and CN variations in 424 general controls. Gene expression array was used to evaluate the effects of CN alterations, and quantitative PCR methods were used to replicate the findings in independent clinical samples.
  
  
  RESULTS
  These 1,173 CRC tumors can be classified into 75 high-frequency MSI (MSI-H) (6.4%), 96 low-frequency MSI (8.2%) and 1,002 MSS (85.4%). Of the 75 MSI-H tumors, 22 had a BRAF mutation and 51 showed MLH1 promoter hypermethylation. There were distinctive differences in the extent of CN alterations between CRC MSS and MSI-H subtypes (300 Mb vs. 42 Mb per genome, p-value < 0.001). Also, chr7, 8q, 13 and 20 gains, and 8p and 18 losses were frequently found in MSS but not in MSI-H. Nearly a quarter of CN alterations were smaller than 100 kb, which might have been missed in previous studies due to low-resolution technology. 514 expressed genes showed CN differences between subtypes, and 271 of them (52%) were differentially expressed.
  
  
  CONCLUSIONS
  Sporadic CRCs with MSI-H displayed distinguishable clinicopathologic features, which differ from those of MSS. Genomic profiling of the two types of sporadic CRCs revealed significant differences in the extent and distribution of CN alterations in the cancer genome. More than half of expressed genes showing CN differences can directly contribute to their expressional diversities, and the biological functions of the genes associated with CN changes in sporadic CRCs warrant further investigation to establish their possible clinical implications.
authors.affiliation: Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Chien-Hsing
authors.initials: CH
authors.lastname: Lin
authors.forename: Jen-Kou
authors.initials: JK
authors.lastname: Lin
authors.forename: Shih-Ching
authors.initials: SC
authors.lastname: Chang
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chang
authors.forename: Hwey-May
authors.initials: HM
authors.lastname: Chang
authors.forename: Jin-Hwang
authors.initials: JH
authors.lastname: Liu
authors.forename: Ling-Hui
authors.initials: LH
authors.lastname: Li
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
authors.forename: Shih-Feng
authors.initials: SF
authors.lastname: Tsai
authors.forename: Wei-Shone
authors.initials: WS
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000368:Aged; D015179:Colorectal Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D005260:Female; D052138:Genes, Neoplasm; D006801:Humans; D008297:Male; D008745:Methylation; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013624:Taiwan
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1