Clinicopathologic and molecular features of sporadic microsatellite- and chromosomal-stable colorectal cancers.
OBJECTIVE
Chromosomal instability (CIN) and microsatellite instability (MSI) are two major causes of colorectal cancers. Recently, a percentage of colorectal cancers were found to be neither CIN nor MSI. This study was performed to explore whether microsatellite- and chromosomal-stable (MACS) colorectal cancers comprise a substantially distinct subtype.


METHODS
Sixty-nine sporadic colorectal cancers were classified into three subsets according to ploidy and microsatellite instability status: CIN+, MSI+, and MACS. Clinicopathologic, genetic, and epigenetic differences among these three groups were investigated by immunohistochemical analysis of p53, APC, hMLH1, and BAX and methylation study of pl4ARF, hMLH1, p161NK4a MGMT, and MINT1 with methylation-specific polymerase chain reaction.


RESULTS
The 69 cases included 49 CIN+, 7 MSI+, and 13 MACS. MACS were found to differ from CIN+ and MSI+ in three aspects. The clinicopathologic features of MACS were similar to MSI+ but distinguished from CIN+. Comparatively, MACS preferred proximal location and poor differentiation (p < 0.05). An immunohistochemical study demonstrated that MACS had a lower rate of loss of hMLH1 or BAX protein than MSI+ and less loss of APC protein than CIN+. In an epigenetic aspect, both MACS and MSI+ had a high rate of CpG island methylator phenotype (46.2 and 42.9%). However, they differed in the presence of hMLH1 methylation (7.7 vs 57.1%, p < 0.05). Otherwise, compared with CIN+, MACS had a more frequent CpG island methylator phenotype and MINT1 methylation (p < 0.05) and relatively more common p161IK4a methylation with marginal significance (p= 0 .056).


CONCLUSIONS
MACS sporadic colorectal cancers may compose a unique phenotype with distinct clinicopathologic and molecular characteristics.
Cai
Guoxiang
G
Department of Abdominal Surgery, Cancer Hospital, Fudan University, 270 Dong An Road, Shanghai 200032, People's Republic of China.
Xu
Ye
Y
Lu
Hongfen
H
Shi
Yingqiang
Y
Lian
Peng
P
Peng
Junjie
J
Du
Xiang
X
Zhou
Xiaoyan
X
Guan
Zuqing
Z
Shi
Daren
D
Cai
Sanjun
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics*; D004171:Diploidy; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D051028:bcl-2-Associated X Protein / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C494826:BAX protein, human; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D051028:bcl-2-Associated X Protein; D000070957:MutL Protein Homolog 1