The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer

被引:234
作者
Goel, Ajay
Nagasaka, Takeshi
Arnold, Christian N.
Inoue, Toru
Hamilton, Cody
Niedzwiecki, Donna
Compton, Carolyn
Mayer, Robert J.
Goldberg, Richard
Bertagnolli, Monica M.
Boland, C. Richard
机构
[1] Baylor Univ, Med Ctr, Gastrointestinal Canc Res Lab, Dallas, TX 75246 USA
[2] Baylor Univ, Med Ctr, Dept Internal Med, Div Gastroenterol, Dallas, TX 75246 USA
[3] Baylor Univ, Med Ctr, Baylor Charles A Sammons Canc Ctr, Dallas, TX 75246 USA
[4] Univ Freiburg, Dept Internal Med, Div Gastroenterol, D-7800 Freiburg, Germany
[5] Osaka City Univ, Grad Sch Med, Dept Surg Oncol, Osaka 558, Japan
[6] Baylor Univ, Med Ctr, Inst Hlth Care Res & Improvement, Waco, TX 76798 USA
[7] Duke Univ, Med Ctr, CALGB Stat Ctr, Durham, NC 27706 USA
[8] McGill Univ, Dept Pathol, Montreal, PQ H3A 2T5, Canada
[9] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA
[10] Univ N Carolina, Chapel Hill, NC 27515 USA
[11] Brigham & Womens Hosp, Boston, MA 02115 USA
关键词
D O I
10.1053/j.gastro.2006.09.018
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: The CpG island methylator phenotype (CIMP) is one of the mechanisms involved in colorectal carcinogenesis (CRC). Although CIMP is probably the cause of high-frequency microsatellite instability (MSI-H) sporadic CRCs, its role in microsatellite stable (MSS) tumors is debated. The majority of MSS CRCs demonstrate chromosomal instability (CIN) with frequent loss of heterozygosity (LOH) at key tumor suppressor genes. We hypothesized that the majority of sporadic CRCs without CIN would be associated with CIMP. Methods: We tested 126 sporadic CRCs for MSI and LOH and categorized tumors into MSI, LOH, or MSI-/LOH- subgroups. Methylation status was evaluated using 6 CIMP-related markers (MINT1, MINT2, MINT31, p10(INK4 alpha), p14(ARF) and hMLH1) and 6 tumor suppressor genes (PTEN, TLMP3, RUNX3, HIC1, APC, and RAR beta 2). BRAF V600E mutation analysis was performed using allele-specific polymerase chain reaction and DNA sequencing. Results: We observed frequent methylation at all 12 loci in all CRCs. BRAF V600E mutations correlated with the MSI (P < .0001) and MSI-/LOH- (P = .03) subgroups. MSI and MSI-/ LOH- tumors exhibited more promoter methylation than CRCs with LOH (P < .0001). We also found an inverse correlation between the frequencies of methylation and LOH (rho = -0.36; P < .0001). Conclusions: The associations between methylation frequencies at CIMP-related markers and MSI or MSI-/LOH- sporadic CRCs suggest that the majority of these tumors evolve through CIMP. These findings suggest that CIN and CIMP represent 2 independent and inversely related mechanisms of genetic and epigenetic instability in sporadic CRCs and confirm that MSI cancers arise as a consequence of CIMP.
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页码:127 / 138
页数:12
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