Correlation analysis between loss of heterozygosity at chromosome 18q and prognosis in the stage-II colon cancer patients.
OBJECTIVE
Colorectal cancer is one of the most common malignant cancers in the world. Although the clinicopathologic staging is the golden criterion for the prognosis at present, the optimum prognostic criteria for colorectal cancer should be a combination of the clinicopathologic staging and the molecular markers. However, there are currently no molecular markers available for the prognosis of colorectal cancer. Several tumor-suppressor genes associated with colorectal cancer have been mapped at the 18q21-23 region. In this study we detected the frequency of loss of heterozygosity (LOH) at chromosome 18q and investigated the relationship between LOH and clinicopathologic features and its prognostic value for patients with stage II colon cancer.


METHODS
A total of 106 samples of tumor tissues and corresponding normal mucosa from patients with sporadic stage-II colon cancer were included in this study. All the samples were formalin-fixed and paraffin-embedded. DNA was extracted from tumor tissues and LOH of D18S474, D18S55, D18S58, D18S61 and D18S64 at chromosome 18q was analyzed using polymerase chain reaction (PCR), polyacrylamide gel-electrophoresis, and DNA sequencing method. Multivariate analysis for association between LOH and prognosis in colon cancer patients was performed with Cox proportional hazards regression model.


RESULTS
The median follow-up time was 68 months. For 106 patients, 5-year survival rate was 83.6%, which was associated with age and gross tumor type (P = 0.011 and 0.034, respectively). Among 102 patients who were eligible for LOH information, the overall frequency of LOH is 49.0% (50/102), and that of LOH at 5 microsatellite loci of D18S474, D18S55, D18S58, D18S61, and D18S64 was 30.2% (26/86), 23.4% (18/77), 28.6% (20/70), 35.0% (28/80), and 20.8%(15/72), respectively. The occurrence of LOH was significantly associated with tumor location and histopathologic grade (P = 0.023, 0.016 and 0.005, respectively). LOH was more frequent on the left-side, poorly-differentiated adenocarcinoma, and nonmucinous colon cancers. The occurrence of 18q-LOH was significantly associated with 5-year overall survival rate and disease free survival rate (P = 0.008 and 0.006, respectively). The occurrence of 18q-LOH at the loci of D18S474 and D18S61 was significantly associated with 5-year overall survival rate (P = 0.010 and 0.005, respectively). The multivariate analysis showed that only the occurrence of 18q-LOH was significantly associated with prognosis (P = 0.021).


CONCLUSIONS
There is a high occurrence of LOH at the loci of 18q. The expression of LOH is significantly associated with tumor location and histopathologic grade. The occurrence of 18q-LOH is an independent poor prognostic factor for the patients with stage-II colon cancer.
Wang
Wei
W
State Key Labortary of Oncology in South China, Guangzhou, Guangdong 510060, P. R. China.
Li
Yuan-Fang
YF
Sun
Xiao-Wei
XW
Chen
Gong
G
Zhan
You-Qing
YQ
Huang
Chun-Yu
CY
Wan
De-Sen
DS
Pan
Zhi-Zhong
ZZ
Zhou
Zhi-Wei
ZW
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000473:pathology / Q000601:surgery; D000231:Adenocarcinoma, Papillary / Q000235:genetics / Q000473:pathology / Q000601:surgery; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D015996:Survival Rate; D055815:Young Adult