In this study, we showed that the status of chromosome 18q in tumors with microsatellite stability and of the gene for the type II receptor for TGF-β1 in tumors with high levels of microsatellite instability could be used to predict the likelihood of survival in patients with stage III colon cancer who received fluorouracil-based adjuvant chemotherapy. We do not know whether these markers reflect resistance or sensitivity to fluorouracil or inherent differences in the biologic characteristics of the tumors.
but not all15,29,52,53
previous studies, loss of heterozygosity at 18q was an indicator of a poor prognosis in patients with stage II cancer, patients with stage III cancer, or both groups. This loss usually involves the DCC
gene, but there are numerous other genes in the deleted region. The product of the DCC
gene is the netrin-1 receptor, which guides the migration of neuronal axons.54–57
In colon cancer, loss of DCC
is associated with metastasis and an adverse prognosis.58–61
If it does not bind to netrin-1, the DCC protein triggers apoptosis.62
For this reason, loss of DCC
as a result of loss of 18q could impair apoptosis, thereby conferring resistance to chemotherapy. The absence of an association between survival and loss of heterozygosity at 8p or 17p suggests that loss of heterozygosity at 18q is a specific marker for survival and not simply a reflection of generalized chromosomal instability.
Our study confirmed the concordance between allelic loss at chromosome 18q and allelic loss at 17p.16
Although alteration of p53
is a plausible predictive marker,15,33,34,63–69
we found no significant relation between survival and the status of the p53
gene or p53 protein. Another study, however, found a higher rate of seven-year survival after adjuvant therapy with fluorouracil and levamisole in patients who had cancer without increased levels of p53 protein than in those who had cancer with increased p53 levels.36
The explanation for these discrepant results in patients in the same clinical trial is not apparent.
protein is a downstream effector of the p53 protein,70,71
and we found an inverse relation between p53 and p21WAF1/CIP1
in colon cancer, as has been reported previously.72,73
Despite the importance of p21WAF1/CIP1
for in vitro responses to chemotherapeutic agents35
and the report that increased levels of p21WAF1/CIP1
were associated with chemosensitivity of metastatic colorectal cancer,74
pretreatment levels of this protein were not related to survival in our study.
A mutation of the gene that encodes the type II receptor for TGF-β
1 in cancers with high levels of microsatellite instability was associated with a favorable outcome, but the mechanism of this effect is uncertain. High levels of microsatellite instability improve the prognosis15,26–33
and may also increase the likelihood of survival after chemotherapy.37,38
Because cancers with high levels of microsatellite instability usually retain 18q alleles, loss of heterozygosity in such tumors is unlikely to be a determinant of outcome after adjuvant chemotherapy. The TGF-β
1 pathway inhibits tumor proliferation by blocking the cell cycle late in the G1 (gap 1) phase,75,76
so continued proliferation due to mutation of the gene for the type II receptor for TGF-β
1 could increase susceptibility to chemotherapy. However, colon-cancer cell lines that are deficient in mismatch-repair activity and that have high levels of microsatellite instability are relatively resistant to fluorouracil in vitro.77
We find that specific molecular markers in resected stage III colon cancer can be used to predict survival after adjuvant fluorouracil-based regimens. Prospective studies are needed to determine whether newer chemotherapeutic agents, such as irinotecan78
and oxaliplatin, would benefit patients with stage III cancer whose tumors have molecular markers associated with a reduced efficacy of fluorouracil-based regimens. Our study is a first step toward the goal of individualized cancer treatment based on the molecular characteristics of the tumor.