We conducted this study to examine the relation between cyclin D1 expression and patient survival in stage I to IV colon cancer. Cyclin D1 (CCND1
, the official gene symbol) activation has been implicated in colon carcinogenesis (1
), among many other molecular changes. We found that cyclin D1 overexpression was associated with longer survival, independent of patient characteristics and other related molecular variables including p53, p21, p27, KRAS
, LINE-1 methylation, MSI, and the CIMP. All of these characteristics are potential confounders in analysis of tumoral cyclin D1 status and patient survival. Our results indicate that cyclin D1 expression in colon cancer is associated with superior prognosis.
It is very common to hypothesize that oncogene activation (or tumor suppressor inactivation) is associated with aggressive tumor behavior. However, this hypothesis does not always hold true. This is well exemplified by the association between MSI and good prognosis (24
). MSI is known to cause inactivation of a number of tumor suppressors (including TGFBR2
, and many others); yet MSI is associated with better patient outcome. This probably reflects a fundamental molecular difference between MSI-high tumors and non–MSI-high tumors. Our current findings also imply a molecular difference between cyclin D1–positive and cyclin D1–negative tumors. It is well known that colon cancers develop through accumulation of multiple genetic and epigenetic events. Some tumors activate cyclin D1, whereas others do not. In order to acquire malignant characteristics, cyclin D1–negative cancers might have bypassed the necessity of cyclin D1 activation, which might cause more aggressive behavior than cyclin D1–activated cancers. Thus, an aberration of a given oncoprotein such as cyclin D1 or tumor suppressor can be associated with indolent behavior.
Examining molecular changes and prognostic factors is important in colon cancer research (44
). Previous studies have examined the relationship between tumoral cyclin D1 expression and clinical outcome in colon cancer (4
). However, those studies have yielded inconsistent results. Although two studies (4
) have shown that cyclin D1 expression has been associated with poor prognosis, most studies have shown no independent prognostic value of cyclin D1 (7
), and one study has shown good prognosis associated with cyclin D1 expression (6
). A study has reported associations of cyclin D1 expression with MSI, CIMP, and BRAF
), and CIMP, MSI, and BRAF
mutation in colon cancer have been related with clinical outcome (25
). Thus, CIMP, MSI, and BRAF
are potential confounders in analysis of cyclin D1 and clinical outcome. However, none of the previous studies (4
) have examined confounding or modifying effect of these tumoral molecular events. Moreover, most previous studies were limited by small sample sizes (n
< 170), and only 3 studies (11
) examined >170 cases (up to n
= 363; ref. 16
). In the current study, we concurrently examined a number of molecular events, which have been related with both tumoral cyclin D1 expression and patient prognosis. In addition, our study had adequate statistical power with a large number (n
= 602) of stage I to IV colon cancers, and our results have been consistent across the two independent cohort studies.
In addition, we found a potential modifying effect of MSI on the relation between cyclin D1 and clinical outcome in colon cancer. Specifically, compared with tumors that were both MSI-low/MSS (microsatellite stable) and cyclin D1–negative, tumors with either cyclin D1–positive or MSI-high seemed to be associated with lower mortalities. We have previously shown that cyclin D1 expression is associated with MSI, independent of CIMP status (23
). Although the mechanistic link between MSI and cyclin D1 has not been elucidated, it is conceivable that cyclin D1 may exert different effects on tumor behavior according to tumoral MSI status.
There are advantages in using the database of the two independent prospective cohort studies, the Nurses' Health Study and Health Professionals Follow-up Study. Exposure and other clinical information were prospectively collected, and entered into the database blinded to patient and tumoral features, and outcome. Data were updated every 2 years. Cohort participants who developed colon cancer were treated at hospitals throughout the United States. Tumor specimen procurement rate has been ~60%, and there were no significant demographic difference between cases with tumor tissue analyzed and those without tumor tissue analyzed (28
). However, a limitation of this study is that data on cancer treatment were limited. Nonetheless, it is unlikely that chemotherapy use differed according to tumoral cyclin D1 status because such data were not available to patients or treating physicians. In addition, beyond cause of mortality, data on cancer recurrences were not available in these cohorts. Nonetheless, given the median survival for metastatic colon cancer was ~10 to 12 months during much of the time period of this study (27
), colon cancer–specific survival should be a reasonable surrogate for cancer-specific outcomes.
There are currently no standardized methods to assess cyclin D1 in colon cancer. Nonuniformity in methods to evaluate tumoral cyclin D1 expression may contribute to the inconsistent results in the previous studies. Nonetheless, our method yielded highly significant associations between cyclin D1 expression and other related molecular variables (including MSI, CIMP, BRAF, and p21; see ). Moreover, any random misclassification of tumors in terms of cyclin D1 expression would drive our results on patient outcome toward the null hypothesis.
In summary, our large cohort study suggests that cyclin D1 expression is independently associated with good prognosis in colon cancer. Our findings may have considerable clinical implications. Future studies are needed to confirm this association as well as to elucidate exact mechanisms by which cyclin D1 affects tumor behavior.