In this large cohort of patients with colon cancer, we found that tumoral FASN overexpression was a significant predictor of reduced cancer-specific mortality, independent of various clinical and molecular variables including tumor stage and statuses of MSI, KRAS, BRAF, and p53. Moreover, the improved outcome associated with FASN overexpression was similar across strata of most patient and disease characteristics and was consistent across the two independent prospective cohort studies in this analysis.
Notably, the effect of FASN overexpression on clinical outcome seemed to be modified by patient BMI. Among normal weight and minimally overweight patients (BMI < 27.5 kg/m2
), FASN overexpression was associated with a reduction in mortality, whereas among moderately overweight and obese patients (BMI ≥ 27.5 kg/m2
), FASN overexpression conferred a significant increased in mortality. Similar findings on FASN expression, BMI, and survival were observed among patients with prostate cancer in the Health Professionals Follow-Up Study and Physicians Health Study cohorts (Nguyen et al, unpublished data). These data suggest that influence of FASN overexpression differs substantially according to the host milieu in which the overexpression occurs. Moreover, consistent with other studies among patients with colon cancer,6-9
higher BMI was associated with an increased mortality, although the deleterious effect of obesity was limited to patients with FASN overexpression.
FASN has been implicated in cancer pathogenesis.1,10
FASN inhibitors, such as C75 and orlistat, have been shown to exhibit antitumor activity.21,22,37
Downregulation of FASN through its enhanced proteasomal degradation results in increased apoptosis, indicating an addiction of tumor cells to FASN.20
Recent data suggest that increased FASN activity in tumor cells is important for function of endoplasmic reticulum to maintain membrane biogenesis.38
These data collectively support that FASN acts as an oncoprotein. In fact, FASN overexpression is commonly observed in human cancers,10,13-15
including colon cancer.16,18,19
Importantly, FASN overexpression confers chemoresistance in breast cancer cells, and inhibition of FASN may enhance the effect of chemotherapy.39,40
FASN overexpression has been reported to confer a significantly worse outcome in patients with breast, ovarian, lung, and prostate cancers,1,13-15
although none of these studies assessed patient BMI. Among patients with colorectal cancer, no significant relation between FASN expression and survival was demonstrated in two smaller studies.16,18
Potential prognostic factors and markers have been investigated in colon cancer.41-46
Dietary factors and altered energy balance represent important risk factors for cancer incidence, recurrence, and death.7-9
Among patients with colon cancer, obesity has been associated with poor clinical outcome.7-9
However, mechanisms of how obesity or altered energy balance influence cancer prognosis are poorly understood. Accumulating evidence suggests that FASN may play a role in the link between dietary and energy factors and pathogenesis of neoplasia; FASN is regulated by energy balance and FASN alterations seem to be important in carcinogenesis.1,10,11
Our current results are particularly intriguing in that the negative influence of obesity on survival may be limited to patients with FASN-overexpressing tumors. Our data support the importance of FASN in determining biologic behavior of colon cancer as well as a significant interaction between energy balance and tumor biology on clinical outcome. One may speculate that colon cancer cells with FASN upregulation may depend on excess energy for growth, leading to more aggressive tumor behavior among obese patients.
Although FASN has been considered to act as an oncoprotein,20-22,37
its overexpression seems to mark a subtype of colon cancer that is associated with indolent behavior among relatively normal-weight patients. It should be noted that upregulation of a particular oncoprotein or downregulation of a particular tumor suppressor does not necessarily imply a poor clinical outcome.47
For example, although MSI has been shown to mutate and inactivate a number of tumor suppressors, leading to cancer development, MSI-high colon cancer has been consistently associated with better outcome.48,49
It is plausible that, among normal-weight patients, colon cancer without FASN upregulation develops through an alternative nonenergy dependent pathway, which is associated with poor clinical outcome.
Our study has several advantages, including a large number of colon cancers derived from the two prospective cohorts as well as extensive data on patient characteristics, disease characteristics, and other important tumoral molecular events. Thus we have been able to demonstrate an effect of FASN on patient survival, independent of clinical and other tumoral characteristics.
In our cohorts, data on cancer treatment were limited. Nonetheless, it is unlikely that chemotherapy use differed according to tumoral FASN status, especially 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. However, given that the median survival for metastatic colon cancer was 10 to 12 months during much of the time period of this study,5
colon cancer–specific survival should be a reasonable surrogate for cancer-specific outcomes.
To date, there is no standardized classification scheme for FASN expression in colon cancer. Nevertheless, previous studies have demonstrated that the results of mRNA expression microarray and immunoblot analyses correlate well with immunohistochemical grading of FASN.13,50
In validation studies of the central, blinded review of tumor specimens, we observed substantial interobserver agreement (93%). Moreover, any random misclassification of FASN overexpression would be expected to bias our results toward the null hypothesis.
In conclusion, this large prospective study of patients with colon cancer suggests that FASN upregulation is a significant independent predictor of improved survival among nonobese patients with colon cancer, whereas among moderately overweight or obese patients (BMI ≥ 27.5 kg/m2), FASN overexpression may predict a worse outcome. Concurrently, the influence of obesity on patient survival may be modified by tumoral FASN expression. Our finding may have significant clinical implications and may offer a potential mechanism by which excess energy balance may influence tumorigenesis and cancer progression.