We conducted this study to examine the prognostic significance of mononucleotide tract mutations in the coding regions of TGFBR2
in MSI-high colorectal cancers. We utilized two prospective cohort studies with a large number of clinically and molecularly well-annotated colorectal cancer cases with adequate follow-up. Our result showed that MSI-high tumors were associated with indolent tumor behavior regardless of TGFBR2
mononucleotide mutation status, independent of CIMP and other key tumor molecular biomarkers. Nonetheless, it may be of interest to examine interactions between these molecular alterations and dietary and lifestyle factors if there is a hypothesis in evolving science of molecular pathological epidemiology 
It should be noted that small studies are more prone to “publication bias” than large studies 
. This phenomenon of publication bias occurs because studies with null findings have a higher likelihood of being unwritten and unpublished compared to those with significant results. Compared to small studies (e.g., studies with a sample size of <200 cancers) with null data, large studies with null data are more likely published. As a result, large studies are less prone to publication bias than small studies. Furthermore, academic pressures might force investigators to design small studies which are easy to complete and get data for haste publications, which might contribute to bias 
. Therefore, we should weigh more on large-scale studies when we evaluate the published literature on prognostic significance of any biomarker such as TGFBR2
mononucleotide mutation. Publishing null data in well-powered studies 
are important because publishing significant results in small underpowered studies leads to publication bias.
Our data are generally consistent with some of previous studies 
(). Watanabe et al. 
used stage II and III cases that underwent adjuvant chemotherapy, and reported that, TGFBR2
mutation was associated with improved 5-year overall survival among 73 MSI-high tumors. In another study 
, among 67 MSI-high tumors, BAX
mutation was associated with poor prognosis. In an underpowered study by Fernández-Peralta et al. 
, among 16 MSI-high tumors, both TGFBR2
mutation and BAX
mutation were associated with better prognosis. The largest study (total N
1427; 170 MSI-high cancers) by Samowitz et al. 
showed no prognostic role of TGFBR2
mutations among MSI-high colorectal cancer cases, in agreement with our current study - the second largest study to date and the only study which examined other key tumor molecular biomarkers such as CIMP, LINE-1 methylation and KRAS
Studying somatic molecular changes and molecular correlates is important in cancer research towards personalized medicine 
. The CpG island methylator phenotype (CIMP) has been established as an epigenomic molecular classifier of colorectal cancer 
. In the past, Iacopetta et al. 
showed no significant association between KRAS
mutation and TGFBR
2 mutation. We assessed the association between tumor molecular variables (CIMP, LINE-1, KRAS
) and TGFBR2
mutation and did not find significant relation between TGFBR2
mutation and KRAS
mutation. Interestingly, we have found that, among MSI-high tumors, TGFBR
2 mutation was associated with CIMP-high, independent of clinical and other molecular features. A recent study 
has reported that genetic variants in the TGFB1 pathway related genes (MAPK1
) are associated with CIMP-high colon cancer. Further studies are needed to elucidate the exact mechanism of the relationship between CIMP and the TGFB1 pathway.
There are limitations in this study. For example, data on cancer treatment were limited. Nonetheless, it is unlikely that chemotherapy use substantially differed according to TGFBR2 or BAX mutation status in tumor, since such data were typically unavailable for treatment decision making. As another limitation, beyond cause of mortality, data on cancer recurrences were unavailable in these cohort studies. Nonetheless, given median follow-up of over 11 years for censored cases, colorectal cancer-specific survival might be a reasonable surrogate of colorectal cancer-specific outcome.
There are advantages in utilizing the database of the two prospective cohort studies, the Nurses' Health Study and the Health Professionals Follow-up Study, to examine prognostic significance of tumor biomarkers. Anthropometric measurements, family history, cancer staging, and other clinical, pathologic, and tumor molecular data were prospectively collected, blinded to patient outcome 
. Cohort participants who developed cancer were treated at hospitals throughout the U.S., and thus more representative colorectal cancers in the U.S. population than patients in one to a few academic hospitals. There were no demographic difference between cases with tumor tissue analyzed and those without tumor tissue analyzed 
. Finally, our rich tumor database enabled us to simultaneously assess pathologic and tumor molecular correlates and control for potential confounding by the tumor molecular features.
In conclusion, our large tumor database has shown that, compared to MSS/MSI-low cases, MSI-high colorectal cancer is associated with longer cancer-specific survival, regardless of TGFBR2 or BAX mononucleotide tract mutation status. The importance of large-scale studies cannot be overemphasized because, compared to large studies, small studies are much more prone to publication bias, which can mislead clinical practice.