We performed this study to examine the prognostic significance of 18q LOH in non–MSI-high colorectal cancer. Because 18q LOH and MSI high are almost mutually exclusive,5
and MSI high is associated with better outcome,17
the association between 18q LOH and poor prognosis might be simply due to the enrichment of MSI-high tumors within 18q LOH-negative cases. Thus it is necessary to examine 18q LOH status in non–MSI-high colorectal cancers to assess the independent prognostic significance of 18q LOH. We found that 18q LOH was not associated with survival among 532 patients with non–MSI-high colorectal cancer. Moreover, the presence of 18q LOH did not significantly influence patient survival within any individual stratum of pathologic stage or any stratum of clinical and molecular predictors of patient outcome.
Examining prognostic factors is important in colon cancer research.39-43
The presence of 18q LOH was associated with recurrence or mortality in colorectal cancer in earlier studies.5,8,9,16,44,45
However, many of the previous studies on prognostic significance of 18q LOH8,9,12,16
did not consider a confounding effect of MSI. Moreover, a meta-analysis on 18q LOH and outcome in colorectal cancers demonstrated evidence for publication bias.18
Large studies (total N > 300) could be published even with null results,13-15
whereas smaller studies were selected for publication based on “significant” results. Smaller studies with nonsignificant results experienced a higher likelihood of being unpublished, leading to publication bias toward a deviation from the null hypothesis.
In the largest study to date, Roth et al15
failed to show independent prognostic significance of 18q LOH in more than 1,200 patients with stage II and III colon cancer. Our current study (N = 532 non–MSI-high tumors), the second largest to date, is in agreement with Roth et al,15
as well as the two other large studies conducted by Halling et al13
(N = 432 non–MSI-high tumors) and Barratt et al14
(N = 279 non–MSI-high tumors). Although, in univariate analyses,Barratt et al14
found an improved survival with 18q LOH and Roth et al15
reported an inferior survival in the subset of patients with stage II cancer, both studies found that the prognostic influence of 18q LOH was no longer apparent in multivariate analyses that adjusted for MSI and other relevant parameters. In notable exception, Watanabe et al5
obtained informative 18q LOH data in 279 colon cancers and showed that 18q LOH was independently associated with poor outcome. Moreover, Watanabe et al5
found a significant relation between 18q LOH and poor survival in stage III non–MSI-high tumors (N = 148), although no such relation was found in stage II tumors. We should be aware that all of these large studies5,13-15
(including our study) used different markers and criteria, which could confound the results and cause the somewhat discrepant findings. It would be necessary to develop a consensus panel to assess 18q LOH in colorectal cancer in future trials. Nonetheless, the frequencies of 18q LOH seem relatively comparable between these investigations. Moreover, we demonstrated the significant associations of 18q LOH with JCVT, KRAS
, and LINE-1 hypomethylation, supporting the validity of our 18q LOH assessment. LINE-1 hypomethylation and JCVT have previously been related with chromosomal instability.29,31,46-49
We recognize potential limitations in our analysis. Data on cancer treatment in our cohorts were limited. Nonetheless, it is unlikely that use of chemotherapy considerably differed according to 18q LOH status, because such data were not typically available for treatment decision making. In addition, beyond cause of mortality, data on cancer recurrences were not available in these cohorts. Nonetheless, given that the median survival for metastatic colon cancer was approximately 10 to 12 months during much of the time period of this study,37
colorectal cancer–specific survival should be a reasonable surrogate for cancer-specific outcomes.
There are advantages in using the database of the two independent prospective cohort studies, the Nurses' Health Study and Health Professionals Follow-Up Study, to examine prognostic significance of 18q LOH and its relationship with tumoral and host factors. Anthropometric measurements, family history of cancer, other clinical information, pathologic and tumor staging data, and tumoral molecular features were prospectively collected and entered into the database, blinded to patient outcome. Cohort participants who developed colorectal cancer were treated at hospitals throughout the United States and thus were more representative of colorectal cancers in the general population than studies based on a single to few hospitals. Tumor specimen procurement rate has been approximately 60%, and there were no demographic differences between cases with tumor tissue analyzed and those without tumor tissue analyzed.20
In addition, our extensive database of clinical, pathologic, and molecular features enabled us to simultaneously adjust for other predictors of patient outcome.
Beyond the influence of 18q LOH on patient prognosis, there remain limited data on the ability of 18q LOH to predict the benefit from treatment. Among the aforementioned large, published studies that assessed the prognostic significance of 18q LOH,5,13-15
only the study by Barratt et al14
examined whether 18q LOH predicted benefit from fluorouracil-based adjuvant therapy. For patients with LOH at one 18q locus (D18S61), adjuvant fluorouracil did not improve survival, whereas among subjects with no LOH at D18S61, adjuvant fluorouracil did confer a significant survival benefit (Pinteraction
An ongoing, large clinical trial (Eastern Cooperative Oncology Group Trial 5202) is prospectively examining whether MSI and 18q LOH can define the optimal use of postoperative adjuvant chemotherapy in patients with curatively resected stage II colon cancer. In that study, patients with either MSI-high tumors or non–MSI-high tumors with retention of 18q will not receive postoperative therapy. In contrast, patients with non–MSI-high tumors that demonstrate 18q LOH will receive postoperative chemotherapy (fluorouracil, leucovorin, and oxaliplatin) with or without bevacizumab.
In summary, our large cohort study did not find a significant prognostic impact for 18q LOH in patients with colorectal cancer or any subset of this study population. Future studies are needed to confirm these results.