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  • br We did not identify a difference in survival based


    We did not identify a difference in survival based on CDX2 immunohistochemical Diphenylterazine status as has been reported previously [6]. Other groups have also reported variable find-ings in terms of CDX2 expression and outcome in colon can-cer [12-15]. The reason for the discordant results is not clear. To exclude an antibody factor, we repeated immunohisto-chemistry with the same antibody used in another study [6] in a subset of our cases (Fig. 4). We found a similar number of CDX2-negative cases in our cohort (11% versus 9%) to the previous study [6]. The rate of CDX2 loss in CRC has been variably reported in the literature from 4% to 29% [6,19,39-41]. The negative effect of CDX2 loss has been suggested to be limited to a specific subgroup of colon cancers with a mes-enchymal gene expression signature [15]. One possible
    explanation for the divergent results may be a larger number of cases with this mesenchymal gene signature in some patient cohorts.
    Our study was powered to detect a difference based on the outcome reported in the previous 2016 study [6]. A very recent Diphenylterazine study has addressed this question using a large cohort of pa-tients with 1157 stage II colon cancer cases and has found a statistically significant but less dramatic effect on outcome with a hazard ratio of 1.54 [42]. Using this effect size, our study would be underpowered to detect a difference in out-come based on CDX2 status in stage II colon cancer. How-ever, in our cohort, Muc2 loss was associated with significantly reduced cancer-specific survival with a hazard ra-tio of 3.32. This suggests that other markers alone or in combi-nation with CDX2 may better predict early-stage colon cancer with a poor prognosis that may benefit from additional therapy.
    Predictive or prognostic biomarkers that test for expression of a gene that is regulated at the level of transcriptional control can be challenging, as they can often result in patchy variable expression detected on immunohistochemistry and do not al-low for testing for genetic changes in equivocal cases. To ad-dress this challenge, we studied a panel of 6 immunohistochemistry markers involved in colonic differenti-ation. We found that CDX2 status in isolation may have lim-ited utility in routine practice to assess for risk in colon cancer. However, Muc2 was identified as a potential marker for prognostication in CRC in our cohort and in gene expres-sion data obtained from the TCGA; the combination of both CDX2 and Muc2 gene expression status was able to identify patients with a worse overall survival and increased rate of dis-ease recurrence from the TCGA database.
    A reproducible but small effect of CDX2 status has been identified in stage II colon cancer patients [6,15,42]; however, our work suggests that Muc2 may be a more effective means of prognostication. Instead of focusing on the expression of one marker by immunohistochemistry, it may be more accu-rate and reproducible to assess gene expression signatures to identify cases of CRC with a more undifferentiated phenotype as reported initially [5]. As next-generation sequencing and RNA-based testing become more prevalent in routine surgical pathology, there may be opportunities to capitalize on this technology to design further trials revising and better defining our prognostic and predictive tools in CRC.
    [3] Benson AB, Schrag D, Somerfield MR, et al. American Society of Clin-ical Oncology recommendations on adjuvant chemotherapy for stage II 
    [5] Merlos-Suárez A, Barriga FM, Jung P, et al. The intestinal stem cell sig-
    CDX2 and Muc2 in stage II colon cancer 79
    [24] Minoo P, Zlobec I, Peterson M, Terracciano L, Lugli A. Characteriza-tion of rectal, proximal and distal colon cancers based on clinico- pathological, molecular and protein profiles. Int J Oncol 2010;37: 707-18.
    [25] Okoń K, Zazula M, Rudzki Z, Papla B, Osuch C, Stachura J. CDX-2 ex-pression is reduced in colorectal carcinomas with solid growth pattern and proximal location, but is largely independent of MSI status. Pol J Pathol 2004;55:9-14.