ABSTRACT
The prognostic value of microsatellite instability (MSI), as well as other histological characteristics such as lymphovascular invasion (LI), perineural invasion (PNI) and extramural vascular invasion (EMVI), is unclear in colorectal mucinous carcinoma (MC). This study aims to determine the relevance of these factors in MC patients and analyses the role of MSI in stage III MC patients treated with adjuvant chemotherapy. A cohort of 650 patients diagnosed with stages I-IV colonic MC from 2000 to 2010 was selected from PALGA, the nationwide Dutch pathology databank. Histopathology was revised and mismatch repair (MMR) status determined. Univariate and multivariate survival analyses were performed. Deficient MMR (dMMR) was found in 33% of MCs and correlated with female gender and right-sidedness, but also with lower tumour stage (stages I/II: 73.2 versus 47%; P < 0.0001) and the absence of EMVI (9.7 versus 23.7%; P < 0.0001) and PNI (5.6 versus 12.7%; P = 0.005). On univariate analysis OS was better for dMMR MC than for proficient MMR (pMMR) MC (median OS of 9.7 versus 5.0 years; P = 0.009), but MMR status was no longer a relevant prognostic factor on multivariate analysis [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.70-1.18]. Stage III MC patients benefited from adjuvant chemotherapy, and dMMR status was associated with better OS in this group (HR = 0.35, 95% CI = 0.13-0.94). EMVI, LI and PNI, but not MMR, status are independent prognostic factors for survival in MC patients. Stage III MC patients benefit from adjuvant chemotherapy and dMMR status is associated with improved survival when adjuvant chemotherapy is given.
Subject(s)
Colonic Neoplasms , Research Design , Female , Humans , Colonic Neoplasms/genetics , PrognosisABSTRACT
AIMS: RNF43 is suggested to be involved in the serrated pathway towards colorectal cancer and encodes a transmembrane Ring-type E3 ubiquitin ligase that negatively regulates the Wnt pathway. This study aimed to elucidate the role of RNF43 gene variants in serrated polyposis syndrome (SPS) and serrated polyps. METHODS AND RESULTS: Three cohorts were tested. The first cohort included germline DNA of 26 SPS patients tested for pathogenic variants in RNF43 by Sanger sequencing all exons. In the second cohort we tested somatic DNA for RNF43 mutations from sporadic serrated lesions: 25 hyperplastic polyps, 35 sessile serrated lesions and 38 traditional serrated adenomas (TSA). In the third cohort we investigated RNF43 mutations in 49 serrated polyps and 60 conventional adenomas from 40 patients with Lynch syndrome. No germline RNF43 pathogenic variants were detected in our SPS cohort. In sporadic colorectal lesions we detected RNF43 deleterious frameshift mutations in three TSA and one SSL. The RNF43 mutations in previously described homopolymeric hot-spots were detected in microsatellite-instable (MSI) polyps and the other RNF43 mutations in microsatellite-stable (MSS) serrated polyps. RNF43 hot-spot mutations were discovered in seven serrated polyps and 12 conventional adenomas from Lynch patients. CONCLUSION: Truncating germline RNF43 mutations are uncommon in SPS patients. Somatic mutations in RNF43 were found in sporadic TSA and SSL and both serrated polyps and adenomas from Lynch syndrome patients, suggesting that they do not develop early in the pathway to CRC and are not specific for serrated polyp subtypes.
Subject(s)
Colonic Neoplasms , Colonic Polyps , Colorectal Neoplasms, Hereditary Nonpolyposis , Ubiquitin-Protein Ligases , Adult , Aged , Cohort Studies , Colon/pathology , Colonic Neoplasms/diagnosis , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Colonic Polyps/diagnosis , Colonic Polyps/genetics , Colonic Polyps/pathology , Colorectal Neoplasms/etiology , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , DNA Mutational Analysis , Diagnosis, Differential , Female , Humans , Male , Microsatellite Instability , Middle Aged , Mutation , Ubiquitin-Protein Ligases/analysis , Ubiquitin-Protein Ligases/genetics , Wnt Signaling PathwayABSTRACT
Approximately half of the colorectal cancer (CRC) patients develop metastatic disease. Fluoropyrimidine-based chemotherapy forms the backbone of treatment in these patients. However, the response to this therapy varies between individuals. Therefore, an important challenge in CRC research is to identify biomarkers that are predictive of this response. In this study, we explored the potential of miRNAs, and the miRNA producing protein Dicer, as biomarkers that can predict chemo-sensitivity to fluoropyrimidine chemotherapy in patients with metastatic colorectal cancer (mCRC). We analyzed the levels of 22 miRNAs and the Dicer protein in primary tumors from patients with mCRC who were treated with first-line capecitabine monotherapy within the CAIRO trial of the Dutch Colorectal Cancer Group. Correlation between the expression status of miRNAs or Dicer in primary tumors and the progression free survival (PFS) were investigated. Patients with low expression of miR-143 in their primary tumor had increased median PFS compared to those with high expression of miR-143. Furthermore, FXYD3, an ion transport regulator and a putative target of miR-143, also showed an association with PFS. These findings warrant further studies to investigate the relationship between miR-143, FXYD3 and fluoropyrimidines, and the clinical utility of miR-143 as biomarker.
