See Covering the Cover synopsis on page 380.BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder associated with an elevated risk of colorectal cancer (CRC). IBD-associated CRC (IBD-CRC) may represent a distinct pathway of tumorigenesis compared to sporadic CRC (sCRC). Our aim was to comprehensively characterize IBD-associated tumorigenesis integrating multiple high-throughput approaches, and to compare the results with in-house data sets from sCRCs. METHODS: Whole-genome sequencing, single nucleotide polymorphism arrays, RNA sequencing, genome-wide methylation analysis, and immunohistochemistry were performed using fresh-frozen and formalin-fixed tissue samples of tumor and corresponding normal tissues from 31 patients with IBD-CRC. RESULTS: Transcriptome-based tumor subtyping revealed the complete absence of canonical epithelial tumor subtype associated with WNT signaling in IBD-CRCs, dominated instead by mesenchymal stroma-rich subtype. Negative WNT regulators AXIN2 and RNF43 were strongly down-regulated in IBD-CRCs and chromosomal gains at HNF4A, a negative regulator of WNTinduced epithelial-mesenchymal transition (EMT), were less frequent compared to sCRCs. Enrichment of hypomethylation at HNF4a binding sites was detected solely in sCRC genomes.
Increasing evidence suggests that cancer progression is strongly influenced by host immune response, which is represented by immune cell infiltrates. T-lymphocyte-based immunoscore has proved to be a prognostic factor in colon cancer, but its significance in pancreatic cancer is poorly known. Total of 108 patients operated (R0/R1) for pancreatic ductal adenocarcinoma (PDAC) (TNM stage I-II) were included in the study. Immune cell score (IS) was determined by scoring the samples from grade 0 to 4 according to the number of immune cells (CD3 and CD8) in tumor core and invasion margin using tissue microarrays, immunohistochemistry, and digital analysis. Tumors with microsatellite instability were identified by MLH1 immunostaining. High IS and low histological grade were significantly associated with better disease-specific survival (DSS) and overall survival (OS). The 5-year DSS rate for low, moderate, and high IS groups were 5.0, 15.2, and 33.4%, respectively (p = 0.007). The 5-year OS rate for the low, moderate, and high IS groups were 4.2, 13.4, and 31.5%, respectively (p = 0.004). In addition, IS and prognosis varied within a single TNM stage. There was no association between IS and any of the clinicopathological variables. IS was shown to be an independent prognostic factor for better DSS and OS in multivariate analysis, together with the histological grade of the tumor and perineural invasion. Five MLH1-negative tumors (4.6%) were found showing no correlation with IS. IS could be a useful prognostic marker in patients with PDAC treated by primary surgery.
The aim of this study was to investigate immune response and its prognostic significance in colon carcinomas using the previously described Immunoscore (IS). A population‐based series of 779 colorectal cancers, operated on between 2000 and 2010, were classified according to tumour, node, metastasis (TNM) status, mismatch repair (MMR), and BRAF mutation status. Rectal cancer cases (n = 203) were excluded as a high proportion of these patients received preoperative neoadjuvant chemoradiotherapy. Tissue microarray (TMA) samples collected from the tumour centre and invasive front were immunostained for CD3 and CD8. Lymphocytes were then digitally calculated to categorize IS from grade 0 to 4. Samples adequate for IS were available from 510 tumours. IS was significantly associated with AJCC/UICC stage, T stage, lymph node and distant metastases, perineural and lymphovascular invasion, MMR status, and BRAF mutation status. For IS0, IS1, IS2, IS3 and IS4, respectively, the 5‐year disease‐free survival (DFS) rates were 59, 68, 78, 83 and 94% (p < 0.001); 5‐year disease‐specific survival (DSS) rates were 47, 55, 75, 80, and 89% (p < 0.001); and 5‐year overall survival (OS) rates were 40, 44, 66, 61, and 76% (p < 0.001). IS was also prognostic for DFS, DSS, and OS within subsets of microsatellite‐stable (MSS) and microsatellite‐instable (MSI) disease. Multivariable analysis showed that IS, AJCC/UICC stage, lymphovascular invasion, and lymph node ratio in AJCC/UICC stage III disease were independent prognostic factors for DFS, DSS, and OS. Age was an independent prognostic factor for DSS and OS. Gender and BRAF mutation were independent prognostic factors for OS. In conclusion, IS differentiated patients with poor versus improved prognosis in MSS and MSI disease and across AJCC/UICC stages. IS, AJCC/UICC stage, lymphovascular invasion, and lymph node ratio in AJCC/UICC stage III disease were independent prognostic factors for DFS, DSS, and OS.
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