Background:The objective of the study was to examine the role of microsatellite instability (MSI) and BRAFV600Emutation in colorectal cancer (CRC) by categorising patients into more detailed subtypes based on tumour characteristics.Methods:Tumour samples from 762 population-based patients with sporadic CRC were analysed for MSI and BRAFV600E by immunohistochemistry. Patient survival was followed-up for a median of 5.2 years.Results:Compared with microsatellite stable (MSS) CRC, MSI was prognostic for better disease-free survival (DFS; 5 years: 85.8% vs 75.3%, 10 years: 85.8% vs 72.9%, P=0.027; HR 0.49, CI 0.30–0.80, P=0.005) and disease-specific survival (DSS; 5 years: 83.2% vs 70.5% 10 years: 83.2 vs 65.0%, P=0.004). Compared with BRAF wild type, BRAFV600E was a risk for poor survival (overall survival; 5 years: 62.3% vs 51.6%, P=0.014; HR 1.43, CI 1.07–1.90, P=0.009), especially in rectal cancer (for DSS, HR: 10.60, CI: 3.04–36.92, P<0.001). The MSS/BRAFV600E subtype was a risk for poor DSS (HR: 1.88, CI: 1.06–3.31, P=0.030), but MSI/BRAFV600E was a prognostic factor for DFS (HR: 0.42, CI: 0.18–0.96, P=0.039). Among stage I–II patients, the MSS/BRAFV600E subtype was independently associated with poor DSS (HR: 5.32, CI: 1.74–16.31, P=0.003).Conclusions:Microsatellite instable tumours were associated with better prognosis compared with MSS. BRAFV600E was associated with poor prognosis unless it occurred together with MSI. The MSI/BRAFV600E subtype was a favourable prognostic factor compared with the MSS/BRAF wild-type subtype. BRAFV600E rectal tumours showed particularly poor prognosis. The MSS/BRAFV600E subtype was associated with increased disease-specific mortality even in stage I–II CRC.

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.

IntroductionBreast carcinoma is the most common cancer in women, but its incidence is not increased in Lynch syndrome (LS) and studies on DNA mismatch repair deficiency (MMR) in LS-associated breast cancers have arrived at conflicting results. This study aimed to settle the question as to whether breast carcinoma belongs to the LS tumor spectrum.MethodsMMR status and epigenetic profiles were determined for all available breast carcinomas identified among 200 LS families from a nation-wide registry (23 tumors from mutation carriers and 18 from non-carriers). Sporadic breast carcinomas (n = 49) and other cancers (n = 105) from MMR gene mutation carriers were studied for comparison.ResultsThe proportion of breast carcinomas that were MMR-deficient based on absent MMR protein, presence of microsatellite instability, or both was significantly (P = 0.00016) higher among breast carcinomas from mutation carriers (13/20, 65%) compared to non-carriers (0/14, 0%). While the average age at breast carcinoma diagnosis was similar in carriers (56 years) and non-carriers (54 years), it was lower for MMR-deficient versus proficient tumors in mutation carriers (53 years versus 61 years, P = 0.027). Among mutation carriers, absent MMR protein was less frequent in breast carcinoma (65%) than in any of seven other tumor types studied (75% to 100%). Tumor suppressor promoter methylation patterns were organ-specific and similar between breast carcinomas from mutation carriers and non-carriers.ConclusionsBreast carcinoma from MMR gene mutation carriers resembles common breast carcinoma in many respects (for example, general clinicopathological and epigenetic profiles). MMR status makes a distinction: over half are MMR-deficient typical of LS spectrum tumors, while the remaining subset which is MMR-proficient may develop differently. The results are important for appropriate surveillance in mutation carriers and may be relevant for LS diagnosis in selected cases.

Background Although high T cell density is a strong favourable prognostic factor in colorectal cancer, the significance of the spatial distribution of T cells is incompletely understood. We aimed to evaluate the prognostic significance of tumour cell-T cell co-localisation and T cell densities. Methods We analysed CD3 and CD8 immunohistochemistry in a study cohort of 983 colorectal cancer patients and a validation cohort (N = 246). Individual immune and tumour cells were identified to calculate T cell densities (to derive T cell density score) and G-cross function values, estimating the likelihood of tumour cells being co-located with T cells within 20 µm radius (to derive T cell proximity score). Results High T cell proximity score associated with longer cancer-specific survival in both the study cohort [adjusted HR for high (vs. low) 0.33, 95% CI 0.20–0.52, Ptrend < 0.0001] and the validation cohort [adjusted HR for high (vs. low) 0.15, 95% CI 0.05–0.45, Ptrend < 0.0001] and its prognostic value was independent of T cell density score. Conclusions The spatial point pattern analysis of tumour cell-T cell co-localisation could provide detailed information on colorectal cancer prognosis, supporting the value of spatial measurement of T cell infiltrates as a novel, robust tumour-immune biomarker.

Breast carcinoma is the most common cancer type in females, but its incidence is generally not increased in Lynch syndrome (LS). Deficient DNA mismatch repair (MMR) is a hallmark of LS tumors that are unequivocal manifestations of the syndrome (e.g., colorectal and breast carcinoma). Because of controversial study results, it is unclear at present whether or not breast carcinoma is specifically associated with LS. We addressed this question by determining the genetic and epigenetic profiles for all available breast carcinomas from LS families from a nation-wide registry, including 24 tumors from MMR gene mutation carriers and 17 tumors from non-carriers. The average age at breast carcinoma diagnosis was similar in mutation carriers and non-carriers (56 years for each). Among breast carcinomas from mutation carriers, 43% showed loss of MMR protein corresponding to the germline mutation, and high-degree microsatellite instability (MSI-H) was present in 36%. Moreover, in mutation carriers, the age at diagnosis was lower for breast carcinomas that were MMR-deficient (by absent MMR protein and/or MSI present) compared to MMR proficient tumors (51 vs. 60 years, p= 0.031). Breast carcinomas showed frequent inactivation of tumor suppressor genes (TSG) by promoter methylation. The average number of methylated TSGs out of 24 per tumor was 3.1 for mutation carriers and 2.8 for non-carriers. The gene-specific distribution of methylation was also similar between the two breast tumor sets. In mutation carriers, the most frequently methylated TSGs were RASSF1 (77%), APC (45%), CDH13 (45%), GSTP1 (32%) and CDKN2B (27%). In non-carriers, the respective frequencies were 75%, 47%, 59%, 35%, and 29%. When compared to tumors arising in other organs from LS mutation carriers, methylation of CDKN2B was seen as a particular characteristic of breast tumorigenesis. Our investigation shows that TSG promoter methylation is a common characteristic of breast carcinomas arising in LS and affects mutation carriers and non-carriers with comparable overall rates and gene-specific distributions. Analysis of MMR protein expression and MSI revealed that while many breast carcinomas from LS mutation carriers follow MMR-driven tumorigenesis characteristic of tumors of the LS spectrum in general, a significant subset of breast tumors also exists that appears to arise and progress along separate pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5018. doi:1538-7445.AM2012-5018