Project description:Colorectal carcinomas arising in the context of Lynch syndrome, the most common inherited cancer syndrome, typically show deficiency of the DNA MMR (mismatch repair) system. Lack of functional MMR leads to accumulation of frameshift mutations at micosatellites (microsatellite instability, MSI). High load of highly immunogenic tumor-specific frameshift neoantigens results in strong immune response against Lynch syndrome MSI cancers. Previous studies have shown systemic immune responses against frameshift neoantigens in Lynch syndrome carriers long before tumor manifestation. In the present study, we analyzed the immune profile of normal colorectal mucosa in Lynch syndrome carriers without current or previous cancer history and in Lynch syndrome colorectal cancer patients, as well as of Lynch syndrome colorectal carcinomas. The unsupervised cluster analysis of gene expression data revealed a sharp differentiation between normal mucosa from Lynch syndrome individuals with and without manifest cancer as well as between normal mucosa in general and Lynch syndrome cancer tissue. Deconvolution analysis for predicting the prevalence of immune cell population among the three groups revealed 10 out of 14 investigated populations to be significantly different between the three tissue types (FDR=10%). In contrast to normal mucosa samples, tumor tissue showed overrepresentation of immune-suppressive cell populations, such as regulatory T cells and neutrophils. Taken together with the quantitative T cell density analysis on the basis of immunohistochemical T cell stainings, our data show strong immune infiltration of the normal colorectal mucosa in Lynch syndrome individuals even in the absence of a manifest cancer.
Project description:A clinically applicably strategy for molecular screening for Lynch Syndrome is being implemented in Denmark.
Based on sequential analysis with immunohistochemistry and methylation analysis, patients with possible hereditary colorectal cancer are identified. These patients are offered genetic risk assessment and counselling.
The study hypothesis is that molecular screening will identify more patients with Lynch Syndrome than the family history alone.
Prospective data collection is performed using established clinical databases.
Project description:A clinically applicably strategy for molecular screening for Lynch Syndrome has been implemented in the Region of Southern Denmark.
Based on sequential analysis with immunohistochemistry and methylation analysis, patients with possible hereditary colorectal cancer are identified. These patients are offered genetic risk assessment and counselling.
The study hypothesis is that molecular screening will identify more patients with Lynch Syndrome than the family history alone.
Prospective data collection is performed using established clinical databases.
Project description:We aimed to provide a molecular description of Lynch syndrome-associated urothelial cancer in relation to molecular subtypes of sporadic bladder cancer. Whole genome mRNA expression profiles of 41 tumors and immunohistochemical stainings against FGFR3, KRT5, CCNB1, RB1, and CDKN2A (p16) of 37 tumors from Lynch syndrome patients were generated. Pathological data, microsatellite instability, anatomic location, and overall survival data was analyzed and compared with data from sporadic bladder cancer.
Project description:Lynch syndrome and Familial colorectal cancer type X (FCCTX) are clinically diagnosed using the same criteria, but genomic differences exist between these two groups and the genomic profiles share similarities with their sporadic counterparts, mismatch repair (MMR) deficient and proficient tumors, respectively. Array-based comparative genomic hybridization was performed on 91 tumors, comprising 23 Lynch syndrome (AH), 23 FCCTX (AA), 23 sporadic MMR deficient (AM) and 22 sporadic MMR proficient tumors, in order to identify differences between Lynch syndrome and FCCTX.
Project description:Lynch syndrome (LS) predisposes to cancer in adulthood and is caused by heterozygous germline variants in a mismatch repair (MMR) gene. Recent studies show an increased prevalence of LS among children with cancer, suggesting a causal relationship. For LS-spectrum (LSS) cancers, including high-grade gliomas and colorectal cancer, causality has been supported by typical MMR-related tumor characteristics, but for non-LSS cancers, causality is unclear. This dataset contains 5 patients with Lynch Syndrome from the INFORM registry.
Project description:Molecular characterization of 20 tumors of 18 children with Lynch syndrome to investigate causality. This characterization includes the investigation of second hits, tumor mutational load, mutational signatures and MMR protein expression.
Project description:Heredity is a major cause of ovarian cancer. Lynch syndrome is associated with 10-12% risk of ovarian cancer, diagnosis at young age and a predilection for endometrioid and clear cell tumors. Global gene expression profiling applied to 25 Lynch syndrome-associated and 42 sporadic ovarian cancers revealed 335 differentially expressed genes and involvement of the mTOR and the MAPK/ERK pathways. The clear cell tumors had distinct expression profiles with upregulation of HER2 and apoptosis signaling pathways. The distinct expression profiles provide clues relevant for hereditary tumorigenesis and may be relevant for therapeutic strategies and refined diagnostics in ovarian cancer linked to Lynch syndrome. Ovarian cancers linked to Lynch syndrome (n=25) were compared to a matched series of sporadic ovarian cancers (n=42), selected from a population-based consecutive series in which hereditary was excluded based on family history, normal MMR protein staining and lack of mutations in BRCA1 and BRCA2.
