Search results for "LYNCH SYNDROME"

The Different Immune Profiles of Normal Colonic Mucosa in Cancer-Free Lynch Syndrome Carriers and Lynch Syndrome Colorectal Cancer Patients.

2021

ABSTRACT Background and aims Due to the high load of immunogenic frameshift neoantigens, tumors arising in individuals with Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, are characterized by a pronounced immune infiltration. However, the immune status of normal colorectal mucosa in LS is not well characterized. We assessed the immune infiltrate in tumor-distant normal colorectal mucosa from LS CRC patients, sporadic microsatellite-unstable (MSI) and microsatellite-stable (MSS) CRC patients, and cancer-free LS carriers. Methods CD3-positive, FOXP3-positive and CD8-positive T cells were quantified in 219, 233 and 201 formalin-fixed paraffin-embedded (FFPE) n…

Somatic mutation profiles as molecular classifiers of ulcerative colitis-associated colorectal cancer.

2021

Ulcerative colitis increases colorectal cancer risk by mechanisms that remain incompletely understood. We approached this question by determining the genetic and epigenetic profiles of colitis-associated colorectal carcinomas (CA-CRC). The findings were compared to Lynch syndrome (LS), a different form of cancer predisposition that shares the importance of immunological factors in tumorigenesis. CA-CRCs (n=27) were investigated for microsatellite instability, CpG island methylator phenotype, and somatic mutations of 999 cancer-relevant genes ("Pan-cancer" panel). A subpanel of "Pan-cancer" design (578 genes) was used for LS colorectal tumors (n=28). Mutational loads and signatures stratifie…

POLE, POLD1, and NTHL1: the last but not the least hereditary cancer-predisposing genes

2021

POLE, POLD1, and NTHL1 are involved in DNA replication and have recently been recognized as hereditary cancer-predisposing genes, because their alterations are associated with colorectal cancer and other tumors. POLE/POLD1-associated syndrome shows an autosomal dominant inheritance, whereas NTHL1-associated syndrome follows an autosomal recessive pattern. Although the prevalence of germline monoallelic POLE/POLD1 and biallelic NTHL1 pathogenic variants is low, they determine different phenotypes with a broad tumor spectrum overlapping that of other hereditary conditions like Lynch Syndrome or Familial Adenomatous Polyposis. Endometrial and breast cancers, and probably ovarian and brain tumo…

Familial aggregation of tumors and detection of hereditary non-polyposis colorectal cancer in 3-year experience of 2 population-based colorectal-canc…

1995

The clinical data of 2 population-based registries, located in areas with different incidence rates of colorectal cancer, were used in order to assess the role of familial factors in the pathogenesis of these tumors. The occurrence of tumors in family members was investigated in 389 subjects with colorectal cancer registered in Modena (Northern Italy, an area characterized by a high incidence of colorectal malignancies) between 1984 and 1986; similar information was obtained in 213 patients with tumors of the large bowel registered in Ragusa (Sicily, Southern Italy, an area of similar magnitude and with low incidence rates for these tumors) in the 3-year period 1988 to 1990. In both series,…

Immunoprofiles and DNA methylation of inflammatory marker genes in ulcerative colitis-associated colorectal tumorigenesis

2021

Immunological and epigenetic changes are interconnected and contribute to tumorigenesis. We determined the immunoprofiles and promoter methylation of inflammation-related genes for colitis-associated colorectal carcinomas (CA-CRC). The results were compared with Lynch syndrome (LS)-associated colorectal tumors, which are characterized by an active immune environment through inherited mismatch repair defects. CA-CRCs (n = 31) were immunohistochemically evaluated for immune cell scores (ICSs) and PDCD1 and CD274 expression. Seven inflammation-associated genes (CD274, NTSR1, PPARG, PTGS2, PYCARD, SOCS1, and SOCS2), the repair gene MGMT, and eight standard marker genes for the CpG Island Methyl…

Contribution of Large Genomic Rearrangements in Italian Lynch Syndrome Patients: Characterization of a Novel Alu-Mediated Deletion

2012

Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainlyMLH1andMSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%. The aim of this study was to examine the contribution of large rearrangements in theMLH1andMSH2genes in a well-characterised series of 63 unrelated Southern Italian Lynch syndrome patients who were negative for pathogenic point mutations in theMLH1,MSH2, andMSH6genes. We identified a large novel delet…

Gut Microbiota Analysis in Postoperative Lynch Syndrome Patients

2019

Lynch syndrome (LS) is a dominantly inherited condition with incomplete penetrance, characterized by high predisposition to colorectal cancer (CRC), endometrial and ovarian cancers, as well as to other tumors. LS is associated with constitutive DNA mismatch repair (MMR) gene defects, and carriers of the same pathogenic variants can show great phenotypic heterogeneity in terms of cancer spectrum. In the last years, human gut microbiota got a foothold among risk factors responsible for the onset and evolution of sporadic CRC, but its possible involvement in the modulation of LS patients’ phenotype still needs to be investigated. In this pilot study, we performed 16S rRNA gene sequencing of ba…

2021

Lynch syndrome (LS) increases cancer risk. There is considerable individual variation in LS cancer occurrence, which may be moderated by lifestyle factors, such as body weight and physical activity (PA). The potential associations of lifestyle and cancer risk in LS are understudied. We conducted a retrospective study with cancer register data to investigate associations between body weight, PA, and cancer risk among Finnish LS carriers. The participants (n = 465, 54% women) self-reported their adulthood body weight and PA at 10-year intervals. Overall cancer risk and colorectal cancer (CRC) risk was analyzed separately for men and women with respect to longitudinal and near-term changes in …

Distinct Mutational Profile of Lynch Syndrome Colorectal Cancers Diagnosed under Regular Colonoscopy Surveillance

2021

Regular colonoscopy even with short intervals does not prevent all colorectal cancers (CRC) in Lynch syndrome (LS). In the present study, we asked whether cancers detected under regular colonoscopy surveillance (incident cancers) are phenotypically different from cancers detected at first colonoscopy (prevalent cancers). We analyzed clinical, histological, immunological and mutational characteristics, including panel sequencing and high-throughput coding microsatellite (cMS) analysis, in 28 incident and 67 prevalent LS CRCs (n total = 95). Incident cancers presented with lower UICC and T stage compared to prevalent cancers (p &lt

Correction:Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrom…

2020

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in ind…