scholarly journals 32Do the risks of Lynch syndrome-related cancers depend on the parent-of-origin of the mutation?

2021 ◽  
Vol 50 (Supplement_1) ◽  
Author(s):  
Shimelis Gemechu ◽  
Christine M. van Vliet ◽  
Aung Ko Win ◽  
Jane C. Figueiredo ◽  
Loic Le Marchand ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endometrial Cancer ◽  
Gene Mutation ◽  
Gene Mutations ◽  
Current Evidence ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Mutation Carriers ◽  
Parent Of Origin ◽  
Colon Cancer Family Registry

Abstract Background Individuals who carry pathogenic mutations in DNA mismatch repair (MMR) genes have high risks of cancer, and small studies have suggested that these risks depend on the sex of the parent from whom the mutation was inherited. We have conducted the first large study of such a parent-of-origin effect (POE). Methods Our study was based on all MMR gene mutation carriers and their relatives in the Colon Cancer Family Registry, comprising 18,226 people. The POE was estimated as a hazard ratio (HR) using a segregation analysis approach that adjusted for ascertainment. HR = 1 corresponds to no POE and HR > 1 corresponds to higher risks for maternal mutations. Results For all MMR genes combined, the estimated POE HRs were 1.02 (95% confidence interval (CI) 0.75-1.39, p = 0.9) for male colorectal cancer, 1.12 (95% CI 0.81-1.54, p = 0.5) for female colorectal cancer and 0.84 (95% CI 0.52-1.36, p = 0.5) for endometrial cancer. Separate results for each MMR gene were similar. Conclusions Despite being well-powered, our study did not find any evidence that cancer risks for MMR gene mutation carriers depend on the parent-of-origin of the mutation. Based on current evidence, we don’t recommend that POEs be incorporated into the clinical guidelines or advice for such carriers. Key messages MMR gene mutations inherited from the maternal and paternal side confer similar risks of developing colorectal and endometrial cancer.

Escherichia coli and colorectal cancer: Unfolding the enigmatic relationship

2021 ◽  
Vol 22 ◽  
Author(s):  
Rogayeh Nouri ◽  
Alka Hasani ◽  
Kourosh Masnadi Shirazi ◽  
Mohammad Reza Aliand ◽  
Bita Sepehri ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Escherichia Coli ◽  
Mammalian Cells ◽  
Chromosomal Rearrangements ◽  
Current Evidence ◽  
Dna Breaks ◽  
Colon Cells ◽  
E Coli ◽  
Dna Mismatch ◽  
Double Strand Dna Breaks

: Colorectal cancer (CRC) is one of the deadliest cancers in the world. Specific strains of intestinal Escherichia coli (E. coli) may influence the initiation and development of CRC by exploiting virulence factors and inflammatory pathways. Mucosa-associated E. coli strains are more prevalent in CRC biopsies in comparison to healthy controls. Moreover, these strains can survive and replicate within macrophages and induce a pro-inflammatory response. Chronic exposure to inflammatory mediators can lead to increased cell proliferation and cancer. Production of colobactin toxin by the majority of mucosa-associated E. coli isolated from CRC patients is another notable finding. Colibactin-producing E. coli strains, in particular, induce double-strand DNA breaks, stop the cell cycle, involve in chromosomal rearrangements of mammalian cells and are implicated in carcinogenic effects in animal models. Moreover, some enteropathogenic E. coli (EPEC) strains are able to survive and replicate in colon cells as chronic intracellular pathogens and may promote susceptibility to CRC by downregulation of DNA Mismatch Repair (MMR) proteins. In this review, we discuss current evidence and focus on the mechanisms by which E. coli can influence the development of CRC.

scholarly journals Recent advances in understanding Lynch syndrome

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2889 ◽  
Author(s):  
Sherief Shawki ◽  
Matthew F. Kalady
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Correct Diagnosis ◽  
Diagnostic Testing ◽  
Gene Mutations ◽  
The United States ◽  
Cancer Syndrome ◽  
Dna Mismatch ◽  
Recent Developments ◽  
Risk Patients

Colorectal cancer affects about 4.4% of the population and is a leading cause of cancer-related death in the United States. Approximately 10% to 20% of cases occur within a familial pattern, and Lynch syndrome is the most common hereditary colorectal cancer syndrome. Lynch syndrome is a hereditary predisposition to forming colorectal and extracolonic cancers, caused by a germline mutation in one of the DNA mismatch repair genes. Identifying at-risk patients and making a correct diagnosis are the keys to successful screening and interventions which will decrease formation of and death from cancers. Knowledge of the genetics and the natural history of Lynch syndrome has continued to be uncovered in recent years, leading to a better grasp on how these patients and their families should be managed. Recent developments include the approach to diagnostic testing, more precise definitions of the syndrome and risk stratification based on gene mutations, surgical decision-making, and chemoprevention.

K-ras gene mutation as an early prognostic marker of colon cancer

2016 ◽  
Vol 88 (1) ◽  
Author(s):  
Łukasz Szpon ◽  
Aleksander Stal ◽  
Marcin Zawadzki ◽  
Anna Lis-Nawara ◽  
Wojciech Kielan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gene Mutation ◽  
Cancer Incidence ◽  
Early Stage ◽  
Tnm Classification ◽  
Gene Mutations ◽  
Diagnostic Methods ◽  
Female Group ◽  
Ras Gene ◽  
Colorectal Cancer Incidence

AbstractDue to increased colorectal cancer incidence there is a necessity of seeking new both prognostic and prediction factors that will allow to evolve new diagnostic tests. K-ras gene seems to be such a factor and its mutations are considered to be an early marker of progression of colorectal cancer.was to find a correlation between K-ras gene mutation in patients with diagnosed colorectal cancer and selected clinical parameters.A total of 104 patients (41 women and 63 men) with diagnosed colorectal cancer were included in this study. The average age of male group was 68.3 and in female group − 65.9. Samples were taken from paraffine blocks with tissue from diagnosed patients and K-ras gene mutation were identified. Afterwards the statistical analysis was made seeking the correlation between K-ras gene mutation incidence and clinical TNM staging system, tumour localisation, histological type, sex, age.K-ras gene mutations were detected in 20.1% of all colorectal cancers. Significantly higher rate of K-ras gene mutations were diagnosed among patients classified at stage I (40%), stage IIC (50%) and stage IV (50%) according to the TNM classification.The results of our study are compatible with other studies and indicate the correlation between K-ras gene mutation and colorectal cancer incidence. Identification of K-ras gene mutation may complement other diagnostic methods at early stage of colorectal cancer.

Abstract 11621: Fibrillin-1 Gene Mutations in Left Ventricular Non-Compaction Cardiomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
John J Parent ◽  
Jeffrey A Towbin ◽  
John L Jefferies
Keyword(s):  
Extracellular Matrix ◽  
Gene Mutation ◽  
Marfan Syndrome ◽  
Gene Mutations ◽  
Left Ventricular ◽  
Current Evidence ◽  
Causative Gene ◽  
Fbn1 Gene ◽  
Gene Testing ◽  
Fibrillin 1

Introduction: Left ventricular non-compaction cardiomyopathy (LVNC) is a rare and unique cardiomyopathy. Its presentation can range from a benign phenotype to overt heart failure and sudden cardiac death. The genetics of LVNC are not completely understood and current genetic testing has a yield of about 30% in identifying a causative gene mutation. We present a series of patients with LVNC and fibrillin-1 (FBN1) gene mutations. Hypothesis: We hypothesize that FBN1 gene mutations can lead to LVNC by way of its role in the myocardial extracellular matrix during cardiac development. Methods: A retrospective review of all patients with LVNC at our institution was performed for purposes of another investigation. The process unexpectedly identified patients with LVNC and FBN1 gene mutations, as well as LVNC and Marfan syndrome. Results: Approximately 150 patients are followed in our clinic with LVNC. We screened this population and found 51 patients on medical therapy for reduced function. We retrospectively reviewed gene testing in these 51 patients, when available, and identified 5 patients (10%) with an FBN1 gene mutation. All 5 patients had a dilated LVNC phenotype and previous or current evidence of left ventricular dysfunction. Syndrome breakdown as follows: 3 with Marfan, 1 with Shprintzen-Goldberg, and 1 with no identifiable syndrome. Dilated cardiomyopathy/LVNC gene testing was performed in 3 patients; 2 had disease causing myosin heavy chain 7 gene defects and 1 had no defects. Conclusions: The role of FBN1 in the human myocardium is not completely understood but it is expressed in the developing fetal heart and is a component of the myocardial extracellular matrix. Although causation has not been proven by our report, it certainly raises interest in a mechanistic relationship between LVNC and FBN1 given the increased prevalence of Marfan syndrome and probable increased prevalence of FBN1 gene mutations in this cohort of LVNC patients in light of FBN1.

scholarly journals Cancer spectrum in DNA mismatch repair gene mutation carriers: results from a hospital based Lynch syndrome registry

2012 ◽  
Vol 11 (3) ◽  
pp. 441-447 ◽  
Author(s):  
Mala Pande ◽  
Chongjuan Wei ◽  
Jinyun Chen ◽  
Christopher I. Amos ◽  
Patrick M. Lynch ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Gene Mutation ◽  
Dna Mismatch Repair ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
Dna Mismatch ◽  
Mutation Carriers ◽  
Dna Mismatch Repair Gene

scholarly journals Molecular Basis of Mismatch Repair Protein Deficiency in Tumors from Lynch Suspected Cases with Negative Germline Test Results

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1853
Author(s):  
Alisa Olkinuora ◽  
Annette Gylling ◽  
Henrikki Almusa ◽  
Samuli Eldfors ◽  
Anna Lepistö ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Germline Mutation ◽  
Mutation Screening ◽  
Gene Mutations ◽  
Epigenetic Mechanism ◽  
Large Rearrangement ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Tumor Studies ◽  
Mutl Homolog 1

Some 10–50% of Lynch-suspected cases with abnormal immunohistochemical (IHC) staining remain without any identifiable germline mutation of DNA mismatch repair (MMR) genes. MMR proteins form heterodimeric complexes, giving rise to distinct IHC patterns when mutant. Potential reasons for not finding a germline mutation include involvement of an MMR gene not predicted by the IHC pattern, epigenetic mechanism of predisposition, primary mutation in another DNA repair or replication-associated gene, and double somatic MMR gene mutations. We addressed these possibilities by germline and tumor studies in 60 Lynch-suspected cases ascertained through diagnostics (n = 55) or research (n = 5). All cases had abnormal MMR protein staining in tumors but no point mutation or large rearrangement of the suspected MMR genes in the germline. In diagnostic practice, MSH2/MSH6 (MutS Homolog 2/MutS Homolog 6) deficiency prompts MSH2 mutation screening; in our study, 3/11 index individuals (27%) with this IHC pattern revealed pathogenic germline mutations in MSH6. Individuals with isolated absence of MSH6 are routinely screened for MSH6 mutations alone; we found a predisposing mutation in MSH2 in 1/7 such cases (14%). Somatic deletion of the MSH2-MSH6 region, joint loss of MSH6 and MSH3 (MutS Homolog 3) proteins, and hindered MSH2/MSH6 dimerization offered explanations to misleading IHC patterns. Constitutional epimutation hypothesis was pursued in the MSH2 and/or MSH6-deficient cases plus 38 cases with MLH1 (MutL Homolog 1)-deficient tumors; a primary MLH1 epimutation was identified in one case with an MLH1-deficient tumor. We conclude that both MSH2 and MSH6 should be screened in MSH2/6- and MSH6-deficient cases. In MLH1-deficient cases, constitutional epimutations of MLH1 warrant consideration.

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