Hereditary Nonpolyposis
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2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Wenli Qiu ◽  
Ke Ding ◽  
Lusheng Liao ◽  
Yongchang Ling ◽  
Xiaoqiong Luo ◽  
...  

Background. MutS homolog 2 (MSH2), with the function of identifying mismatches and participating in DNA repair, is the “housekeeping gene” in the mismatch repair (MMR) system. MSH2 deficiency has been reported to enhance cancer susceptibility for the association of hereditary nonpolyposis colorectal cancer. However, the expression and prognostic significance of MSH2 have not been studied from the perspective of pan-cancer. Methods. The GTEx database was used to analyze the expression of MSH2 in normal tissues. The TCGA database was used to analyze the differential expression of MSH2 in pan-cancers. The prognostic value of MSH2 in pan-cancer was assessed using Cox regression and Kaplan-Meier analysis. Spearman correlations were used to measure the relationship between the expression level of MSH2 in pan-cancer and the level of immune infiltration, tumor mutational burden (TMB), and microsatellite instability (MSI). Results. MSH2 is highly expressed in most type of cancers and significantly correlated with prognosis. In COAD, KIRC, LIHC, and SKCM, the expression of MSH2 was significantly positively correlated with the abundance of B cells, CD4+ T cells, CD8+ T cells, dendritic cells, macrophages, and neutrophils. In THCA, MSH2 expression correlated with CD8+T Cell showed a significant negative correlation. MSH2 had significantly negative correlations with stromal score and immune score in a variety of cancers and significantly correlated with TMB and MSI of a variety of tumors. Conclusions. MSH2 may play an important role in the occurrence, development, and immune infiltration of cancer. MSH2 can emerge as a potential biomarker for cancer diagnosis and prognosis.


2021 ◽  
Vol 12 (6) ◽  
pp. 134-146
Author(s):  
Tjahjadi Robert Tedjasaputra ◽  
Mochammad Hatta ◽  
Muh Nasrum Massi ◽  
Rosdiana Natzir ◽  
Agussalim Bukhari ◽  
...  

2021 ◽  
Vol 12 (6) ◽  
pp. 130-142
Author(s):  
Tjahjadi Robert Tedjasaputra ◽  
Mochammad Hatta ◽  
Muh Nasrum Massi ◽  
Rosdiana Natzir ◽  
Agussalim Bukhari ◽  
...  

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Farzana Haque ◽  
Patrick Lillie ◽  
Farhana Haque ◽  
Anthony Maraveyas

Abstract Background Several independent risk factors have been reported to influence viral shedding following COVID-19 infection, but the influence of host-related molecular factors has not yet been described. We report a case of a cancer patient with Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) who manifested SARS-CoV-2 PCR (polymerase chain reaction) positivity for at least 54 days after contracting mild COVID-19 illness. We propose that deficient mismatch repair (MMR) may play a role in the prolonged SARS-CoV-2 RNA shedding. Case presentation A patient with Lynch syndrome was under surveillance for metastatic adenocarcinoma after completing palliative chemotherapy in October 2019. Between the period of April 2020 to June 2020, he was admitted multiple times to address several clinical needs mainly related to his underlying malignancy. These included progressive disease observed in the aortocaval lymph nodes leading to recurrent episodes of upper gastrointestinal bleeding, dehydration resulting in acute kidney injury and a short-lived episode of pyrexia. A SARS-CoV-2 PCR of the nasopharyngeal swab (NPS) was positive at his initial admission with mild COVID-19 symptoms. He remained positive on subsequent admissions when tested routinely for SARS-CoV-2 without demonstrating any apparent clinical features of COVID-19 infection. The MMR pathway, a component of DNA damage response (DDR), is impaired in Lynch syndrome due to an inherited genetic mutation. This pathway is also required for viral clearance from the host cells following certain RNA viral infections like influenza virus and other coronaviridae. Here we provide a current understanding of the importance of DDR deficiencies in the clearance of RNA virus and suggest how this may play a similar role in the clearance of COVID-19, as evident in our case that demonstrated persistent positivity. Conclusion The importance of understanding the scientific basis of extended viral shedding during the COVID-19 pandemic is now centre-stage in the establishment of robust track and trace services to allow the recovery and function of societies and economies. This patient with Lynch syndrome recovered from infection but had prolonged viral positivity, which might merit further investigation to better understand the effect of this condition on infection duration and outcome.


2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Chun-Kai Liao ◽  
Yueh-Chen Lin ◽  
Yu-Jen Hsu ◽  
Yih-Jong Chern ◽  
Jeng-Fu You ◽  
...  

Abstract Background Although extended colectomy (EC) was recommended for HNPCC patients, previous studies did not show significantly improved overall survival. Immunohistochemical (IHC) stain of mismatch repair (MMR) gene protein expression is now a feasible and reliable test clinically. Therefore, we tried to investigate whether we could use MMR IHC stain to select operation types in HNPCC patients. Patients and methods Between 1995 and 2013, 186 HNPCC patients were collected. Status of MMR protein expression, perioperative clinic-pathological variables and post-operative follow up status were analyzed by multivariate analyses. Results Sixty-five percent (121 of 186) patients of these HNPCC patients demonstrated loss of at least one MMR protein. There were several significant differences existing between deficient MMR (dMMR) and proficient MMR (pMMR) subgroups in terms of clinic-pathological characteristics. With the average follow-up duration of 93.9 months, we observed significantly high risk of developing metachronous CRC between SC and EC subgroups (crude rate 8.5% vs. 0%, p = 0.035). However, no significant difference was observed among the presence of extra-colonic tumors (12.4% vs. 5.8%, p = 0.284). The positive and negative prediction rate of metachronous CRC in dMMR subgroup was 12.8 and 87.2% while 1.9 and 98.1% in the pMMR subgroup. Survival outcomes were significantly affected by MMR status and resection types by multivariate analysis. Significantly better OS in dMMR subgroup (HR = 0.479, 95% CI: 0.257–0.894, p = 0.021) comparing with pMMR subgroup was observed. However, significant improved DFS (HR = 0.367, 95% CI: 0.172–.0787, p = 0.010) but not significant for OS (HR = 0.510, 95% CI: 0.219–1.150, p = 0.103) for EC subgroup compared with SC subgroup. Differences existing among different subgroups by combing extent of resection and MMR status. In dMMR subgroup, SC, compared with EC, demonstrated significantly worse DFS by multivariate analyses (HR = 3.526, 95% CI: 1.346–9.236, p = 0.010) but not for OS (HR = 2.387, 95% CI: 0.788–7.229, p = 0.124), however, no significantly differences of OS and DFS in pMMR subgroup between SC and EC were found. Conclusions Significantly better overall survival and higher rate of metachronous CRC exist in dMMR subgroup of HNPCC patients comparing with pMMR subgroup. Extended colectomy significantly improved DFS and was thus recommended for dMMR subgroup but not pMMR subgroup of HNPCC patients.


Author(s):  
Mohammad Hassan Jokar ◽  
Sima Sedighi ◽  
Maliheh Moradzadeh

Introduction: Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) is an autosomal dominant genetic disease. The disease is caused by a mutation in one of four genes of the DNA mismatch repair system and increases the risk for various cancers, especially the uterine and colon cancers. The prevalence of this disease in the general population is about 1 in 500 and it causes about 2-3% of colorectal cancers. Lynch syndrome is diagnosed in two stages: 1) the person is suspected of having the disease (because a patient is unusually diagnosed with cancer at a young age), and 2) evidence of incomplete repair defect is seen in the tumor tissue (microsatellite instability). The detection of a pathogenic mutation confirms the diagnosis in these patients and enables predictive testing for other family members. Diagnostic evaluation of Lynch syndrome should be performed with appropriate genetic counseling. Systemic colonoscopy surveillance could identify colon cancers at an earlier stage before patients present clinical symptoms. Conclusion: Although many studies have been done, but the benefits of an individualized, risk-adapted surveillance strategy are still unclear. Until this is identified, Lynch syndrome patients and healthy carriers with causative mutations should be monitored by annual colonoscopy and annual gynecological examination (for women).  


2021 ◽  
Vol 22 (2) ◽  
pp. 531
Author(s):  
Andrea Katharina Lindner ◽  
Gert Schachtner ◽  
Gennadi Tulchiner ◽  
Martin Thurnher ◽  
Gerold Untergasser ◽  
...  

Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1, MSH2, MSH6, and PMS2, and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in MSH2 mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years.


2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Wan Khairunnisa Wan Juhari ◽  
Khairul Bariah Ahmad Amin Noordin ◽  
Wan Faiziah Wan Abdul Rahman ◽  
Andee Dzulkarnaen Zakaria ◽  
Ahmad Shanwani Mohd Sidek ◽  
...  

Background: Hereditary nonpolyposis colorectal cancer (HNPCC) also known as Lynch syndrome is commonly caused by genetic alterations in any of the four mismatch repair (MMR) genes; MLH1, MSH2, MSH6 and PMS2. This is the first study aimed to investigate genetic variants in Malay HNPCC families. Methods: Six Malay HNPCC families who fulfilled any of the Bethesda criteria were recruited into this study. A total of 3 ml of blood was withdrawn from each patient in the families. The samples were further analyzed using polymerase chain reaction and direct sequencing of the selected exons of MLH1 and MSH2 genes. Results: Two missense mutations and four single nucleotide polymorphisms (SNPs) were identified in six patients. These variants in the MLH1 and MSH2 genes were identified in four families who met the revised Bethesda guidelines. In two families, no mutation and polymorphism was identified in both the exon and intron of the respective genes. Of the mutations and polymorphisms identified, five have never been reported in Malay HNPCC families before. A missense mutation was detected in exon 5 of the MLH1 gene, c.394G>C (p.Asp132His) and four mutations and polymorphisms were detected in the MSH2 gene; heterozygous c.211+98T>C and c.211+9C>G and homozygous c.211+98T>C and c.211+9C>G, c.367-86A>C and c.382C>G. Conclusion: The results represented a new spectrum of mutations and polymorphisms in the Malay HNPCC families. However, a larger study involving additional families and analysis is required to determine the impact and nature of the identified mutations and polymorphisms.


2020 ◽  
Author(s):  
Farzana Haque ◽  
Patrick Lillie ◽  
Farhana Haque ◽  
Anthony Maraveyas

Abstract Background:Several independent risk factors have been reported to influence viral shedding following COVID-19 infection, but host related molecular factors have not been described yet. We report a case of a cancer patient with Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) who manifested SARS-COV-2 PCR (polymerase chain reaction) positivity for at least 54 days after contracting mild COVID-19 illness and propose that deficient mismatch repair (MMR) may have a role in the prolonged SARS-CoV-2 RNA shedding.Case Presentation:A patient with Lynch syndrome was on surveillance for metastatic adenocarcinoma after completion of palliative chemotherapy in October 2019. Between the period of April 2020 to June 2020, he required multiple admissions addressing several clinical needs mainly related to his underlying malignancy. These included progressive disease in the interaortocaval lymph nodes leading to recurrent episodes of upper gastrointestinal bleeding, dehydration resulting in acute kidney injury and a short-lived episode of pyrexia. A SARS-COV-2 PCR of the nasopharyngeal swab (NPS) was positive at his initial admission with mild COVID-19 symptoms. He remained positive on subsequent admissions when tested routinely for SARS-COV-2 without demonstrating any obvious clinical features of COVID-19 infection.The MMR pathway, a component of DNA damage response (DDR), is impaired in Lynch syndrome due to an inherited genetic mutation. This pathway is also required for viral clearance from the host cells following certain RNA viral infections like influenza virus and other coronaviridae. Here we provide current understanding of the importance of DDR deficiencies in the clearance of RNA virus and suggest how this may play a similar role in the clearance of COVID-19 as evident in our case that demonstrated persistent positivity.Conclusion:The importance of understanding the scientific basis of extended viral shedding during the COVID-19 pandemic is now centre-stage in the establishment of robust track and trace services to allow the recovery and function of societies and economies. We propose that deficient-MMR may contribute to the persistence of SARS-CoV-2 RNA shedding. Future studies could open new avenues for research and may give rise to epidemiological or early therapeutic interventions.


Diagnostics ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 786 ◽  
Author(s):  
Joanna Sobocińska ◽  
Tomasz Kolenda ◽  
Anna Teresiak ◽  
Natalia Badziąg-Leśniak ◽  
Magda Kopczyńska ◽  
...  

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a disorder caused by an autosomal dominant heterozygous germline mutation in one of the DNA mismatch repair (MMR) genes. Individuals with LS are at an increased risk of developing colorectal and extracolonic cancers, such as endometrial, small bowel, or ovarian. In this review, the mutations involved with LS and their diagnostic methods are described and compared, as are their current uses in clinical decision making. Nowadays, LS diagnosis is based on a review of family medical history, and when necessary, microsatellite instability (MSI) or/and immunohistochemistry (IHC) analyses should be performed. In the case of a lack of MMR protein expression (dMMR) or MSI-H (MSI-High) detection in tumor tissue, molecular genetic testing can be undertaken. More and more genetic testing for LS is based mainly on next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA), which provide better and quicker information about the molecular profile of patients as well as individuals at risk. Testing based on these two methods should be the standard and commonly used. The identification of individuals with mutations provides opportunities for the detection of cancer at an early stage as well as the introduction of proper, more effective treatment, which will result in increased patient survival and reduced costs of medical care.


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