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Constitutional Mismatch Repair Deficiency (CMMRD) is a rare childhood cancer predisposition syndrome, caused by biallelic pathogenic germline variants in the mismatch repair genes. Diagnosis and management of this syndrome is challenging, especially in low-resource settings. This study describes a patient diagnosed with colorectal cancer and grade 3 astrocytoma at the age of 11 and 12 respectively. Immunohistochemistry analysis showed a loss of MSH2 and MSH6 protein expression in CRC tissues of the patient. We identified by Targeted Exome Sequencing a homozygous pathogenic germline variant in exon 9 of the MSH6 gene (c.3991 C > T; p.Ala1268Glyfs*6). Genetic investigation of the family showed that the father was heterozygous for the identified pathogenic variant while the brother was wild type for this variant. Our study highlights the importance of a correct and timely diagnosis of CMMRD which can have implications for treatment. It also underlines the imperative need to enhance awareness, diagnostic standards, and surveillance that are crucial for patients and their families. [ABSTRACT FROM AUTHOR]

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Lynch syndrome (LS) predisposes individuals to early-onset colorectal and other Lynch-associated cancer. This disorder is an autosomal dominant genetic disturbance caused by germline mutations in one of the mismatch repair genes. Different clinical and molecular criteria are used to diagnose LS. Microsatellite instability testing and immunohistochemistry are two widely used methods for the molecular screening of LS-associated cancers. According to the immunohistochemistry and Microsatellite instability testing, we introduce three Persian families with Lynch-like syndrome (LLS) who met clinical Amsterdam-II criteria and their probands were mismatch repair deficient. In the case of immunohistochemistry-MLH1 absent, BRAF-V600E mutation was evaluated to rule out the sporadic colorectal cancer cases. No pathogenic germline variants were found by next generation sequencing method. Multiplex ligation-dependant probe amplification technique was done to find large in/dels within MLH1/MSH2 genes of the probands. A two-exon deletion within MLH1 gene was eventually identified in one of the patients. Finally, we have represented a molecular pipeline to diagnose LLS based on literature review and the introduced cases.

Instruction: Lynch syndrome (LS) is the most common inherited cancer predisposition disorder of colorectal cancer (CRC) which is associated with pathogenic variants in 4 mismatch repair (MMR) genes. Here, we reported a multi-generation Chinese family clinically diagnosed with LS. Methods: To identify the underlying pathogenic gene variants, 30 whole blood samples and 4 colorectal cancer tissue samples and their clinical data were obtained from this four-generation family. Microsatellite instability-high (MSI) testing, immunohistochemistry (IHC), and Whole-Exome Sequencing (WES) were performed to identify the MMR/MSI and the underlying gene variants. The minigene splicing assay and in vitro splicing assay were used to explore the function of this variant. Results: MSI-H and dMMR was revealed by the MSI testing and IHC, Whole-Exome Sequencing (WES) in 3 patients successfully identified a splicing variant (c.793-1G>A) in intron 4 of MSH2. Sanger sequencing validated the WES results, and all the "healthy" individuals carrying the variant have been identified in the family by PCR. Bioinformatics analysis and in vitro minigene assay showed that the pathogenic variant affected the splicing process of MSH2 gene to generate 2 kinds defective transcription products, and consequently reduced the expression of MSH2 protein. The mutation carriers were later recommended for colonoscopy and other important cancer diagnostic inspections every 1-2 years because they both have a higher risk of LS. Discussion: We found a pathogenic splicing variant (rs863225397, c.793-1G>A) of MSH2 gene, and furtherly confirmed that this mutation plays an important role in LS patients of this pedigree based on the vitro study. Our study indicates that one splicing mutation in the MSH2 gene (c.793-1G>A) causes LS and highlights the importance of LS gene testing. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS), an autosomal dominant genetic disorder caused by mismatch repair gene defects, is characterized by the susceptibility to multi-system malignancies. LS associated endometrial cancer (LS-EC) is the most common extraintestinal sentinel cancer of LS. In the era of precision medicine, early screening of LS-EC is of great significance to preventing the occurrence of other LS related malignant tumors. This paper reviews the research progress on screening methods and prevention of LS-EC, in order to provide reference for precise diagnosis and prevention of LS-related tumors.

Background Lynch syndrome (LS) is an autosomal dominant condition due to the germline mutation in the mismatch repair (MMR) genes including MLH1, MSH2, MSH6, and PMS2 (post-meiotic segregation increased 2). The MMR mutation carriers have high risk for cancers. Pathogenic PMS2 variants are rarely reported in LS-associated colorectal cancer (CRC) with colorectal polyps. The aim of the study was to investigate the genetic etiology of CRC in an individual with CRC with multiple colorectal polyps and a family history of cancers. Patients and Methods The index patient was an African male affected by CRC with multiple colorectal polyps. The clinical diagnostic for LS was based on the Amsterdam II criteria and pedigree. Next-generation sequencing with inherited cancer genes panel was used to detect the pathogenic variant. Results The patient fulfilled the Amsterdam II criteria and the pedigree revealed a family history of recurrent CRC. A deleterious PMS2 germline heterozygous mutation c.2192_2196delTAACT was detected. Conclusion Our study supports the notion that LS may be associated with polyps and shows the predisposition of PMS2 heterozygous mutation in LS-associated CRC at young age.

Lynch syndrome (LS) predisposes individuals to early-onset colorectal and other Lynch-associated cancer. This disorder is an autosomal dominant genetic disturbance caused by germline mutations in one of the mismatch repair genes. Different clinical and molecular criteria are used to diagnose LS. Microsatellite instability testing and immunohistochemistry are two widely used methods for the molecular screening of LS-associated cancers. According to the immunohistochemistry and Microsatellite instability testing, we introduce three Persian families with Lynch-like syndrome (LLS) who met clinical Amsterdam-II criteria and their probands were mismatch repair deficient. In the case of immunohistochemistry-MLH1 absent, BRAF-V600E mutation was evaluated to rule out the sporadic colorectal cancer cases. No pathogenic germline variants were found by next generation sequencing method. Multiplex ligation-dependant probe amplification technique was done to find large in/dels within MLH1/MSH2 genes of the probands. A two-exon deletion within MLH1 gene was eventually identified in one of the patients. Finally, we have represented a molecular pipeline to diagnose LLS based on literature review and the introduced cases. [ABSTRACT FROM AUTHOR]

Background Lynch syndrome (LS) is an autosomal dominant condition due to the germline mutation in the mismatch repair (MMR) genes including MLH1 , MSH2 , MSH6, and PMS2 (post-meiotic segregation increased 2). The MMR mutation carriers have high risk for cancers. Pathogenic PMS2 variants are rarely reported in LS-associated colorectal cancer (CRC) with colorectal polyps. The aim of the study was to investigate the genetic etiology of CRC in an individual with CRC with multiple colorectal polyps and a family history of cancers. Patients and Methods The index patient was an African male affected by CRC with multiple colorectal polyps. The clinical diagnostic for LS was based on the Amsterdam II criteria and pedigree. Next-generation sequencing with inherited cancer genes panel was used to detect the pathogenic variant. Results The patient fulfilled the Amsterdam II criteria and the pedigree revealed a family history of recurrent CRC. A deleterious PMS2 germline heterozygous mutation c.2192_2196delTAACT was detected. Conclusion Our study supports the notion that LS may be associated with polyps and shows the predisposition of PMS2 heterozygous mutation in LS-associated CRC at young age. [ABSTRACT FROM AUTHOR]

Here, we determined the frequency of microsatellite instability (MSI) and the impact of MSI-high (MSI-H) on clinical outcomes of Thai patients with endometrial cancer (EC). Tissue samples of 110 Thai patients with EC, who had undergone surgical staging, were tested for mismatch repair (MMR) gene deficiency, and the patients were grouped into MSI-H and MSI-stable (MSI-S) groups; 24.5% had MSI-H. Unlike MSI-S group patients, MSI-H group patients had synchronous and metachronous cancer. They showed better 3-year disease-free survival (DFS) than those in the MSI-S group (p=.182; 92.3% vs. 82.6%). The 3-year overall survival was 96.2% in MSI-H and 86.4% in MSI-S groups (p=.163). Multivariate analyses showed lower uterine involvement (p=.004), myometrial invasion ≥50% (p=.032), lymphovascular space invasion (p<.001) and MSI-S (p=.006) as prognostic factors for DFS. Our study showed that the prevalence of MMR gene deficiency in Thai patients with EC is common and associated with better outcomes. What is already known on this subject? Microsatellite instability (MSI) occurs in approximately 20–40% of endometrial cancer (EC) cases. MSI analysis in EC can identify patients at higher risk of hereditary nonpolyposis colorectal cancer and those having prognostic factors. Additionally, it is predictive of immune checkpoint inhibitor treatment. However, current evidence shows a correlation between clinicopathological characteristics and EC prognosis. Studies on EC and MSI status effect on survival outcome have yielded inconsistent results regarding the pathological significance of MSI in such malignancies. What do the results of this study add? The prevalence of mismatch repair (MMR) gene deficiency in Thai patients with EC is common (24.5%) and associated with better outcomes. What are the implications of these findings for clinical practice and/or further research? This study highlights the prevalence and impact of MSI on oncological outcomes in patients with EC in a low-incidence country. Future studies should focus on the detection of germline mutation to understand the accurate prevalence of Lynch syndrome in Thai patients with EC. [ABSTRACT FROM AUTHOR]

The aim of this study was to conduct a systematic review of research investigating the potential role of microsatellite instability (MSI) and loss of heterozygosity (LOH) in oral squamous cell carcinoma (OSCC), with a focus on molecular mechanisms, detection methods, and therapeutic approaches. Search for articles involved the PubMed and Scopus. Previous retrospective and prospective studies identified variations between oral cancers that exhibit microsatellite stability and LOH. In this search, 294 articles were initially retrieved. Of these, 70 were excluded due to duplication, 106 were identified as ineligible by automated tools, and 24 were excluded as they were published in languages other than English. An additional 94 articles were excluded, 32 of which focused on head and neck cancers broadly, and 8 could not be accessed due to withdrawal. Ultimately, a systematic review was conducted based on 54 selected articles. Among the chromosomes analyzed for MSI and LOH, the highest frequency of LOH was observed on chromosome 9p. The MSI subtype is particularly susceptible to immunotherapeutic methods, such as the use of anti-PD-L1 and anti-CTLA4 antibodies, owing to its strong immunogenicity and ubiquitous expression of immune checkpoint ligands. Given the distinct characteristics and clinical behavior of oral cancer with MSI compared to microsatellite stable disease, it is advisable to incorporate MSI testing into the diagnostic process for all stages of tumor development. This ensured that each patient had received precise and effective treatment., (© 2024 The Author(s). Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Background: The development mechanisms of Lynch syndrome (LS)-related breast cancer (BC) and rectal cancer are complex and variable, leading to personalized variations in diagnosis and treatment plans., Case Summary: This paper presents a comprehensive review of clinical diagnosis and treatment data from a patient with LS-associated BC and rectal cancer. Moreover, screening data and management guidelines, as well as relevant literature on LS, are included in this report. This study summarizes the molecular pathogenesis, clinicopathological features, and screening and management protocols for LS-associated BC and rectal cancer., Conclusion: Implementing early screening, prevention, and timely diagnosis and treatment measures is expected to reduce mitigate the incidence and mortality of LS-related BC and rectal cancer., Competing Interests: Conflict-of-interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Microsatellite instability (MSI)-high status is associated with good responsiveness to immune checkpoint inhibitors. Although MSI-high status has been actively investigated in pediatric brain tumors, studies of other pediatric solid tumors are lacking. Among 334 consecutive pediatric patients with solid tumors, we retrospectively analyzed formalin-fixed paraffin-embedded tumor tissues of 36 of 74 patients (49%) who died of disease. We assessed the MSI status in these tissues using five multiplexed markers. The results revealed that none of the patients had an MSI-high status. These results indicate that MSI-high status is a rare event in pediatric patients with refractory/relapsed solid tumors. Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.1998266 [ABSTRACT FROM AUTHOR]

Abstract Background Constitutional mismatch repair deficiency (CMMRD) is caused by biallelic pathogenic variants in one of the mismatch repair genes, and results in early onset colorectal cancer, leukemia, brain tumors and other childhood malignancies. Here we report a case of CMMRD with compound heterozygous variants in the MSH6 gene, including a de novo variant in multiple colorectal cancers. Case presentation An 11-year-old girl, who presented with multiple spots resembling café-au-lait macules since birth, developed abdominal pain, diarrhea and bloody stool over two months. Colonoscopy revealed multiple colonic polyps, including a large epithelial tumor, and pathological examination revealed tubular adenocarcinoma. Brain magnetic resonance imaging (MRI) showed an unidentified bright object (UBO), commonly seen in neurofibromatosis type 1 (NF1). Genetic testing revealed compound heterozygous variants, c. [2969T > A (p.Leu990*)] and [3064G > T (p.Glu1022*)] in the MSH6 gene; c.2969T > A (p.Leu990*) was identified as a de novo variant. Conclusions We present the first report of a CMMRD patient with a de novo variant in MSH6, who developed colorectal cancer in childhood. CMMRD symptoms often resemble NF1, as observed here. Physicians should become familiar with CMMRD clinical phenotypes for the screening and early detection of cancer.

Objective To investigate the defect of expression of mismatch repair genes(MMR) including MLH1, MSH2, MSH6 and PMS2 in sporadic colon cancer, and analyze the expression of MMR related to pathological change of patients with right colon cancer. Methods The data of 206 patients with colon cancer including 116 cases with left colon cancer and 90 cases with right colon cancer in our hospital were collected from January 2015 to August 2020. The expression of MMR including MLH1, MSH2, MSH6 and PMS2 was detected by immunohistochemistry. The relation of defect in expression of MMR to pathological changes in colon cancer was analyzed. Results The rate of expression defect of MMR in patients with right colon cancer was higher than that in patients with left colon cancer. The expression defect of MMR was significantly related to tumor differentiation and neural invasion in patients with right colon cancer (P

Yuan Gao,1,* Xiuping Zhang,2,* Tian Wang,1 Ye Zhang,1 Qingxuan Wang,1 Yuanjing Hu1 1Department of Gynecological Oncology, Tianjin Central Hospital of Gynecology & Obstetrics, Tianjin, People’s Republic of China; 2Reproductive Center, Shanxi Maternal and Child Health Hospital, Taiyuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuanjing Hu Department of Gynecological OncologyTianjin Central Hospital of Gynecology & Obstetrics, Tianjin 300100, People’s Republic of ChinaTel +86-18920196053Email huyuanjingtianjin@163.comPurpose: To investigate the genes of patients with sporadic endometrial cancer (EC) and suspected Lynch syndrome (LS)-related EC in the Chinese population. Identification of meaningful mutation sites can provide theoretical basis for molecular targeted therapy, aiming to improve the prognosis of patients with EC.Methods: We recruited 388 patients with EC for mismatch repair (MMR) immunohistochemistry and MLH1 methylation analysis. Based on the results, they were divided into four groups: MMR without deletion group (sporadic EC group 1); MLH1&PMS2 deletion and MLH1 methylation group (sporadic EC group 2); MSH2 and/or MSH6 deletion group (suspected LS group); and unclassified group (remainder cases). Patients from each group were randomly screened for whole-exome sequencing detection. Genome Analysis Toolkit, VarScant, MuTect, and CONTRA were used to detect the insertions/deletions, single nucleotide polymorphisms, and copy number variations. Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed with Database for Annotation, Visualization and Integrated Discovery. Protein–protein interaction analysis was accomplished through the STRING database.Results: The MMR immunohistochemistry results were positive (without MMR deletion) and negative in 299 patients and 89 patients, respectively. The 32, 10, 13, and 7 patients in the sporadic EC group 1, sporadic EC group 2, suspected LS group, and unclassified group were randomly selected for whole-exome sequencing, respectively. These three groups had a total of 86 common mutation sites, which were distributed on 26 genes. Among the top 30 common high-frequency mutation sites, 12, 5, 4, and 3 mutation sites were located on HNRNPCL1, PRAMEF1, HNRNPCL2, and CFAP74, respectively. Protein–protein interaction analysis showed that DFFB was associated with the most genes. There were some differences in the number of specific mutations in the families of different LS-related EC proband.Conclusion: HNRNPCL1, PRAMEF1, CFAP74, and DFFB may be potential biomarkers for EC or LS-related EC.Keywords: endometrial cancer, Lynch syndrome, whole-exome sequencing, WES, mismatch repair gene, gene mutation

Abstract Background Lynch syndrome (LS), which is known as a hereditary cancer syndrome, is distinguished by microsatellite instability, represented by the altered number of repetitive sequences in the coding and/or non-coding region. Immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins (e.g., MLH1, MSH2, MSH6, and PMS2) has been recognized as an useful technique for screening of LS. Previous study has shown that the assessment of IHC, however, requires specific caution due to variable staining patterns even without germline mutations in MMR genes. Case presentation A 48-year-old man, who had been treated for anaplastic astrocytoma, was referred to our department for the precise examination of progressing anemia. Whole-body examination revealed two advanced carcinomas in descending colon and stomach. A hypo-vascular mass lesion was detected in liver as well. Pathological diagnosis (on surgical specimens) was poorly differentiated adenocarcinoma in descending colon, moderately differentiated tubular adenocarcinoma in stomach, and liver metastasis, which is possibly from colon. It was suspected that this case would be Turcot’s syndrome-type-1 due to its specific family history having two cases of colon cancer within the second relatives. Pathogenic frameshift mutations in codon 618 of MLH1 gene was identified. Immunohistochemical analyses (IHC) demonstrated complete loss of MLH1 immuno-expression as well as of PMS2 except for those in brain tumor. Although frameshift mutation was not found in MSH6 gene, histological expression of MSH6 was patchy in primary colon carcinoma and was completely lost in the metastatic site in liver. MSH6 expression in gastric carcinoma, a coincidental cancer in this case, was intact. An abnormal (C)8 region was identified by the cloned PCR of colon and liver tumors but not from gastric cancer. Frameshift mutation in a (C)8 tract in exon 5 of the MSH6 gene was also detected in liver metastasis. Conclusion This case supports a plausible mechanism, proposed by a previous literature, for the reduced expression of MSH6 in a somatic mutation manner, which might preferentially happen in colon cancer rather than in stomach carcinoma in MLH1/PMS2-deficient type of Turcot’s syndrome type 1.

Wei-Hua Shao,1– 4,* Cheng-Yu Wang,4,5,* Lei-Yun Wang,1– 4 Fan Xiao,1– 4 De-Sheng Xiao,6 Hao Yang,4,5 Xue-Ying Long,7 Le Zhang,8 Heng-Gui Luo,9 Ji-Ye Yin,1– 4 Wei Wu4,5 1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410078, People’s Republic of China; 2Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, People’s Republic of China; 3Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, People’s Republic of China; 4Department of Geratic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People’s Republic of China; 5National Clinical Research Center for Geriatric Disorders, Changsha, Hunan 410008, People’s Republic of China; 6Department of Pathology, Xiangya Hospital/School of Basic Medicine, Central South University, Changsha 410078, Hunan, People’s Republic of China; 7Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China; 8Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 9Department of General Surgery, The Central Hospital of Xiangtan City, Xiangtan, Hunan, People’s Republic of China *These authors contributed equally to this workCorrespondence: Wei WuDepartment of Geratic Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, Hunan, People’s Republic of ChinaTel +86 731 89753053Email wwtw1972@126.comPurpose: In order to clarify which variants of the MMR gene could provide current “healthy” members in affected families a more accurate risk assessment or predictive testing.Patients and Methods: One family, which meets the criteria according to both Amsterdam I/II and Bethesda guidelines, is reported in this study. The proband and some relatives of the patient have been investigated for whole genome sequencing, microsatellite instability, immunohistochemical MMR protein staining and verified by Sanger sequencing.Results: A heterozygous insertion of uncertain significance (c.420dup, p.Met141Tyrfs) in MSH2 gene was found in proband (III-16) and part of His relatives. The variant was associated with a lack of expression of MSH2 protein (MMR deficient) and high microsatellite instability analysis (MSI) status in tumor tissues of LS patients. In addition, we found that the variant could affect the expression of MSH2 and the response to chemotherapy drugs in vitro.Conclusion: We identified an insertion mutation (rs1114167810, c.420dup, p.Met141Tyrfs) in MSH2 in LS using whole genome-wide sequencing (WGS). We further confirmed that this mutation plays an important role in LS patients of this pedigree based on in vivo and vitro study.Keywords: Lynch syndrome, genetic variation, mismatch repair gene, MSH2, chemotherapy resistance

Muir–Torre syndrome (MTS), a rare subtype of Lynch syndrome, is mostly autosomal dominant, which is caused by germline mutations in DNA mismatch repair (MMR) genes, the resulting microsatellite instability (MSI) of which increases the risk of developing sebaceous and other visceral tumors. Several reports have showed an association between immunosuppressive agents and the progression of latent MTS. In this report, we described a 41-year-old man with a history of kidney transplantation, having a rapid growth of the nodule on the anterior chest under immunosuppressive therapy, which was histologically proved to be sebaceous carcinoma. Systemic evaluation for visceral malignancies revealed sigmoid adenocarcinoma. These findings were consistent with the clinical diagnosis of MTS. Histological findings showed an absence of MMR proteins, including MSH2 and MSH6 both in the sebaceous carcinoma and sigmoid adenocarcinoma on immunohistochemical (IHC) analysis. A frame-shift mutation of c.229_230delAG (p. Ser77fs) in the MSH2 exon 2 in the lesion was detected by next-generation sequencing (NGS) analysis. This case report not only reveals a new site of MSH2 mutation in this family of East Asian descent but also highlights the importance of adequate diagnosis for Muir–Torre syndrome, as well as further prevention of the development of latent visceral tumors in kidney transplant recipients.

Muir–Torre syndrome (MTS), a rare subtype of Lynch syndrome, is mostly autosomal dominant, which is caused by germline mutations in DNA mismatch repair (MMR) genes, the resulting microsatellite instability (MSI) of which increases the risk of developing sebaceous and other visceral tumors. Several reports have showed an association between immunosuppressive agents and the progression of latent MTS. In this report, we described a 41-year-old man with a history of kidney transplantation, having a rapid growth of the nodule on the anterior chest under immunosuppressive therapy, which was histologically proved to be sebaceous carcinoma. Systemic evaluation for visceral malignancies revealed sigmoid adenocarcinoma. These findings were consistent with the clinical diagnosis of MTS. Histological findings showed an absence of MMR proteins, including MSH2 and MSH6 both in the sebaceous carcinoma and sigmoid adenocarcinoma on immunohistochemical (IHC) analysis. A frame-shift mutation of c.229_230delAG (p. Ser77fs) in the MSH2 exon 2 in the lesion was detected by next-generation sequencing (NGS) analysis. This case report not only reveals a new site of MSH2 mutation in this family of East Asian descent but also highlights the importance of adequate diagnosis for Muir–Torre syndrome, as well as further prevention of the development of latent visceral tumors in kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Abstract Background Sebaceous carcinoma is a rare but progressive malignant skin cancer, and the incidence is approximately five times higher in post-transplant patients than in people who have not received kidney transplants. Sebaceous carcinoma is sometimes found concurrently with visceral cancers and a genetic abnormality, Muir–Torre syndrome. We report the case of a female kidney transplant recipient with sebaceous carcinoma concurrent with colon cancer 10 years after transplantation. Case presentation A 43-year-old woman was admitted due to a rapidly progressive tumor on her head. Histologically, the tumor was diagnosed as sebaceous carcinoma. We diagnosed her with Muir–Torre syndrome based on the following evidence: 1) high prevalence of microsatellite instability in gene locus assay, 2) absence of mismatch repair proteins in the sebaceous carcinoma on immunohistochemical analysis, and 3) a genetic mutation of 1226_1227delAG in the MSH2 exon 7 in the lesion detected by DNA sequencing analysis. Several reports have shown an association between immunosuppressive agents and latent Muir–Torre syndrome progression. Therefore, the progression of colon cancer in this case originated from her genetic mutation for Muir–Torre syndrome and long-term use of immunosuppressive agents. Conclusion This case report not only highlights the importance of adequate diagnosis and therapy for Muir–Torre syndrome, but also suggests the further prevention of the development of malignant tumors in kidney transplant recipients. Physicians should be mindful that sebaceous carcinoma in kidney transplant recipients is highly concurrent with Muir–Torre syndrome.

Abstract Background Lynch syndrome (LS) is the commonest inherited cancer syndrome caused by pathogenic variants of germline DNA mismatch repair (g.MMR) genes. Genome‐wide sequencing is now increasingly applied for tumor characterization, but not for g.MMR. The aim of this study was to evaluate the incidence and pathogenicity of g.MMR variants in Japanese cancer patients. Methods Four g.MMR genes (MLH1, MSH2, MSH6, and PMS2) were analyzed by next generation sequencing in 1058 cancer patients (614 male, 444 female; mean age 65.6 years) without past diagnosis of LS. The g.MMR variant pathogenicity was classified based on the ClinVar 2015 database. Tumor MMR immunohistochemistry, microsatellite instability (MSI), and BRAF sequencing were also investigated in specific cases. Results Overall, 46 g.MMR variants were detected in 167 (15.8%) patients, 17 likely benign variants in 119 patients, 24 variants of uncertain significance (VUSs) in 68 patients, two likely pathogenic variants in two patients, and three pathogenic variants in three (0.3%) patients. The three pathogenic variants included two colorectal cancers with MLH1 loss and high MSI and one endometrial cancer with MSH6 loss and microsatellite stability. Two likely pathogenic variants were shifted to VUSs by ClinVar (2018). One colon cancer with a likely benign variant demonstrated MLH1 loss and BRAF mutation, but other nonpathogenic variants showed sustained MMR and microsatellite stability. Conclusions Universal sequencing of g.MMR genes demonstrated sundry benign variants, but only a small proportion of cancer patients had pathogenic variants. Pathogenicity evaluation using the ClinVar database agreed with MSI, MMR immunohistochemistry, and BRAF sequencing.

Objective: This study aims to assess the accuracy of Amsterdam II criteria (AMII) and Revised Bethesda Guidelines (RBG) compared to molecular tests in Thai patients. Material and Methods: One hundred eighty-one patients were enrolled. Demographic data and pathological features and locations of tumors were recorded. Family history of the patients was reviewed by AMII and RBG. Tissue samples were collected and molecular testing was tested by microsatellite instability (MSI) analysis and immunohistochemistry (IHC). Statistical analysis was used to estimate the sensitivity and specificity of AMII and RBG compared to molecular testing. Results: Of the patients, 2.8% fulfilled the AMII criteria and 28.1% met the RBG criteria. Molecular testing showed 16.57% and 13.8% of the samples lost at least 1 out of 4 mismatch repair (MMR) proteins in the IHC test. In addition, 10.5% of patients had both microsatellite instability high (MSI-H) and loss of protein MMR expression. The sensitivity and specificity of AMII were 6.7% and 98.0%, respectively, while for the RBG they were 70.0% and 82.1%, respectively. Conclusion: The present study suggests that for patients who complete the AMII, doctors should be highly suspicious of Lynch syndrome, due to its high specificity. The RBG is useful for screening for Lynch syndrome and the selection of individuals for further molecular testing.

We present a case of a 69-year-old male patient diagnosed with high grade (T1 HG) urothelial carcinoma of the bladder who progressed rapidly towards muscle invasive disease and eventually death despite neoadjuvant chemotherapy and radical cystectomy. We postulate that this may be due to a deleterious underlying somatic gene mutation. Molecular pathologic data obtained on the initial, non-muscle invasive tumor and the final cystectomy specimen, revealed the same TP53 mutation (p.Arg110Pro) in both specimens with a variant allele frequency of 44%. The tumor was tested for 50 common gene mutations in urothelial carcinoma and no other identifiable DNA repair mutations were found, suggesting that this specific TP53 aberration, one that has never been reported in the bladder cancer literature, could be particularly deleterious. Knowing that bladder cancer cell lines that lack TP53 are more resistant to cisplatin and because the tumor lacked any other DNA mutation, this patient may have been a candidate for upfront surgery without neoadjuvant chemotherapy. In addition to histological analysis of the tumor, early molecular and cytogenetic characterization of resected tissue is essential in predicting progression and eventual prognosis of the disease based on identifiable gene mutations. Further comparative prospective studies are required to clarify the importance of molecular heterogeneity and subtyping in bladder cancer. [ABSTRACT FROM AUTHOR]

Background: Constitutional mismatch repair deficiency (CMMRD) is caused by biallelic pathogenic variants in one of the mismatch repair genes, and results in early onset colorectal cancer, leukemia, brain tumors and other childhood malignancies. Here we report a case of CMMRD with compound heterozygous variants in the MSH6 gene, including a de novo variant in multiple colorectal cancers.Case Presentation: An 11-year-old girl, who presented with multiple spots resembling café-au-lait macules since birth, developed abdominal pain, diarrhea and bloody stool over two months. Colonoscopy revealed multiple colonic polyps, including a large epithelial tumor, and pathological examination revealed tubular adenocarcinoma. Brain magnetic resonance imaging (MRI) showed an unidentified bright object (UBO), commonly seen in neurofibromatosis type 1 (NF1). Genetic testing revealed compound heterozygous variants, c. [2969T > A (p.Leu990*)] and [3064G > T (p.Glu1022*)] in the MSH6 gene; c.2969T > A (p.Leu990*) was identified as a de novo variant.Conclusions: We present the first report of a CMMRD patient with a de novo variant in MSH6, who developed colorectal cancer in childhood. CMMRD symptoms often resemble NF1, as observed here. Physicians should become familiar with CMMRD clinical phenotypes for the screening and early detection of cancer. [ABSTRACT FROM AUTHOR]

We report the case of an 11-month-old child who presented with a change in voice, increased weight, and hirsutism, who was also found to have elevated levels of serum cortisol and testosterone, showing three synchronous malignancies in the liver, left adrenal gland, and posterior mediastinum. Clinical exome sequencing report revealed germline TP53 (P177A) and MLH3 (V741P) mutations with NMYC positive neuroblastoma. At the outset, this may look like a Li-Fraumeni syndrome (LFS) with TP53 germline mutation but lacks other features to be termed as LFS or Li-Fraumeni-like syndrome. The gene mutation variant found in this case (P177A) is a novel missense mutation which has never been reported, and the MLH3 gene mutation variant V741P has not been previously associated with any of the malignancies seen in this child. [ABSTRACT FROM AUTHOR]

Background: Lynch syndrome (LS), which is known as a hereditary cancer syndrome, is distinguished by microsatellite instability, represented by the altered number of repetitive sequences in the coding and/or non-coding region. Immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins (e.g., MLH1, MSH2, MSH6, and PMS2) has been recognized as an useful technique for screening of LS. Previous study has shown that the assessment of IHC, however, requires specific caution due to variable staining patterns even without germline mutations in MMR genes. Case presentation: A 48-year-old man, who had been treated for anaplastic astrocytoma, was referred to our department for the precise examination of progressing anemia. Whole-body examination revealed two advanced carcinomas in descending colon and stomach. A hypo-vascular mass lesion was detected in liver as well. Pathological diagnosis (on surgical specimens) was poorly differentiated adenocarcinoma in descending colon, moderately differentiated tubular adenocarcinoma in stomach, and liver metastasis, which is possibly from colon. It was suspected that this case would be Turcot's syndrome-type-1 due to its specific family history having two cases of colon cancer within the second relatives. Pathogenic frameshift mutations in codon 618 of MLH1 gene was identified. Immunohistochemical analyses (IHC) demonstrated complete loss of MLH1 immuno-expression as well as of PMS2 except for those in brain tumor. Although frameshift mutation was not found in MSH6 gene, histological expression of MSH6 was patchy in primary colon carcinoma and was completely lost in the metastatic site in liver. MSH6 expression in gastric carcinoma, a coincidental cancer in this case, was intact. An abnormal (C)8 region was identified by the cloned PCR of colon and liver tumors but not from gastric cancer. Frameshift mutation in a (C)8 tract in exon 5 of the MSH6 gene was also detected in liver metastasis. Conclusion: This case supports a plausible mechanism, proposed by a previous literature, for the reduced expression of MSH6 in a somatic mutation manner, which might preferentially happen in colon cancer rather than in stomach carcinoma in MLH1/PMS2-deficient type of Turcot's syndrome type 1. [ABSTRACT FROM AUTHOR]

Background: Paired tumor-normal targeted next-generation sequencing (NGS) is primarily used to identify actionable somatic mutations, but can also detect germline variants including pathogenic germline mutations in DNA mismatch repair (MMR) genes that underlie Lynch syndrome. In the present study we examined paired NGS data from lung cancer patients to identify germline mutations in MMR genes. As lung cancer is not one of the recognized Lynch syndrome-associated neoplasms, we also investigated whether these lung cancer cases are due to Lynch syndrome or are instead sporadic cancers occurring in Lynch syndrome patients.Methods: A retrospective study of 1,179 lung cancer patients with available paired NGS data was performed to identify germline mutations in the MMR genes MLH1, MSH2, MSH6, and PMS2, and evaluate tumor mutation burden (TMB). Microsatellite instability (MSI) testing was done on select cases with MMR gene mutations by either NGS or PCR/capillary electrophoresis approach. Immunohistochemistry (IHC) for MMR proteins was performed in select patients.Results: Pathogenic or likely-pathogenic germline mutations in PMS2, MSH2, or MSH6 were detected in 0.5% (6/1,179) of lung cancer patients; three of the patients had a family history of colon or gastric cancer. The median age at diagnosis of these cases was 68.5 years old. None of these six patients exhibited MSI or loss of MMR protein expression. Among them, no second hit somatic mutations in MMR genes (including single-nucleotide variants, small insertions or deletions and copy number alterations) were detected, and the median TMB was 4.5 muts/MB. Subsequent genetic testing of family members identified new Lynch syndrome cases in two first-degree relatives.Conclusion: These data imply that lung cancers in Lynch syndrome patients are unrelated to the underlying Lynch syndrome diagnosis and occur spontaneously. Nonetheless, paired tumor-normal NGS can identify germline mutations to help reveal Lynch syndrome in cancer patients. This has important implications for cancer screening and risk reduction in these patients and their families.

Aim: Microsatellite instability (MSI), which reflects loss of DNA mismatch repair (MMR) activity, and immunohistochemistry (IHC) for MMR proteins are employed as screening examinations for Lynch syndrome (LS). Recent studies revealed that there is a population of MSI‐high tumors in sporadic endometrial cancer (EC). However, MSI data for Japanese EC patients are scarce. Furthermore, sporadic estrogen‐dependent EC (type I) is generally considered to arise from hyperplasia. Because LS is usually associated with type I EC, we hypothesized that MSI might be involved in the oncogenic process in some sporadic EC. We conducted MSI testing to reveal MSI status in sporadic Japanese EC. IHC for MMR proteins was also performed. Methods: Ninety‐eight tissue samples of sporadic ECs from Japanese patients were used for IHC and MSI examinations. We also evaluated MMR protein expressions in the background normal endometrium. Results: Microsatellite instability‐high was observed in 10.2% of 98 cases with sporadic EC, a lower percentage than that in Western studies. Loss of some MMR proteins was observed in 23 cases (23.5%) and there was a significant correlation with MSI‐high status (P < 0.001). Concerning the background endometrium, two cases showed partial loss of MLH1 and PMS2, corresponding to adjacent EC lesions, suggesting that MMR deficiency may already be present in the background endometrium. Conclusion: The MSI‐high rate was low in our Japanese cohort. Our data confirmed the usefulness of MMR protein assessment for MSI screening in Japanese EC patients. Furthermore, IHC of the background endometrium might reveal the mechanism of MSI‐high tumorigenesis. [ABSTRACT FROM AUTHOR]

Background: Lynch syndrome (LS) is the commonest inherited cancer syndrome caused by pathogenic variants of germline DNA mismatch repair (g.MMR) genes. Genome‐wide sequencing is now increasingly applied for tumor characterization, but not for g.MMR. The aim of this study was to evaluate the incidence and pathogenicity of g.MMR variants in Japanese cancer patients. Methods: Four g.MMR genes (MLH1, MSH2, MSH6, and PMS2) were analyzed by next generation sequencing in 1058 cancer patients (614 male, 444 female; mean age 65.6 years) without past diagnosis of LS. The g.MMR variant pathogenicity was classified based on the ClinVar 2015 database. Tumor MMR immunohistochemistry, microsatellite instability (MSI), and BRAF sequencing were also investigated in specific cases. Results: Overall, 46 g.MMR variants were detected in 167 (15.8%) patients, 17 likely benign variants in 119 patients, 24 variants of uncertain significance (VUSs) in 68 patients, two likely pathogenic variants in two patients, and three pathogenic variants in three (0.3%) patients. The three pathogenic variants included two colorectal cancers with MLH1 loss and high MSI and one endometrial cancer with MSH6 loss and microsatellite stability. Two likely pathogenic variants were shifted to VUSs by ClinVar (2018). One colon cancer with a likely benign variant demonstrated MLH1 loss and BRAF mutation, but other nonpathogenic variants showed sustained MMR and microsatellite stability. Conclusions: Universal sequencing of g.MMR genes demonstrated sundry benign variants, but only a small proportion of cancer patients had pathogenic variants. Pathogenicity evaluation using the ClinVar database agreed with MSI, MMR immunohistochemistry, and BRAF sequencing. [ABSTRACT FROM AUTHOR]

The incidence of bilateral testicular germ cell tumor (TGCT) is 1% to 5%. Despite the high rate of treatment success, resistance to chemotherapy has a detrimental effect. Some studies found MMR and BRAF gene mutations to be associated with chemotherapy resistance, which has not been found by others. However, the role of microsatellite instability (MSI) and BRAF mutations in bilateral disease has not been investigated. In this article, we studied the clinicopathologic characteristics and immunohistochemical expressions of MMR and BRAF in 13 patients with bilateral TGCT. Bilateral tumors were found in 4% of patients in our data. The mean ages at the first and subsequent diagnoses were 26.9 and 28.3 years, respectively. Eleven patients had metachronous disease; and the mean period between both tumors was 4.9 years. Six had mixed GCTs (MGCT) initially and later developed contralateral seminoma, 3 had bilateral MGCTs; 1 initially had pure embryonal carcinoma and subsequently MGCT and finally, 1 patient had initial seminoma and contralateral germ cell neoplasia in situ only. Of the patients with synchronous GCT, 1 had a MGCT and contralateral non-seminoma and 1 had seminoma and contralateral MGCT. In metachronous cases, 40% and 78% had an initial and subsequent stage of pT1, respectively. Hormonal and/or metastatic recurrence was observed in 30% of metachronous tumors. Six patients received chemotherapy, including patients with metastasis. No progression occurred after therapy. MLH1, PMS2, MSH2, and MSH6 staining was retained in all tumors. No BRAF staining was found. In conclusion, we found no association between bilateral TGCT and the MMR/MSI pathway and that subsequent metachronous tumors behaved much more indolently. [ABSTRACT FROM AUTHOR]

Lynch syndrome is a cancer-predisposing syndrome inherited in an autosomal-dominant manner, wherein colon cancer and endometrial cancer develop frequently in the family, it results from a loss-of-function mutation in one of four different genes (MLH1, MSH2, MSH6, and PMS2) encoding mismatch repair proteins. Being located immediately upstream of the MSH2 gene, EPCAM abnormalities can affect MSH2 and cause Lynch syndrome. Mismatch repair proteins are involved in repairing of incorrect pairing (point mutations and deletion/insertion of simple repetitive sequences, so-called microsatellites) that can arise during DNA replication. MSH2 forms heterodimers with MSH6 or MSH3 (MutSα, MutSβ, respectively) and is involved in mismatch-pair recognition and initiation of repair. MLH1 forms a complex with PMS2, and functions as an endonuclease. If the mismatch repair system is thoroughly working, genome integrity is maintained completely. Lynch syndrome is a state of mismatch repair deficiency due to a monoallelic abnormality of any mismatch repair genes. The phenotype indicating the mismatch repair deficiency can be frequently shown as a microsatellite instability in tumors. Children with germline biallelic mismatch repair gene abnormalities were reported to develop conditions such as gastrointestinal polyposis, colorectal cancer, brain cancer, leukemia, etc., and so on, demonstrating the need to respond with new concepts in genetic counseling. In promoting cancer genome medicine in a new era, such as by utilizing immune checkpoints, it is important to understand the genetic and genomic molecular background, including the status of mismatch repair deficiency. [ABSTRACT FROM AUTHOR]

As inherited genetic alterations are important etiological factors causing endometrial cancer (EC), our study aimed to outline the ethnic‐related prevalence and the associated clinical and biological characteristics of germline mutations in cancer predisposition genes in Chinese EC patients. One hundred ninety‐eight Chinese EC patients were screened for germline mutations in a panel of cancer susceptibility genes using next‐generation sequencing combined with multiplex ligation‐dependent probe amplification. First, we found that among patients under 50 years of age, 26% (18/69) carried germline genetic mutations, all involving mismatch repair (MMR) genes except for one mutation affecting BRCA1. Second, when we focused on Lynch syndrome (LS) with additional selected patients, 45 were identified to carry pathogenic mutations in MMR genes, with a higher frequency found in MSH2 and MSH6. We found that age at onset, personal and familial history together with immunohistochemical assay results were the most useful criteria for the diagnosis of LS although limitations in routine practice and the sensitivity and specificity of each parameter should be taken into account. One pathogenic mutation in the PALB2 gene was detected in a patient with no breast cancer in her family. Interestingly, we identified a family carrying pathogenic variant in both PMS2 and BRCA1 genes with distinct clinical phenotypes. Multigene panel testing should be recommended to patients based on their clinical information and tumor phenotype. Our study also showed the genetic complexity in EC, which requires further investigations. What's new? Endometrial cancer incidence is increasing in China, presumably owing in part to greater exposure to environmental risk factors such as obesity and hormone therapy. The degree to which hereditary factors influence endometrial cancer burden in Asian populations remains uncertain. Here, screening for germline mutations shows that more than one‐fourth of young Asian endometrial cancer patients carry variants in cancer predisposition genes, primarily mismatch repair (MMR) genes. Most variants affected MMR genes associated with Lynch syndrome. Multigene panel testing further led to the identification of rare mutations in patients with no apparent family history, highlighting a clinical need for mutational screening. [ABSTRACT FROM AUTHOR]

Background: Paired tumor-normal targeted next-generation sequencing (NGS) is primarily used to identify actionable somatic mutations, but can also detect germline variants including pathogenic germline mutations in DNA mismatch repair (MMR) genes that underlie Lynch syndrome. In the present study we examined paired NGS data from lung cancer patients to identify germline mutations in MMR genes. As lung cancer is not one of the recognized Lynch syndrome-associated neoplasms, we also investigated whether these lung cancer cases are due to Lynch syndrome or are instead sporadic cancers occurring in Lynch syndrome patients. Methods: A retrospective study of 1,179 lung cancer patients with available paired NGS data was performed to identify germline mutations in the MMR genes MLH1, MSH2, MSH6 , and PMS2 , and evaluate tumor mutation burden (TMB). Microsatellite instability (MSI) testing was done on select cases with MMR gene mutations by either NGS or PCR/capillary electrophoresis approach. Immunohistochemistry (IHC) for MMR proteins was performed in select patients. Results: Pathogenic or likely-pathogenic germline mutations in PMS2, MSH2 , or MSH6 were detected in 0.5% (6/1,179) of lung cancer patients; three of the patients had a family history of colon or gastric cancer. The median age at diagnosis of these cases was 68.5 years old. None of these six patients exhibited MSI or loss of MMR protein expression. Among them, no second hit somatic mutations in MMR genes (including single-nucleotide variants, small insertions or deletions and copy number alterations) were detected, and the median TMB was 4.5 muts/MB. Subsequent genetic testing of family members identified new Lynch syndrome cases in two first-degree relatives. Conclusion: These data imply that lung cancers in Lynch syndrome patients are unrelated to the underlying Lynch syndrome diagnosis and occur spontaneously. Nonetheless, paired tumor-normal NGS can identify germline mutations to help reveal Lynch syndrome in cancer patients. This has important implications for cancer screening and risk reduction in these patients and their families. [ABSTRACT FROM AUTHOR]

Background: Lynch syndrome (LS) is a predominantly inherited syndrome caused by a pathological germline mutation in one of the mismatch repair (MMR) genes. Whether breast cancer (BC) is one of the LS-associated tumors is controversial. The aim of this retrospective cohort study was to evaluate the clinical features of BC in Japanese patients with LS. Methods: Of 38 mutation carriers, 4 females with BC were examined in this study. Results: Two of the four patients had multiple BC. Their median age at the diagnosis of BC was 63 (range, 47–84) years. The TNM (6th revision) stages of the six BCs were as follows: stage I, 33% (2/6); stage IIA, 50% (3/6); and stage IIB, 17% (1/6). Histological examination revealed four scirrhous, one papillotubular, and one medullary carcinoma. The positive ratios for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth receptor 2 (HER2) were 83.3% (5/6), 83.3% (5/6), and 16.7% (1/6), respectively. Two of the three specimens showed MSI-H and one showed MSS. These MSI-H BCs had tumor-infiltrating lymphocytes. Two of the three specimens showed an absence of MLH1 and PMS2 proteins on immunohistochemistry. The cumulative risks for a person with LS to develop BC were 4.35% at the age of 50 years, 8.70% at 60 years, and 21.5% at 70 years. Conclusions: Our study results showed BC in Japanese females with LS to be an MSI-H tumor, which was ER and PgR positive and HER2 negative. [ABSTRACT FROM AUTHOR]

Abstract To investigate the relationship between DNA repair gene methylation and chronic coal-burning fluorosis. The methylation rates of O6-methylguanine-DNA- methyltransferase gene MGMT, a DNA repair gene and mismatch repair gene MutL homolog 1 (MLH1) were analysed by methylation of specific PCR (MSP), and the levels of mRNA in the blood of the chronic fluorosis rats and the patients in the region of endemic coal-burning fluorosis were determined by real-time PCR. The levels of mRNA and protein of MGMT and MLH1 in the liver tissue of the chronic fluorosis rats were determined by real-time PCR and Western blot respectively. The results showed an increased methylation of the MGMT and MLH1 genes in the blood of the patients in the fluorosis region that correlated positively with the severity of fluorosis. The mRNA levels of MGMT and MLH1 genes from the patients in fluorosis region were lower than those of a control group, and also showed a positive correlation with the severity of fluorosis. Both the protein and mRNA levels of MGMT and MLH1 genes from the blood of rats and liver tissue in a fluoride-treated group were lower than those of a control non-fluoride treated group. These results indicate that the degree of methylation of MGMT and MLH1 genes is altered in fluorosis disease, the resulting changed expression of these repair genes may play a role in the liver damage caused by fluoride. [ABSTRACT FROM AUTHOR]

Mismatch repair genes mutS homologs 6/2 (MSH6/2) expressions are involved in tumor growth and programmed cell death 1 ligand 1 (PD-L1) expression in tumor immunity, but the direct association with pituitary adenomas (PAs) is not well understood. We aimed to clarify the effects of MSH6/2 and PD-L1 expression on tumor proliferation and invasiveness in nonfunctioning (NF) PAs. We performed immunohistochemistry to classify the NFPAs into gonadotroph adenoma (GAs), silent corticotroph adenomas (SCAs), null cell adenoma (NCAs), and pituitary transcription factor 1 (PIT1) lineage PAs. We evaluated MSH6/2 and PD-L1 mRNA expressions in NFPAs by real-time PCR (n = 73), and statistically analyzed the expressions and clinicopathological factors. We also investigated the effect of MSH6 knockout on PD-L1 expression in AtT-20ins and GH3. MSH6/2 expressions were significantly lower in invasive NFPAs than in non-invasive NFPAs, and lower in SCAs and NCAs than in GAs. MSH6/2 expressions were positively associated with PD-L1 expression. PD-L1 expression was significantly lower in invasive NFPAs than in non-invasive NFPAs, and lower in SCAs and NCAs than in GAs. Although MSH6/2 expressions also tended to be lower in PIT1 lineage PAs than in GAs, PIT1 lineage PAs expressed PD-L1 equivalently to GA, which was unlike SCAs and NCAs. MSH6 knockout in AtT-20ins and GH3 significantly decreased PD-L1 expression (75% and 34% reduction, respectively) with cell proliferation promotion. In conclusion, differences in MSH6/2 and PD-L1 expressions of SCAs, NCAs, and PIT1-lineage PAs from those of GAs appear to contribute to their clinically aggressive characteristics, such as more proliferation and invasiveness.

Turcot’s syndrome is a rare genetic disorder clinically characterised by concomitant occurrence of primary brain tumour and colorectal polyposis. It is commonly seen in association with two other syndromes, namely, hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP). It is characterized by an increased risk for early onset of other tumours including of endometrium, stomach, small intestine, hepatobiliary system, kidney, ureter, brain and ovary. We report the rare occurrence of Turcot syndrome in a 13-year-old girl who presented with focal seizure.

Background: Early-stage colon cancer is increasingly detected by colonoscopic screening. The development of adjuvant chemotherapy in patients with stage-II colon cancer remains a challenge. In Thailand, the clinicopathological risk factors [CPR] are currently used as criteria for the selection of adjuvant chemotherapy in each patient. Previous reports showed that mismatch repair gene [MMR] status could be a prognostic factor for the decision on adjuvant chemotherapy. Objective: To determine the characteristics of MMR status and CPR of Thai colon cancer cases, with treatment follow-up in stage-II colon cancer by MMR and CPR. Materials and Methods: This was a preliminary report of patients with stage-II colon cancer who received treatment at Chulabhorn Hospital. MMR status was determined by microsatellite instability [MSI] testing and CPR was determined in each patient. Patients with deficient MMR and low CPR received post-surgery surveillance whereas those with proficient MMR and/or high CPR were treated with adjuvant chemotherapy (5-FU/LV). The follow-up of adverse events, serious adverse events, disease-free survival [DFS], and overall survival [OS] was at the third and fifth years. Results: During July 4,2014 to December 31,2016, there were 31 cases of stage-II colon cancer. All of them were at the stage of T3NoMo (IIA). High CPR and low CPR were found in 20 cases (64.52%) and 11 cases (35.48%), respectively. There were 28 cases with MMR testing results. Proficient MMR (MSI-low) was observed in 23 cases (82.14%). There were 3 cases with disease recurrence, all of which were in proficient MMR group and received adjuvant chemotherapy. Serious adverse events were found in 2 cases with infection during febrile neutropenia after chemotherapy but no treatment-related death was observed. DFS and OS could not yet be evaluated. Conclusion: Incidence of proficient MMR (MSI-low) in Thai patients with stage-II colon cancer was comparable to that of other countries (80 to 90%). Treatment by adjuvant chemotherapy using MMR status and CPR was feasible with low serious adverse events. [ABSTRACT FROM AUTHOR]

Lynch syndrome(LS) is the most common hereditary colorectal cancer syndrome， an autosomal dominant inherited disease which is caused by mismatch repair system defect. Learning knowledge in the genetics and diagnosis of LS， and identifying at-risk patients and making a correct diagnosis are the keys to successful screening and surgical decision-making and chemoprevention which is important to decrease formation of and death from cancers. This article reviews recent developments in mainly the clinical features， genetics，current diagnostic standard and diagnosis， surveillance， management， treatment and other related syndromes of LS. [ABSTRACT FROM AUTHOR]