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Familial colorectal cancer (CRC) is a major public health problem by virtue of its relatively high frequency. Some 15-20% of all CRCs are familial. Among these, familial adenomatous polyposis (FAP), caused by germline mutations in the APC gene, accounts for less than 1%. Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome...
Citations
... Lynch syndrome (LS) is an autosomal-dominantly inherited cancer-predisposing disorder caused by a germline pathogenic variant (PV) in one of the mismatch repair (MMR) genes or deletions in the 3′ region of the EPCAM gene [1]. LS is associated with a very high lifetime risk of developing primarily colorectal cancer (CRC) and extracolonic cancers at a younger age, compared to the general population [1][2][3]. The lifetime risk of developing cancer in LS variant heterozygotes (LSVH) ranges from 30% to 80% depending on the mutated gene, cancer type, and other factors such as lifestyle, environmental exposure, epigenetic changes, and genetic risk modifiers [4][5][6]. ...
Lynch syndrome (LS) is an inherited cancer predisposition disorder associated with an elevated risk of developing various solid cancers, but mostly colorectal cancer (CRC). Despite having the same germline pathogenic variant (PV) in one of the mis-match repair genes or the EPCAM gene, Lynch syndrome variant heterozygotes (LSVH) exhibit a remarkable phenotypic variability in the risk of developing cancer. The role of human leukocyte antigen (HLA) in modifying cancer development risk prompted our hypothesis into whether HLA variations act as potential genetic modifiers influencing the age at cancer diagnosis in LSVH. To investigate this, we studied a unique cohort of 426 LSVH carrying the same germline PV in the hMLH1 gene (MLH1:c.1528C > T) in South Africa. We intuitively selected 100 LSVH with the greatest diversity in age at cancer diagnosis (n = 80) and the oldest cancer unaffected LSVH (n = 20) for a high-throughput HLA genotyping of 11 HLA class I and class II loci using the shotgun next-generation sequencing (NGS) technique on the Illumina MiSeq platform. Statistical analyses employed Kaplan–Meier survival analyses with log-rank tests, and Cox proportional hazards using binned HLA data to minimize type I error. Significant associations were observed between young age at cancer diagnosis and HLA-DPB1*04:02 (mean age: 37 y (25–50); hazard ratio (HR) = 3.37; corrected p-value (q) = 0.043) as well as HLA-DPB1 binned alleles (including HLA-DPB1*09:01, HLA-DPB1*10:01, HLA-DPB1*106:01, HLA-DPB1*18:01, HLA-DPB1*20:01, HLA-DPB1*26:01, HLA-DPB1*28:01, HLA-DPB1*296:01, and HLA-DPB1*55:01) (mean age: 37 y (17–63); HR = 2.30, q = 0.045). The involvement of HLA-DPB1 alleles in the age at cancer diagnosis may highlight the potential role of HLA class II in the immune response against cancer development in LSVH. When validated in a larger cohort, these high-risk HLA-DPB1 alleles could be factored into cancer risk prediction models for personalized cancer screening in LSVH.
... Integrative Genomics Viewer image of next-generation sequencing data of PIK3CA 179199217 A>G variant detected.can impair the correction of DNA replication errors, leading to MSI and an increased risk of CRC(Lynch and De la Chapelle, 1999) • Protein Tyrosine Phosphatase, Receptor Type J (PTPRJ):PTPRJ is a receptor-type protein tyrosine phosphatase involved in cell adhesion and signaling. In CRC, mutations in PTPRJ may disrupt cellular communication and adhesion, contributing to cancer progression) • PMS2 (PMS1 Homolog 2, Mismatch Repair System Component): PMS2 is a key player in the DNA mismatch repair system. ...
Colorectal cancer (CRC) ranks as the third leading cause of cancer-related deaths globally. It is characterized as a genomic disorder marked by diverse genomic anomalies, including point mutations, genomic rearrangements, gene fusions, and alterations in chromosomal copy numbers. This research aims to identify previously undisclosed genetic variants associated with an increased risk of CRC by employing next-generation sequencing technology. Genomic DNA was extracted from blood specimens of five CRC patients. The sequencing data of the samples are utilized for variant identification. In addition, the Integrative Genomic Viewer software (IGV) is used to visualize the identified variants. Furthermore, various in silico tools, including Mutation Taster and Align GVGD, are used to predict the potential impact of mutations on structural features and protein function. Based on the findings of this research, 12 different genetic variations are detected among individuals with CRC. Inherited variations are located within the following genes: MSH6, MSH2, PTPRJ, PMS2, TP53, BRAF, APC, and PIK3CA.
... Thus, it is also important in this subtype of endometrial carcinoma to evaluate a counselling procedure to identify the risk of Lynch syndrome. This syndrome is an autosomal dominant inherited cancer susceptibility, which is associated with germline mutations in one set of MMR genes (MLH1, MSH2, MSH6, and PMS) [29]. ...
Simple Summary
In a neoplasm, dedifferentiation is characterised by the presence of a high-grade neoplasm which can occur de novo, be juxtaposed to, or arise as a recurrence of a previously well-differentiated tumour. Usually, this occurrence results in mesenchymal neoplasms. In epithelial malignant neoplasms, dedifferentiation has been observed in salivary gland carcinomas including adenoid cystic carcinoma, mucoepidermoid carcinoma, myoepithelial carcinoma, and acinic cell carcinoma. In addition, dedifferentiated carcinomas have been reported in the pancreas and in the gastrointestinal and urinary tracts. In the female genital tract, dedifferentiated carcinoma have been described in the endometrium and ovary. Histologically, this entity is characterised by both low-grade endometrioid carcinoma and a solid undifferentiated component. It is especially important to recognise this subtype of the malignancy due to its fulminant clinical outcomes and a poorer prognosis than high-grade endometrioid carcinoma. From a review of the literature, we have extracted clinical, morphological, and immunohistochemical data useful for an accurate diagnosis and prognosis of this rare endometrial malignancy.
Abstract
Dedifferentiated endometrioid adenocarcinoma is characterised by the coexistence of an undifferentiated carcinoma and a low-grade endometrioid adenocarcinoma. The low-grade component in this subtype of endometrial carcinoma is Grade 1 or 2 according to the Federation of Gynaecology and Obstetrics (FIGO) grading system. The coexistence of low-grade endometrial carcinoma and solid undifferentiated carcinoma can cause diagnostic problems on histological examination. In fact, this combination can often be mistaken for a more common Grade 2 or Grade 3 endometrial carcinoma. Therefore, this subtype of uterine carcinoma can often go under-recognised. An accurate diagnosis of dedifferentiated endometrial carcinoma is mandatory because of its poorer prognosis compared to Grade 3 endometrial carcinoma, with a solid undifferentiated component that can amount to as much as 20% of the entire tumour. The aim of this review is to provide clinical, immunohistochemical, and molecular data to aid with making an accurate histological diagnosis and to establish whether there are any findings which could have an impact on the prognosis or therapeutic implications of this rare and aggressive uterine neoplasm.
... The genes MLH1, MSH2, MSH6, and PMS2 are crucial for the correction of base-base and insertion/deletion mismatches generated during DNA replication and recombination, thereby preventing mutations from being permanent in dividing cells [1]. Inactivation in one of these genes can lead to various types of cancer in humans [2,3]. ...
... Inherited pathogenic, mono-allelic mutations in one of the four MMR genes can lead to Lynch syndrome (LS; autosomal dominant) with increased risk of colorectal cancers, endometrial cancers, and other malignancies in the fourth and fifth decades of life [3]. LS-associated tumors can also develop due to somatic loss of remaining wild-type alleles, leading to DNA damage and microsatellite instability (MSI) [4]. ...
Defective repair of DNA when heterozygous leads to Lynch syndrome (LS) which is inherited in an autosomal dominant fashion. When homozygous, defective repair of DNA leads to constitutional mismatch repair deficiency syndrome (CMMRD), inherited in an autosomal recessive fashion with a predisposition to develop a pattern of childhood malignancies including hematological and solid cancers. We report such a case of a 21-year-old male who developed anaplastic astrocytoma, Burkitt lymphoma, osteochondroma, and colon cancer successively. Each cancer was treated successfully except for colon cancer which developed liver metastasis after the initial treatment with curative intent. However, the patient has been treated for liver metastasis with curative intent and is currently on follow-up. This case report highlights the importance of maintaining a low threshold for investigating CMMRD and other potential cancer predisposition syndromes when a patient presents with multiple cancers in the early years of their life.
... APC is a tumour suppressor gene encoding a large 312 kDa protein with an important role in the wntsignalling pathway, intercellular adhesion, cytoskeleton stabilisation, cell cycle regulation, and apoptosis [41].Inactivating, predominantly truncating, mutations of APC are thought to allow unregulated transcription of oncogenes such as c-myc and cyclin D1, therefore promoting tumorigenesis [42,43].The p53 tumour suppressor gene encodes a nuclear phosphoprotein with the ability to bind directly to DNA and act as a transcriptional activator. Genes activated by p53 cause cell cycle arrest allowing a damaged cell to either repair itself or be targeted for apoptosis [44]. ...
Effect of Feeding Functional Snack “Khakhra” on Blood Glucose and Antioxidant Status of Type II Diabetic Males Residing in Anand
... Worldwide, colorectal cancer (CRC) is estimated to be the third and second most common cancer among men and women, respectively, with an increasing prevalence. 1,2 Although the 5-year survival rates was reported to be 90% and 71% for localized and regionalized CRC, respectively, the 5-year survival rate for metastatic CRC remains low at 14%. 3 CRC is associated with several risk factors, such as a diet high in red and processed meat, 4,5 heavy smoking and alcohol intake, 6 obesity, 7 and a family history of CRC. 8 Genes responsible for the carcinogenesis of CRC are already known partially, including the following: microsatellite instability (MSI) as a manifestation of mismatch repair (MMR) gene (MLH1, MSH2, MSH6, PMS1, and PMS2) germline deficiency, 9,10 biallelic MUTYH mutations leading younger-age onset of CRC, 11 and germline mutation of genes coding for deoxyribonucleic acid (DNA) polymerase (POLE and POLD). 12 Somatic mutations of CRC like KRAS, NRAS, BRAF PIK3CA, and ARID1A have also been identified. ...
Background:
This study aimed to investigate the validity of pathological diagnosis of early CRC (E-CRC) from the genetic background by comparing data of E-CRC to colorectal adenoma (CRA) and The Cancer Genome Atlas (TCGA) on advanced CRC (AD-CRC).
Methods:
TCGA data on AD-CRC were studied in silico, whereas by next-generation sequencer, DNA target sequences were performed for endoscopically obtained CRA and E-CRC samples. Immunohistochemical staining of mismatch repair genes and methylation of MLH1 was also performed. The presence of oncogenic mutation according to OncoKB for the genes of the Wnt, MAPK, and cell-cycle-signaling pathways was compared among CRA, E-CRC, and AD-CRC.
Results:
The study included 22 CRA and 30 E-CRC lesions from the Chiba University Hospital and 212 AD-CRC lesions from TCGA data. Regarding the number of lesions with driver mutations in the Wnt and cell-cycle-signaling pathways, E-CRC was comparable to AD-CRC, but was significantly greater than CRA. CRA had significantly more lesions with a driver mutation for the Wnt signaling pathway only, versus E-CRC.
Conclusions:
In conclusion, the definition of E-CRC according to the Japanese criteria had a different genetic profile from CRA and was more similar to AD-CRC. Based on the main pathway, it seemed reasonable to classify E-CRC as adenocarcinoma. The pathological diagnosis of E-CRC according to Japanese definition seemed to be valid from a genetic point of view.
... It has a prevalence of approximately 3% in CRC and 2.8% in patients with EC. [3,4] Most LS patients present with CRC below the age of 50 years. [5] The pathogenic mechanism of LS involves germline mutations in the Deoxyribonucleic mismatch repair genes (MMR). [6] The genes affected in LS are MLH1, MSH2, MSH6, PMS2 and EPCAM. ...
Introduction:
The primary objective of this study was to evaluate the baseline characteristics of Lynch syndrome (LS). Furthermore, the study aimed to evaluate overall survival (OS) among patients with LS.
Materials and methods:
This was a retrospective study of colorectal cancer patients registered from January 2010 to August 2020 with an immunohistochemical diagnosis of LS.
Results:
A total of 42 patients were assessed. The mean age at presentation was 44 years, with male predominance (78%). Demographic preponderance was from the North of Pakistan (52.4%). The family history was positive in 32 (76.2%) patients. The colonic cancer distribution was 32 (76.2%) on the right side. Most of the patients presented with Stage II disease (52.4%), and the common mutations were MLH1 + PMS2 16 (38.1%) followed by MSH2 + MSH6 9 (21.4%). The 10-year OS was found to be 88.1%. However, the OS was 100% post pancolectomy.
Conclusion:
LS is prevalent in the Pakistan population, especially in the North of Pakistan. Clinical presentation and survivals are similar to the Western population.
... Lynch syndrome Heterozygous germline alterations in certain DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) give rise to Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC) 70 . Lynch syndrome is an autosomal dominant disorder that accounts for 3-5% of colorectal cancer cases and approximately 2.5% of endometrial cancer cases 71,72 . ...
The discovery of synthetic lethal interactions with genetic deficiencies in cancers has highlighted several candidate targets for drug development, with variable clinical success. Recent work has unveiled a promising synthetic lethal interaction between inactivation/inhibition of the WRN DNA helicase and tumours with microsatellite instability, a phenotype that arises from DNA mismatch repair deficiency. While these and further studies have highlighted the therapeutic potential of WRN inhibitors, compounds with properties suitable for clinical exploitation remain to be described. Furthermore, the complexities of MSI development and its relationship to cancer evolution pose challenges for clinical prospects. Here, we discuss possible paths of MSI tumour development, the viability of WRN inhibition as a strategy in different scenarios, and the necessary conditions to create a roadmap towards successful implementation of WRN inhibitors in the clinic.
... Among these, MSI has been observed in several cancers, including colorectal cancers [5], glioblastoma [5], gastric [6], ovarian [7], endometrial, and prostate tumors [8]. It has been shown that MSI could not only improve the prognosis of tumors [9,10], but also be a predictive mark of chemotherapy resistance as well as immunotherapy [11][12][13]. Thus, detecting MSI status from patient samples can provide valuable information for cancer diagnosis, prognosis, and therapy selection. ...
Microsatellite instability (MSI), a vital mutator phenotype caused by DNA mismatch repair deficiency, is frequently observed in several tumors. MSI is recognized as a critical molecular biomarker for diagnosis, prognosis, and therapeutic selection in several cancers. Identifying MSI status for current gold standard methods based on experimental analysis is laborious, time-consuming, and costly. Although several computational methods based on machine learning have been proposed to identify MSI status, we need to further understand which machine learning model would favor identification for MSI and which feature subset is strongly related to MSI. On this basis, more effective machine learning-based methods can be developed to improve the performance of MSI status identification. In this work, we present MSINGB, an NGBoost-based method for identifying MSI status from tumor somatic mutation annotation data. MSINGB first evaluates the prediction performance of 11 popular machine learning algorithms and 9 deep learning models to identify MSI. Among 20 models, NGBoost, a novel natural gradient boosting method, achieves the overall best performance. MSINGB then introduces two feature selection strategies to find the compact feature subset, which is strongly related to MSI, and employs the SHAP approach to interpreting how selected features impact the model prediction. MSINGB achieves a better prediction performance on both the tenfold cross-validation test and independent test compared with state-of-the-art methods.
... Among these, MSI has been observed in several cancers, including colorectal cancers [ 5 ], glioblastoma [ 5 ], gastric [ 6 ], ovarian [ 7 ], endometrial, and prostate tumors [ 8 ]. It has been shown that MSI could not only improve the prognosis of tumors [ 9,10 ], but also be a predictive mark of chemotherapy resistance as well as immunotherapy [ 11,12,13 ]. Thus, detecting MSI status from patient samples can provide valuable information for cancer diagnosis, prognosis, and therapy selection. ...
Microsatellite instability (MSI), a vital mutator phenotype caused by DNA mismatch
repair deficiency, is frequently observed in several tumours. MSI is recognized as a
critical molecular biomarker for diagnosis, prognosis, and therapeutic selection in
several cancers. Identifying MSI status for current gold standard methods based on
experimental analysis is laborious, time-consuming, and costly. Although several
computational methods based on machine learning have been proposed to identify
MSI status, we need to further understand which machine learning model would favour
identification for MSI and which feature subset is strongly related to MSI. On this basis,
more effective machine learning-based methods can be developed to improve the
performance of MSI status identification. In this work, we present MSINGB, an
NGBoost-based method for identifying MSI status from tumour somatic mutation
annotation data. MSINGB first evaluates the prediction performance of 11 popular
machine learning algorithms and nine deep learning models to identify MSI. Among 20
models, NGBoost, a novel natural gradient boosting method, achieves the overall best
performance. MSINGB then introduces two feature selection strategies to find the
compact feature subset, which is strongly related to MSI, and employs the SHAP
approach to interpreting how selected features impact the model prediction. MSINGB
achieves a better prediction performance on both the 10-fold cross-validation test and
independent test compared with state-of-the-art methods.
