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Modern Pathology : An Official Journal... Sep 2023Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite...
Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n = 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LS-associated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients.
Topics: Female; Humans; Microsatellite Repeats; Colorectal Neoplasms, Hereditary Nonpolyposis; Microsatellite Instability; Colonic Neoplasms; DNA Mismatch Repair; Endometrial Neoplasms; DNA-Binding Proteins; Colorectal Neoplasms
PubMed: 37307877
DOI: 10.1016/j.modpat.2023.100240 -
EBioMedicine May 2024Both defects in mismatch repair (dMMR) and high microsatellite instability (MSI-H) have been recognised as crucial biomarkers that guide treatment strategies and disease...
BACKGROUND
Both defects in mismatch repair (dMMR) and high microsatellite instability (MSI-H) have been recognised as crucial biomarkers that guide treatment strategies and disease management in colorectal cancer (CRC). As MMR and MSI tests are being widely conducted, an increasing number of MSI-H tumours have been identified in CRCs with mismatch repair proficiency (pMMR). The objective of this study was to assess the clinical features of patients with pMMR/MSI-H CRC and elucidate the underlying molecular mechanism in these cases.
METHODS
From January 2015 to December 2018, 1684 cases of pMMR and 401 dMMR CRCs were enrolled. Of those patients, 93 pMMR/MSI-H were identified. The clinical phenotypes and prognosis were analysed. Frozen and paraffin-embedded tissue were available in 35 patients with pMMR/MSI-H, for which comprehensive genomic and transcriptomic analyses were performed.
FINDINGS
In comparison to pMMR/MSS CRCs, pMMR/MSI-H CRCs exhibited significantly less tumour progression and better long-term prognosis. The pMMR/MSI-H cohorts displayed a higher presence of CD8+ T cells and NK cells when compared to the pMMR/MSS group. Mutational signature analysis revealed that nearly all samples exhibited deficiencies in MMR genes, and we also identified deleterious mutations in MSH3-K383fs.
INTERPRETATION
This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H.
FUNDING
This work was supported by the Science and Technology Commission of Shanghai Municipality (20DZ1100101).
Topics: Humans; Microsatellite Instability; Colorectal Neoplasms; DNA Mismatch Repair; Female; Male; Middle Aged; Prognosis; Aged; Mutation; Biomarkers, Tumor; Adult; Gene Expression Profiling; MutS Homolog 3 Protein; Neoplasm Staging
PubMed: 38691939
DOI: 10.1016/j.ebiom.2024.105142 -
Cancer Medicine Oct 2023Therapeutic approaches for extrahepatic cholangiocarcinoma (EHCC) are limited, due to insufficient understanding to biomarkers related to prognosis and drug response....
BACKGROUND
Therapeutic approaches for extrahepatic cholangiocarcinoma (EHCC) are limited, due to insufficient understanding to biomarkers related to prognosis and drug response. Here, we comprehensively assess the molecular characterization of EHCC with clinical implications.
METHODS
Whole-exome sequencing (WES) on 37 tissue samples of EHCC were performed to evaluate genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI).
RESULTS
Mutation of KRAS (16%) was significantly correlated to poor OS. ERBB2 mutation was associated with improved OS. ERBB2, KRAS, and ARID1A were three potentially actionable targets. TMB ≥10 mutations per megabase was detected in 13 (35.1%) cases. Six patients (16.2%) with MSIsensor scores ≥10 were found. In multivariate Cox analysis, patients with MSIsensor sore exceed a certain threshold (MSIsensor score ≥0.36, value approximately above the 20th percentile as thresholds) showed a significant association with the improved OS (HR = 0.16; 95% CI: 0.056-0.46, p < 0.001), as well as patients with both TMB ≥3.47 mutations per megabase (value approximately above the 20th percentile) and MSIsensor score ≥0.36.
CONCLUSIONS
TMB and MSI are potential biomarkers associated with better prognosis for EHCC patients. Furthermore, our study highlights important genetic alteration and potential therapeutic targets in EHCC.
Topics: Humans; Immune Checkpoint Inhibitors; Proto-Oncogene Proteins p21(ras); Prognosis; Cholangiocarcinoma; Mutation; Biomarkers, Tumor; Microsatellite Instability; Bile Ducts, Intrahepatic; Bile Duct Neoplasms
PubMed: 37814942
DOI: 10.1002/cam4.6441 -
Cancers Jul 2023Immune checkpoint inhibitors have revolutionized the management of mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) gastrointestinal cancers,... (Review)
Review
Immune checkpoint inhibitors have revolutionized the management of mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) gastrointestinal cancers, particularly colorectal cancer. Cancers with the MMR-D/MSI-H genotype often carry a higher tumor mutation burden with frameshift alterations, leading to increased mutation-associated neoantigen (MANA) generation. The dramatic response seen with immune checkpoint inhibitors (ICIs), which are orchestrated by MANA-primed effector T cells, resulted in the rapid development of these novel therapeutics within the landscape of MSI-H gastrointestinal cancers. Recently, several clinical trials have utilized ICIs as potential neoadjuvant therapies for MSI-H gastrointestinal cancers and demonstrated deep clinical and pathological responses, creating opportunities for organ preservation. However, there are potential challenges to the neoadjuvant use of ICIs for certain disease types due to the clinical risk of overtreatment for a disease that can be cured through a surgery-only approach. In this review article, we discuss neoadjuvant management approaches with ICI therapy for patients with MSI-H gastrointestinal cancers, including those with oligometastatic disease. We also elaborate on potential challenges and opportunities for the neoadjuvant utilization of ICIs and provide further insight into the changing treatment paradigm of MMR-D/MSI-H gastrointestinal cancers.
PubMed: 37568648
DOI: 10.3390/cancers15153833 -
Journal of Immunotherapy and Precision... Feb 2024AT-rich interaction domain 1A (ARID1A), a mammalian switch/sucrose nonfermenting complex subunit, modulates several cellular processes by regulating chromatin... (Review)
Review
AT-rich interaction domain 1A (ARID1A), a mammalian switch/sucrose nonfermenting complex subunit, modulates several cellular processes by regulating chromatin accessibility. It is encoded by , an immunosuppressive gene frequently disrupted in a many tumors, affecting the proliferation, migration, and invasion of cancer cells. Targeting molecular pathways and epigenetic regulation associated with ARID1A loss, such as inhibiting the PI3K/AKT pathway or modulating Wnt/β-catenin signaling, may help suppress tumor growth and progression. Developing epigenetic drugs like histone deacetylase or DNA methyltransferase inhibitors could restore normal chromatin structure and function in cells with ARID1A loss. As deficiency correlates with enhanced tumor mutability, microsatellite instability, high tumor mutation burden, increased programmed death-ligand 1 expression, and T-lymphocyte infiltration, ARID1A-deficient cells can be a potential therapeutic target for immune checkpoint inhibitors that warrants further exploration. In this review, we discuss the role of in carcinogenesis, its crosstalk with other signaling pathways, and strategies to make ARID1A-deficient cells a potential therapeutic target for patients with cancer.
PubMed: 38327752
DOI: 10.36401/JIPO-22-37 -
DNA Repair Jul 2024Multiple separate repair mechanisms safeguard the genome against various types of DNA damage, and their failure can increase the rate of spontaneous mutagenesis. The... (Review)
Review
Multiple separate repair mechanisms safeguard the genome against various types of DNA damage, and their failure can increase the rate of spontaneous mutagenesis. The malfunction of distinct repair mechanisms leads to genomic instability through different mutagenic processes. For example, defective mismatch repair causes high base substitution rates and microsatellite instability, whereas homologous recombination deficiency is characteristically associated with deletions and chromosome instability. This review presents a comprehensive collection of all mutagenic phenotypes associated with the loss of each DNA repair mechanism, drawing on data from a variety of model organisms and mutagenesis assays, and placing greatest emphasis on systematic analyses of human cancer datasets. We describe the latest theories on the mechanism of each mutagenic process, often explained by reliance on an alternative repair pathway or the error-prone replication of unrepaired, damaged DNA. Aided by the concept of mutational signatures, the genomic phenotypes can be used in cancer diagnosis to identify defective DNA repair pathways.
Topics: Humans; Mutagenesis; DNA Repair; Animals; Neoplasms; DNA Damage; Genomic Instability; DNA Mismatch Repair
PubMed: 38788323
DOI: 10.1016/j.dnarep.2024.103694 -
Aging Jan 2024Microsatellite instability-high (MSI-H) has gained considerable interests since it was approved as a tumor-agnostic biomarker in immunotherapy. However, the reported... (Review)
Review
Microsatellite instability-high (MSI-H) has gained considerable interests since it was approved as a tumor-agnostic biomarker in immunotherapy. However, the reported characteristics of MSI-H gastric cancer (GC) are inconsistent due to the biological complexity. Here, we aim to clarify the prevalence, risk factors, clinicopathological/molecular features and outcomes of MSI-H GC though a comprehensive review on 43246 patients from 134 cohorts. Overall, the proportion of MSI-H GC was 14.5% (95% CI, 13.3%-15.8%). Patients with MSI-H GC were less likely to have Epstein-Barr virus infection. High incidences of MSI-H GC were associated with female, older age, lower gastric body, Lauren intestinal histology, WHO tubular and mucinous subtypes, and early disease stage. Additionally, patients with MSI-H GC harbored more mutation, PD-L1 positivity, CD8 overexpression, and higher TMB, but less HER2 positivity and mutation. When treated with conventional strategy, the 5-year survival rates in MSI-H patients (70.3%) and MSI-L/MSS patients (43.7%) were significantly different (<0.001). Patients with MSI-H GC derived larger benefit from immunotherapy in term of overall survival (<0.001) and objective response (=0.02). Since the prevalence of MSI-H GC is relatively high and associated with distinct clinicopathological and molecular characteristics, MSI testing should be conducted during standard diagnostical activity. Moreover, giving MSI-H tumors are often diagnosed at early stage and have favorable outcomes, less aggressive treatment strategies may be considered in clinical practice. In summary, this panoramic review may assist in design and/or interpretation of clinical trials, provide references in drug development, and constitute complementary information in drafting the clinical practice guideline.
Topics: Humans; Female; Stomach Neoplasms; Microsatellite Instability; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Biomarkers, Tumor; Risk Factors; Prognosis
PubMed: 38224334
DOI: 10.18632/aging.205431 -
Genes Jul 2023Microsatellite instability (MSI) represents an accumulation of frameshifts in short tandem repeats, microsatellites, across the genome due to defective DNA mismatch... (Review)
Review
Microsatellite instability (MSI) represents an accumulation of frameshifts in short tandem repeats, microsatellites, across the genome due to defective DNA mismatch repair (dMMR). MSI has been associated with distinct clinical, histological, and molecular features of tumors and has proven its prognostic and therapeutic value in different types of cancer. Recently, another type of microsatellite instability named elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) has been reported across many different tumors. EMAST tumors have been associated with chronic inflammation, higher tumor stage, and poor prognosis. Nevertheless, the clinical significance of EMAST and its relation to MSI remains unclear. It has been proposed that EMAST arises as a result of isolated MSH3 dysfunction or as a secondary event in MSI tumors. Even though previous studies have associated EMAST with MSI-low phenotype in tumors, recent studies show a certain degree of overlap between EMAST and MSI-high tumors. However, even in stable tumors, (MSS) frameshifts in microsatellites can be detected as a purely stochastic event, raising the question of whether EMAST truly represents a distinct type of microsatellite instability. Moreover, a significant fraction of patients with MSI tumors do not respond to immunotherapy and it can be speculated that in these tumors, EMAST might act as a modifying factor.
Topics: Humans; Microsatellite Instability; Colorectal Neoplasms; Microsatellite Repeats; Prognosis; DNA Mismatch Repair
PubMed: 37510378
DOI: 10.3390/genes14071474 -
Molecular and Clinical Oncology Jan 2024Colorectal cancer (CRC) ranks as the third leading cause of cancer-related mortality worldwide. Recent years have witnessed an increase in the incidence of CRC among... (Review)
Review
Colorectal cancer (CRC) ranks as the third leading cause of cancer-related mortality worldwide. Recent years have witnessed an increase in the incidence of CRC among adults <50 years old on a global scale. The increased incidence is associated with several modifiable risk factors, including obesity, type II diabetes, physical inactivity and frequent antibiotic use. In younger individuals, haematochezia and abdominal pain are the most common symptoms, predominantly affecting the left-side colon. While certain cases of early-onset CRC (eoCRC) are associated with a genetic predisposition, the majority result from sporadic mutations in the genes , , and , which trigger uncontrolled cell proliferation and tumour formation. Colorectal carcinogenesis involves three major pathways: The chromosomal instability (CIN), microsatellite instability and CpG island methylator phenotype pathways. Dysregulation of the CIN pathway accounts for 85% of sporadic cases of eoCRC. Notably, eoCRC exhibits a distinctive molecular profile, characterized by a decreased prevalence of mutations, an increased prevalence of mutations and 1 hypomethylation, and involvement of the Microsatellite and Chromosomal Stable pathway. Prevention strategies for eoCRC primarily centre on lifestyle modifications and the development of screening programs targeting younger populations. Further exploration into the molecular mechanisms involved in the identification of novel risk factors associated with eoCRC is imperative. These efforts, in conjunction with the development of specific screening strategies, hold the potential to reduce morbidity and mortality in the future.
PubMed: 38125745
DOI: 10.3892/mco.2023.2706 -
Medical Image Analysis Oct 2023Microsatellite instability (MSI) refers to alterations in the length of simple repetitive genomic sequences. MSI status serves as a prognostic and predictive factor in...
Microsatellite instability (MSI) refers to alterations in the length of simple repetitive genomic sequences. MSI status serves as a prognostic and predictive factor in colorectal cancer. The MSI-high status is a good prognostic factor in stage II/III cancer, and predicts a lack of benefit to adjuvant fluorouracil chemotherapy in stage II cancer but a good response to immunotherapy in stage IV cancer. Therefore, determining MSI status in patients with colorectal cancer is important for identifying the appropriate treatment protocol. In the Pathology Artificial Intelligence Platform (PAIP) 2020 challenge, artificial intelligence researchers were invited to predict MSI status based on colorectal cancer slide images. Participants were required to perform two tasks. The primary task was to classify a given slide image as belonging to either the MSI-high or the microsatellite-stable group. The second task was tumor area segmentation to avoid ties with the main task. A total of 210 of the 495 participants enrolled in the challenge downloaded the images, and 23 teams submitted their final results. Seven teams from the top 10 participants agreed to disclose their algorithms, most of which were convolutional neural network-based deep learning models, such as EfficientNet and UNet. The top-ranked system achieved the highest F1 score (0.9231). This paper summarizes the various methods used in the PAIP 2020 challenge. This paper supports the effectiveness of digital pathology for identifying the relationship between colorectal cancer and the MSI characteristics.
Topics: Humans; Microsatellite Instability; Artificial Intelligence; Prognosis; Fluorouracil; Colorectal Neoplasms
PubMed: 37494811
DOI: 10.1016/j.media.2023.102886