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Molecular subtype classification of urothelial carcinoma in Lynch syndrome
... Fifteen studies reported on clinical and pathological features of 250 LS patients, as summarised in Table 3 [7,9,10,12,13,19,[23][24][25][26][27][28][29][30]38]. The mean age at diagnosis varied between 56 [38] and 67 yr [9]. ...
... The symptomatic onset of LSrelated UTUC was reported in two studies [24,26], including macrohaematuria (63% [26] and 58% [24] of cases) and renal colic (5% [26]), while asymptomatic detection during screening protocols was recorded in 21% [26] and 25% [24] of individuals. UTUC location was reported in six publications [23][24][25][26][27][28]: the ureter was more frequently involved than the renal pelvis [23,24,26,27], whereas multifocality was rare [23,25,26]. Overall, pT 1 was recorded in 52 out of 113 patients (46%) [9,10,12,[23][24][25]27,28,38], while metastasis disease [24,38] was observed in one patient (8%) [24]. ...
... The symptomatic onset of LSrelated UTUC was reported in two studies [24,26], including macrohaematuria (63% [26] and 58% [24] of cases) and renal colic (5% [26]), while asymptomatic detection during screening protocols was recorded in 21% [26] and 25% [24] of individuals. UTUC location was reported in six publications [23][24][25][26][27][28]: the ureter was more frequently involved than the renal pelvis [23,24,26,27], whereas multifocality was rare [23,25,26]. Overall, pT 1 was recorded in 52 out of 113 patients (46%) [9,10,12,[23][24][25]27,28,38], while metastasis disease [24,38] was observed in one patient (8%) [24]. ...
Context
Upper tract urothelial carcinoma (UTUC) represents the third most frequent malignancy in Lynch syndrome (LS).
Objective
To systematically review the available literature focused on incidence, diagnosis, clinicopathological features, oncological outcomes, and screening protocols for UTUC among LS patients.
Evidence acquisition
Medline, Scopus, Google Scholar, and Cochrane Database of Systematic Reviews were searched up to May 2021. Risk of bias was determined using the modified Cochrane tool. A narrative synthesis was undertaken.
Evidence synthesis
Overall, 43 studies between 1996 and 2020 were included. LS patients exhibited a 14-fold increased risk of UTUC compared with the general population, which further increased to 75-fold among hMSH2 mutation carriers. Patients younger than 65 yr and patients with personal or family history of LS-related cancers should be referred to molecular testing on tumour specimen and subsequent genetic testing to confirm LS. Newly diagnosed LS patients may benefit from a multidisciplinary management team including gastroenterologist and gynaecologist specialists, while genetic counselling should be recommended to first-degree relatives (FDRs). Compared with sporadic UTUC individuals, LS patients were significantly younger (p = 0.005) and exhibited a prevalent ureteral location (p = 0.01). Radical nephroureterectomy was performed in 75% of patients (5-yr cancer-specific survival: 91%). No consensus on screening protocols for UTUC was achieved: starting age varied between 25–35 and 50 yr, while urinary cytology showed sensitivity of 29% and was not recommended for screening.
Conclusions
Urologists should recognise patients at high risk for LS and address them to a comprehensive diagnostic pathway, including molecular and genetic testing. Newly diagnosed LS patients should be referred to a multidisciplinary team, while genetic counselling should be recommended to FDRs.
Patient summary
In this systematic review, we analysed the existing literature focused on upper tract urothelial carcinoma (UTUC) among patients with Lynch syndrome (LS). Our purpose is to provide a comprehensive overview of LS-related UTUC to reduce misdiagnosis and improve patient prognosis.
... Deficient DNA mismatch repair renal pelvic/ureteral cancers are histopathologically characterized by an inverted growth pattern and a low stage, while there are no sites of predilection for these cancers [45]. Lynch syndrome-associated renal pelvic/ureteral cancers develop at a younger age as compared with general pelvic/ureteral cancers, and the risk of developing it increases in women to a level equal to that in men [46]. There is also a report that more than half of Lynch syndrome-related renal pelvic/ureteral cancers are MSS/ MSI-L [46]. ...
... Lynch syndrome-associated renal pelvic/ureteral cancers develop at a younger age as compared with general pelvic/ureteral cancers, and the risk of developing it increases in women to a level equal to that in men [46]. There is also a report that more than half of Lynch syndrome-related renal pelvic/ureteral cancers are MSS/ MSI-L [46]. Besides renal pelvic/ureteral cancers, it has been reported that some prostate cancers, germ cell tumors, and bladder cancers may be related to Lynch syndrome [44]. ...
Background:
Clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. The accumulated evidence of tumor agnostic agent has been made since PD-1 inhibitor was approved and used in clinical practice. Therefore, we have revised the guideline "Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition".
Methods:
Clinical questions regarding medical care were formulated for patients with dMMR advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO and the public comments among all societies' members were done.
Results:
The current guideline describes two clinical questions and eight recommendations for whom, when, and how MMR status should be tested.
Conclusion:
In this guideline, the committee proposed eight recommendations for performing MMR testing properly to select patients who are likely to benefit from immunotherapy.
... Compared with BC, CUL3, BCL2L1, and FGFR1 have been recognized as mutation events in UTUC that can potentially be used for its classification (Figure 1). These properties may be due to UTUC-related symptoms, such as Lynch syndrome (which develops in the mesodermderived epithelium) and aberrant aristolochic acid (AA) production [3,4]. HRAS, ERBB2, TP53, and RB1 can be used as molecular markers in both types of urothelial cancer because their actions differ between normal tissues and primary tumors [5]. ...
... As a practical application, Kim et al. detected FGFR3 alterations and analyzed the immune response in metastatic urothelial cancer (GSE176307). Phung et al. and Therkilden et al. used formalin-fixed paraffin-embedded tissue from a single Lynch Syndrome patient (GSE146670 and GSE104922) and studied changes across time, tissues, and space [3]. Sjodahl made some array chips to examine differentially expressed molecules in the early stage of advanced urothelial cancer (GSE128959) [116]. ...
Urothelial cancer is a malignant tumor with metastatic ability and high mortality. Malignant tumors of the urinary system include upper tract urothelial cancer and bladder cancer. In addition to typical genetic alterations and epigenetic modifications, metabolism-related events also occur in urothelial cancer. This metabolic reprogramming includes aberrant expression levels of genes, metabolites, and associated networks and pathways. In this review, we summarize the dysfunctions of glycolytic enzymes in urothelial cancer and discuss the relevant phenotype and signal transduction. Moreover, we describe potential prognostic factors and risks to the survival of clinical cancer patients. More importantly, based on several available databases, we explore relationships between glycolytic enzymes and genetic changes or drug responses in urothelial cancer cells. Current advances in glycolysis-based inhibitors and their combinations are also discussed. Combining all of the evidence, we indicate their potential value for further research in basic science and clinical applications.
... Deficient DNA mismatch repair renal pelvic/ureteral cancers are histopathologically characterized by an inverted growth pattern and a low stage, while there are no sites of predilection for these cancers [40]. Lynch-associated renal pelvic/ureteral cancers develop at a younger age and are more common in women than general pelvic/ureteral cancers [41]. There is also a report that more than half of Lynch-associated renal pelvic/ureteral cancers are MSS/MSI-L [41]. ...
... Lynch-associated renal pelvic/ureteral cancers develop at a younger age and are more common in women than general pelvic/ureteral cancers [41]. There is also a report that more than half of Lynch-associated renal pelvic/ureteral cancers are MSS/MSI-L [41]. Besides renal pelvic/ureteral cancers, it has been reported that some prostate cancers, germ cell tumors, and bladder cancers may be Lynch-associated [39]. ...
Background
Novel therapeutic agents have improved survival outcomes in patients with advanced solid tumors. In parallel, the development of predictive biomarkers to identify patients who are likely to benefit from a certain treatment has also contributed to the improvement of survival. Recently, clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. In Japan, a PD-1 inhibitor for dMMR advanced solid tumors, regardless of the primary tumor site, has been approved. However, there are some issues related to administering immune checkpoint inhibitors in the clinical practice setting, making it necessary to develop the guidelines.
Methods
Clinical questions (CQs) regarding medical care were formulated for patients with dMMR advanced solid tumors, and evidence to the CQs was collected by manual search to prepare recommendations. Then, the committee members voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other factors.
Results
The current guideline, which we consider a provisional clinical opinion at this point, describes the 11 requirements to be considered in terms of patients for whom dMMR testing is recommended, the timing and methods of dMMR testing, and clinical care systems required to perform dMMR testing properly and to administer immune checkpoint inhibitors safely.
Conclusion
This provisional clinical opinion proposes the requirements for performing dMMR testing properly to select patients who are likely to benefit from immune checkpoint inhibitors and administering them safely.
... Additionally, the gene expression profiles and detailed clinical annotations of eight BCa-associated Gene Expression Omnibus (GEO) cohorts were extracted from the supplementary files of original manuscript or downloaded from http://www.ncbi.nlm. nih.gov/geo/ through "GEOquery" R package (Davis and Meltzer, 2007), including GSE13507 based on platform GPL6102 (with 188 BLCA samples) Lee et al., 2010), GSE32894 based on platform GPL6947 (with 308 BLCA samples) , GSE32548 based on platform GPL6947 (with 131 BLCA samples) (Lindgren et al., 2012), GSE128959 based on platform GPL6244 (with 200 BLCA samples) (Sjödahl et al., 2020), GSE31684 based on platform GPL570 (with 93 BLCA samples) (Riester et al., 2012;Riester et al., 2014), GSE48075 based on platform GPL6947 (with 142 BLCA samples) (Choi et al., 2014;Guo et al., 2020), GSE104922 based on platform GPL6244 (with 41 BLCA samples) (Therkildsen et al., 2018), GSE83586 based on platform GPL6244 (with 307 BLCA samples) (Sjödahl et al., 2017). The ComBat algorithm of "sva" R Package was utilized for eliminating the batch effects caused by non-biological technical biases (Leek et al., 2012). ...
Background: Bladder cancer (BCa) is the leading reason for death among genitourinary malignancies. RNA modifications in tumors closely link to the immune microenvironment. Our study aimed to propose a promising model associated with the “writer” enzymes of five primary RNA adenosine modifications (including m⁶A, m⁶Am, m¹A, APA, and A-to-I editing), thus characterizing the clinical outcome, immune landscape and therapeutic efficacy of BCa.
Methods: Unsupervised clustering was employed to categorize BCa into different RNA modification patterns based on gene expression profiles of 34 RNA modification “writers”. The RNA modification “writers” score (RMS) signature composed of RNA phenotype-associated differentially expressed genes (DEGs) was established using the least absolute shrinkage and selection operator (LASSO), which was evaluated in meta-GEO (including eight independent GEO datasets) training cohort and the TCGA-BLCA validation cohort. The hub genes in the RMS model were determined via weighted gene co-expression network analysis (WGCNA) and were further validated using human specimen. The potential applicability of the RMS model in predicting the therapeutic responsiveness was assessed through the Genomics of Drug Sensitivity in Cancer database and multiple immunotherapy datasets.
Results: Two distinct RNA modification patterns were determined among 1,410 BCa samples from a meta-GEO cohort, showing radically varying clinical outcomes and biological characteristics. The RMS model comprising 14 RNA modification phenotype-associated prognostic DEGs positively correlated with the unsatisfactory outcome of BCa patients in meta-GEO training cohort (HR = 3.00, 95% CI = 2.19–4.12) and TCGA-BLCA validation cohort (HR = 1.53, 95% CI = 1.13–2.09). The infiltration of immunosuppressive cells and the activation of EMT, angiogenesis, IL-6/JAK/STAT3 signaling were markedly enriched in RMS-high group. A nomogram exhibited high prognostic prediction accuracy, with a concordance index of 0.785. The therapeutic effect of chemotherapeutic agents and antibody-drug conjugates was significantly different between RMS-low and -high groups. The combination of the RMS model and conventional characteristics (TMB, TNB and PD-L1) achieved an optimal AUC value of 0.828 in differentiating responders from non-responders to immunotherapy.
Conclusion: We conferred the first landscape of five forms of RNA modifications in BCa and emphasized the excellent power of an RNA modifications-related model in evaluating BCa prognosis and immune landscape.
... The spectrum of malignancies that developed in our Lynch syndrome study cohort largely reflected the known Lynch-spectrum [13]. In Lynch-spectrum malignancies a high fraction of MSI-H/dMMR tumors was observed, which was comparable to the fraction calculated in previous studies [19][20][21][22][23][24][25]. Observed differences are probably due to stochastic variation due to small numbers or biases in patient selection, as individuals with a gPV in MLH1 or MSH2 have a larger fraction of MSI-H/dMMR malignancies than those with a gPV in MSH6 of PMS2. ...
Background:
Individuals with Lynch syndrome are at increased hereditary risk of colorectal and endometrial carcinomas with microsatellite instability (MSI-H) and mismatch repair-deficiency (dMMR), which make these tumors vulnerable to therapy with immune checkpoint inhibitors. Our aim is to assess how often other tumor types in these individuals share these characteristics.
Methods:
We retrieved the full tumor history of a historical clinic-based cohort of 1,745 individuals with Lynch syndrome and calculated the standard incidence ratio (SIR) for all tumor types. MSI status, somatic second hit alterations and immunohistochemistry-based MMR status were analyzed in 236 non-colorectal and non-endometrial malignant tumors.
Results:
In individuals with Lynch syndrome MSI-H/dMMR occurred both in Lynch-spectrum and in non-Lynch-spectrum malignancies (84% vs. 39%, P<0.01). MSI-H. MSI-H/dMMR malignancies were found in nearly all non-Lynch-spectrum tumor types. Almost all breast carcinomas had medullary features and most of them were MSI-H/dMMR. Breast carcinoma with medullary features were shown to be associated with Lynch syndrome (SIR: 38.8, 95%CI 16.7-76.5).
Conclusions:
In individuals with Lynch syndrome MSI-H/dMMR occurs in more than half of the malignancies other than colorectal and endometrial carcinomas including tumor types without increased incidence. The Lynch-spectrum tumors should be expanded to breast carcinomas with medullary features. All malignancies in patients with Lynch syndrome, independent of subtype, should be tested for MSI-H/dMMR in case therapy with immune checkpoint inhibitors is considered. Moreover, Lynch syndrome should be considered as underlying cause of all MSI-H/dMMR malignancies other than colorectal and endometrial carcinomas.
... When considering therapeutic approaches, radical nephroureterectomy [17,28,35,39,42] (41 patients) was over twice as common as kidney-sparing surgery, including ureteroscopic laser ablation [38] (13 patients with 15 lesions) and segmental ureterectomy [35] (1 patient). Hubosky et al. [38] performed ureteroscopic laser ablation involving neodymium:yttrium aluminum garnet (YAG) laser and holium:YAG laser for coagulation and ablation or resection, respectively. ...
Objective
Lynch syndrome (LS) is an autosomal dominant hereditary disorder resulting from germline mutation in at least one of the four mismatch repair genes or in EPCAM gene. From a clinical perspective, LS patients exhibit an increased predisposition to multiple primary malignancies and early age of onset compared to general population. We aimed to provide a comprehensive overview of all the genitourinary manifestations of LS, focusing on incidence, diagnosis, clinical features, therapeutic strategies, and screening protocols.
Methods
Previous literature was assessed through Medline, Scopus, and Google Scholar databases. A narrative review of the most relevant articles on urological manifestations of LS was provided.
Results
In the LS tumor spectrum upper tract urothelial carcinoma (UTUC) represents the third most frequent malignancy, and the first most common cancer in the urological field, with an approximately 14-fold increased risk of developing UTUC compared to general population. LS diagnosis among patients experiencing UTUC as first malignancy is a step-by-step process, including (i) clinical criteria, (ii) molecular testing, and (iii) genetic testing to confirm the hereditary disorder. The current European Association of Urology (EAU) guidelines recommend to perform molecular testing among UTUC patients <65 years old, or UTUC patients with personal history of LS-related tumor, or UTUC patients with one first-degree relative with LS-related tumor <50 years old, or UTUC patients with two first-degree relatives with LS-related tumor regardless of age of onset. Newly diagnosed LS patients should be referred to a multidisciplinary management, including gastroenterologists and gynecologists. Finally, considering the increased risk of metachronous recurrence, treatments other than radical nephroureterectomy may be a valuable therapeutic alternative. Whether urological malignancies other than UTUC should be included in the LS tumor spectrum is still controversial.
Conclusion
Considering the strict association between UTUC and LS, we believe that the urologist should recognize patients at increased risk for hereditary disease according to current EAU clinical criteria and address them to a comprehensive diagnostic algorithm, including molecular evaluation and genetic testing. To date, literature lacks clear evidence regarding the role of LS in developing bladder cancer, prostate cancer, or renal cell carcinoma, and current data are still inconclusive, highlighting the urgent need for further studies.
... Additionally, the gene expression pro les and detailed clinical annotations of eight BCa-associated Gene-Expression Omnibus (GEO) cohorts were extracted from the supplementary les of original manuscript or downloaded from http://www.ncbi.nlm.nih.gov/geo/ through "GEOquery" R package [67], including GSE13507 based on platform GPL6102 (with 188 BLCA samples) [68, 69], GSE32894 based on platform GPL6947 (with 308 BLCA samples) [70], GSE32548 based on platform GPL6947 (with 131 BLCA samples) [71], GSE128959 based on platform GPL6244 (with 200 BLCA samples) [72], GSE31684 based on platform GPL570 (with 93 BLCA samples) [73,74], GSE48075 based on platform GPL6947 (with 142 BLCA samples) [75,76], GSE104922 based on platform GPL6244 (with 41 BLCA samples) [77], GSE83586 based on platform GPL6244 (with 307 BLCA samples) [78]. The ComBat algorithm of "sva" R Package was utilized for eliminating the batch effects caused by non-biological technical biases [79]. ...
Background
Bladder cancer (BCa) is the leading reason for death among malignancies in genitourinary system. RNA modifications participate in pivotal tumor-promoting mechanisms in specific epigenetic contexts. Our study aimed to propose a novel model associated with the “writer” enzymes of five primary RNA adenosine modifications (including m⁶A, m⁶Am, m¹A, alternative polyadenylation, and adenosine-to-inosine editing), which could predict the clinical outcome and immunotherapeutic efficacy of BCa, thus conferring a promising orientation for BCa predictive, preventive, and personalized medicine (PPPM/3PM).
Methods
Unsupervised clustering was employed to categorize BCa into different RNA modification patterns on the basis of gene expression profiles of 34 RNA modification “writers”. The RNA modification “writers” score (RMS) signature composed of RNA phenotype-associated differentially expressed genes (DEGs) was established using the least absolute shrinkage and selection operator (LASSO). The prognostic power of the RMS model was evaluated using Kaplan-Meier analysis and receiver operating characteristic curves. A visualized nomogram was established for BCa risk stratification. The potential applicability of the RMS model in predicting the therapeutic responsiveness was assessed through the Genomics of Drug Sensitivity in Cancer database and multiple immunotherapy datasets.
Results
Two distinct RNA modification patterns were determined among 1410 BCa samples, showing radically varying clinical outcomes and biological characteristics. The RMS model comprising 14 RNA modification phenotype-associated prognostic DEGs was positively correlated with the unsatisfactory outcome of BCa patients in a meta-GEO training cohort (HR = 3.00, 95% CI = 2.19–4.12) and the TCGA-BLCA validation cohort (HR = 1.53, 95% CI = 1.13–2.09). The infiltration of immunosuppressive cells and the activation of EMT, angiogenesis, IL-6/JAK/STAT3 signaling were markedly enriched in RMS-high cohort. A nomogram including age, N classification and the RMS exhibited high prognostic prediction accuracy, with a concordance index of 0.745. The combination of the RMS model and conventional characteristics (TMB, TNB and PD-L1) achieved an optimal area under the curve of 0.828 in differentiating responders from non-responders to immunotherapy based on IMvigor210 cohort.
Conclusion
Our report conferred the first landscape of five forms of RNA modifications in BCa and emphasized the excellent power of the RNA modifications-related model in evaluating prognosis and immunotherapeutic efficacy. In accordance with our model, physicians can not only conduct early identification of high-risk patients to confer them with priority attention and targeted prevention, but also judge patients’ responses to immunotherapy in advance to render personalized therapy, which is conducive to the research and practice of PPPM/3PM in BCa.
... Previous molecular genetic studies have shown a relationship between urothelial carcinomas and microsatellite instability (MSI). Namely, between 1.1 and 28% of urothelial carcinomas present MSI [4][5][6][7][8][9][10][11][12][13][14]. MSI is caused by mutations in the genes of the DNA repair system, known as Mismatch repair (MMR) [11], which fail to repair DNA duplication errors. ...
Introduction
Microsatellite instability occurs due to a series of mutations in the DNA pairing error repair (Mismatch repair; MMR) genes, which can affect germ cells as occurs in Lynch syndrome, whose patients are at high risk of developing multiple cancers. The loss of MMR protein is commonly determined by immunohistochemical studies. Although the relation between microsatellite instability and urothelial carcinomas has been widely studied, its evaluation is not currently performed in the analysis of urothelial carcinomas.
Methods
In this study, the microsatellite status of 139 urothelial carcinomas was analyzed and their clinicopathological characteristics were evaluated. We identified that 10.3% (13 patients) of urothelial carcinomas had loss of MMR protein expression (9 MLH1; 5 MSH2; 2 PMS2; 2 PSH6; n = 139).
Results
Results suggest that these tumors occur more frequently in males, are more frequently located in the bladder or ureters, and present a high tumor grade with a papillary histological pattern that does not infiltrate the lamina propria or, in the case of infiltrating tumors, that grows into perivesical tissues.
Conclusions
We identified patients with the aforementioned tumor characteristics as patients with a high probability of presenting loss of MMR protein expression, and consider that only these patients should undergo further immunohistochemical and molecular techniques for proper diagnosis. Therefore, we propose that the clinicopathological characteristics found in the present study could become possible markers to determine which cases should undergo additional tests.
... The cumulative lifetime risk of developing UC of the UUT is 7.6-22-fold higher than that in the general population (12). LS-related UC is known to develop more commonly in younger and female patients with MSH2 variants (13,14). However, this patient was a relatively elderly man with mutations in MLH1 and MSH2. ...
Lynch syndrome (LS) is an inherited syndrome associated with an increased risk of cancer caused by abnormalities in DNA mismatch repair (MMR) genes. Immune checkpoint inhibitors (ICIs) have been reported to lead to a good response in cancers accompanied by LS. However, ICI therapy can cause immune-related adverse events (irAEs). In addition, post ICI treatment, some patients can show a falsely aggravated response, called pseudoprogression, causing difficulties in initial drug response evaluation. A 61-year-old man presented with back and pelvic bone pain. He had a history of surgery for stomach and colon cancer, and his daughter was treated for endometrial cancer. The patient was diagnosed with primary urothelial carcinoma (UC) in the left ureter with adrenal gland and multiple bone metastases. Through nextgeneration sequencing (NGS), mutations in MLH1 and MSH2 were identified, and diagnosis of LS was confirmed. On the 11th day from the start of atezolizumab, left pleural effusion occurred with exacerbation of the rib metastasis; the amount of effusion increased, and percutaneous catheter drainage (PCD) was performed. On the 27th day, right pleural effusion developed, and drainage was initiated. After the third cycle of atezolizumab, the bilateral pleural fluid decreased, and the drainage tube was removed. Positron emission tomography/computed tomography (PET-CT) revealed improvement in the cancer lesions, including metastatic bone lesions. This is a rare case of bilateral pleural effusion due to pseudoprogression of rib lesions after atezolizumab treatment in a patient with ureter cancer accompanied by LS. UC associated with LS is expected to show a good response to ICI therapy. For proper identification of pseudoprogression, appropriate response evaluation and close monitoring of the side effects are necessary.
... Among the tumors, only 20% were associated with genomically unstable or basal/squamous cell features (based on the six-class Lund subtype system). There were also no expression pattern differences in LS-BC or LS-UTUC tumors, and LS-UTUC/BC mostly grouped with BC tumors of the uro/luminal subtypes, being comparable with sporadic BC [42]. ...
Context
While upper tract urothelial carcinoma (UTUC) share histological appearance with bladder cancer (BC), the former has differences in etiology and clinical phenotype consistent with characteristic molecular alterations.
Objective
To systematically evaluate current genomic sequencing and proteomic data examining molecular alterations in UTUC.
Evidence acquisition
A systematic review using PubMed, Scopus, and Web of Science was performed in December 2019 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement.
Evidence synthesis
A total of 46 publications were selected for inclusion in this report, including 13 studies assessing genome-wide alterations, 18 studies assessing gene expression or microRNA expression profiles, three studies assessing proteomics, one study assessing genome-wide DNA methylation, and 14 studies evaluating distinct pathway alteration patterns. Differences between sporadic and hereditary UTUC, and between UTUC and BC, as well as molecular profiles associated with exposure to aristolochic acid are highlighted. Molecular pathways relevant to UTUC biology, such as alterations in FGFR3, TP53, or microsatellite instability, are discussed. Our findings are limited by tumor and patient heterogeneity and different platforms used in the studies.
Conclusions
Molecular events in UTUC and BC can be shared or distinct. Consequently, molecular subtypes differ according to location. Further work is needed to define the epigenomic and proteomic features of UTUC, and understand the mechanisms by which they shape the clinical behavior of UTUC.
Patient summary
We report the current data on the molecular alterations specific to upper tract urothelial carcinoma (UTUC), resulting from novel genomic and proteomic technologies. Although UTUC biology is comparable with that of bladder cancer, the rates and UTUC-enriched alterations support its uniqueness and the need for precision medicine strategies for this rare tumor type.
IntroductionMicrosatellite instability occurs due to a series of mutations in the DNA pairing error repair (Mismatch repair; MMR) genes, which can affect germ cells as occurs in Lynch syndrome, whose patients are at high risk of developing multiple cancers. The loss of MMR protein is commonly determined by immunohistochemical studies. Although the relation between microsatellite instability and urothelial carcinomas has been widely studied, its evaluation is not currently performed in the analysis of urothelial carcinomas.Methods In this study, the microsatellite status of 139 urothelial carcinomas was analyzed and their clinicopathological characteristics were evaluated. We identified that 10.3% (13 patients) of urothelial carcinomas had loss of MMR protein expression (9 MLH1; 5 MSH2; 2 PMS2; 2 PSH6; n = 139). ResultsResults suggest that these tumors occur more frequently in males, are more frequently located in the bladder or ureters, and present a high tumor grade with a papillary histological pattern that does not infiltrate the lamina propria or, in the case of infiltrating tumors, that grows into perivesical tissues.Conclusions
We identified patients with the aforementioned tumor characteristics as patients with a high probability of presenting microsatellite instability, and consider that only these patients should undergo further immunohistochemical and molecular techniques for proper diagnosis. Therefore, we propose that the clinicopathological characteristics found in the present study could become possible markers to determine which cases should undergo additional tests.
Although substantial progress has been made in cancer biology and treatment, clinical outcomes of bladder carcinoma (BC) patients are still not satisfactory. The tumor micro-environment (TME) is a potential target. Here, by single-cell RNA sequencing on 8 BC tumor samples and 3 para tumor samples, we identify 19 different cell types in the BC micro-environment, indicating high intra-tumoral heterogeneity. We find that tumor cells down regulated MHC-II molecules, suggesting that the downregulated immunogenicity of cancer cells may contribute to the formation of an immunosuppressive microenvironment. We also find that monocytes undergo M2 polarization in the tumor region and differentiate. Furthermore , the LAMP3 + DC subgroup may be able to recruit regulatory T cells, potentially taking part in the formation of an immunosuppressive TME. Through correlation analysis using public datasets containing over 3000 BC samples, we identify a role for inflammatory cancer-associated fibroblasts (iCAFs) in tumor progression, which is significantly related to poor prognosis. Additionally, we characterize a regulatory network depending on iCAFs. These results could help elucidate the protumor mechanisms of iCAFs. Our results provide deep insight into cancer immunology and provide an essential resource for drug discovery in the future.
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