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1.
Pathol Oncol Res ; 28: 1610638, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36338826

RESUMO

Immune checkpoint inhibitors (ICIs) have shown encouraging outcomes against Lynch syndrome (LS)-associated colorectal cancer (CRC) and endometrial cancer with mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H). However, there is as yet no clarity on the safety and efficacy of immunotherapy combined with chemotherapy in LS-associated urothelial carcinoma (UC). Here, we report a patient with recurrent and metastatic LS-associated UC who achieved sustained response to programmed death protein 1 (PD-1) inhibitor combined with chemotherapy over 31 months, during which the side effects of immunotherapy could be controlled and managed. Our findings indicate that the dMMR/MSI status and PD-1 expression in UC may have potential predictive value for the response to PD-1-targeted immunotherapy. Our case supports the inclusion of such combination and/or monotherapy for UC in clinical studies and using dMMR/MSI status and PD-1 expression as potential predictive biomarkers for assessment of the therapeutic response.


Assuntos
Carcinoma de Células de Transição , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Neoplasias da Bexiga Urinária , Feminino , Humanos , Instabilidade de Microssatélites , Receptor de Morte Celular Programada 1 , Reparo de Erro de Pareamento de DNA , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Imunoterapia , Neoplasias Colorretais/patologia
2.
BMC Cancer ; 22(1): 1156, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36352365

RESUMO

BACKGROUND: We evaluated the prognostic role of deficient mismatch repair (dMMR) systems in stage II and stage III colon cancer patients during different postoperative periods. We also assessed whether patients aged ≥75 could benefit from chemotherapy. METHODS: This retrospective study was conducted across three medical centers in China. Kaplan-Meier survival methods and Cox proportional hazards models were used to evaluate the differences in overall survival (OS) and disease-free survival (DFS) rates. Propensity score matching was performed to reduce imbalances in the baseline characteristics of the patients. Landmark analysis was performed to evaluate the role of dMMR during different postoperative periods. RESULTS: The median follow-up time for all patients was 45.0 months (25-75 IQR: 38.0-82.5). There was no significant OS (p = 0.350) or DFS (p = 0.752) benefit associated with dMMR for stage II and III patients during the first postoperative year. However, significant OS (p < 0.001) and DFS (p < 0.001) benefits were observed from the second postoperative year until the end of follow-up. These differences remained after propensity score matching. Moreover, chemotherapy produced no OS (HR = 0.761, 95% CI: 0.43-1.34, p = 0.341) or DFS (HR = 0.98, 95% CI: 0.51-1.88, p = 0.961) benefit for patients aged ≥75 years. CONCLUSION: The benefits of dMMR in stage III patients were observed from the second postoperative year until the end of follow-up. However, the prognosis of patients with dMMR is not different from that of patients with proficient mismatch repair (pMMR) during the first postoperative year. In addition, elderly patients aged ≥75 years obtained no significant survival benefits from postoperative chemotherapy.


Assuntos
Neoplasias do Colo , Neoplasias Testiculares , Idoso , Masculino , Humanos , Reparo de Erro de Pareamento de DNA , Estudos Retrospectivos , Quimioterapia Adjuvante , Fluoruracila/uso terapêutico , Estadiamento de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prognóstico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/cirurgia , Neoplasias Testiculares/tratamento farmacológico , Período Pós-Operatório
3.
Cancer Treat Rev ; 111: 102480, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36335756

RESUMO

Survival in mismatch-repair proficient (MMRp) metastatic colorectal cancer (mCRC) remains poor and chemotherapy is the mainstay of treatment. Immunotherapy has demonstrated durable responses and a favourable side-effect profile in various cancer types and multiple clinical trials have been conducted in MMRp mCRC. In this review we summarise emerging trial data which demonstrate promising immunotherapy combinations in MMRp mCRC. We outline barriers to success, evaluate emerging biomarkers and discuss potential strategies to increase the effectiveness of immunotherapy in MMRp mCRC.


Assuntos
Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Imunoterapia
6.
Zhonghua Bing Li Xue Za Zhi ; 51(10): 993-999, 2022 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-36207912

RESUMO

Objective: To investigate the molecular classification and clinicopathological features of endometrial carcinoma(EC). Methods: One hundred cases of EC diagnosed in the Department of Pathology, Tianjin Central Hospital of Gynecology and Obstetrics from November 2020 to November 2021 were selected. Sanger sequencing and immunohistochemical staining were used for molecular classification according to the 5th WHO classification. The clinicopathological characteristics of each molecular subtype was analyzed. Results: The 100 EC patients had a mean age of 53 years (range 26 to 72 years). There were 10 cases of POLE mutation (POLE mut), including two cases (2/10) of "binary-classifier" EC, two cases (2/10) of FIGO Grade 3 endometrioid endometrial carcinoma (G3-EEC), and three cases (3/10) of other high-grade subtypes. There were 38 cases of mismatch repair deficiency (dMMR), including one case (1/38, 2.6%) of "binary-classifier" EC and 36 cases (36/38, 94.7%) were EEC. Twenty-one cases (21/38, 55.3%) showed simultaneous loss of expression of MLH1 and PMS2, and 20 cases (20/21, 95.2%) were positive for MLH1 methylation, indicating that they were sporadic EC. Six patients (6/38, 15.8%) were tested for germline detection of Lynch syndrome (LS) related genes, and one patient was LS-related EC. There were 44 cases of non-specific molecular profile (NSMP), including 34 cases (34/44, 77.3%) of G1-2 EEC and seven cases (7/44, 15.9%) of G3-EEC. There were eight cases of p53 abnormality (p53 abn), including four cases (4/8) of G3-EEC, two cases (2/8) of other high-grade subtypes, and one patient had hereditary breast cancer and ovarian cancer syndrome. Conclusions: Correct interpretation of POLE mutation, MMR and p53 immunohistochemistry is the key of molecular classification. The interpretation must strictly follow standard diagnostic procedures and specifications to ensure the accuracy of molecular classification.


Assuntos
Carcinoma Endometrioide , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias do Endométrio , Adulto , Idoso , Carcinoma Endometrioide/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
7.
Int J Mol Sci ; 23(19)2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36232318

RESUMO

The polarization of tumor-associated macrophages (TAMs) plays a key role in tumor development and immunotherapy in colorectal cancer (CRC) patients. However, the impact of apoptosis on TAM polarization and immunotherapy efficacy in patients with different mismatch repair statuses (MMR) remains unclear. Here, we constructed an atlas of macrophage and found a higher rate of infiltration of M2-like TAM subpopulation in pMMR CRC tumor tissues compared with that in dMMR CRC tumor tissues. Importantly, a lower infiltration rate of M2c-like TAMs was associated with immunotherapy response. The M2 polarization trajectory revealed the apoptosis of M2c-like TAMs in dMMR while the differentiation of M2c-like TAMs in pMMR, implying a higher polarization level of M2 in pMMR. Furthermore, we found that a high expression of S100A6 induces the apoptosis of M2c-like TAMs in dMMR. In conclusion, we identified apoptotic TAM subpopulations in the M2 polarization trajectory and found that apoptosis caused by the high expression of S100A6 reduces their infiltration in tumors as well as the level of M2 polarization and contributes to a favorable immunotherapy response. These findings provide new insights into the potential role of apoptosis in suppressing tumors and enhancing immunotherapeutic efficacy.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Apoptose , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA , Humanos , Imunoterapia , Macrófagos/metabolismo
8.
Int J Mol Sci ; 23(19)2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36232851

RESUMO

Lynch syndrome (LS) is the main hereditary colorectal cancer syndrome. There have been few reports regarding the clinical and molecular characteristics of LS patients in Latin America; this is particularly true in the Mexican population, where no information is available. The present study aims to describe the clinical and molecular spectrum of variants in a cohort of patients diagnosed with LS in Mexico. We present a retrospective analysis of 412 patients with suspected LS, whose main site of cancer diagnosis was the colon (58.25%), followed by the endometrium (18.93%). Next-generation sequencing analysis, with an extensive multigene panel, showed that 27.1% (112/414) had a variant in one of the genes of the mismatch repair pathway (MMR); 30.4% (126/414) had a variant in non-MMR genes such as CHEK2, APC, MUTYH, BRCA1, and BRCA2; and 42.5% (176/414) had no genetic variants. Most of the variants were found in MLH1. Pathogenic variants (PVs) in MMR genes were identified in 65.7% (96/146) of the total PVs, and 34.24% (45/146) were in non-MMR genes. Molecular and clinical characterization of patients with LS in specific populations allowed personalized follow-up, with the option for targeted treatment with immune checkpoint inhibitors and the development of public health policies. Moreover, such characterization allows for family cascade testing and consequent prevention strategies.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Inibidores de Checkpoint Imunológico , México/epidemiologia , Proteína 2 Homóloga a MutS/genética , Estudos Retrospectivos
9.
Int J Mol Sci ; 23(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36293153

RESUMO

Lynch syndrome (LS) is the most common cause of inherited endometrial cancer (EC). The prevalence and molecular characteristic of LS in Middle Eastern women with EC have been underexplored. To evaluate the frequency of LS in a cohort of EC patients from Saudi Arabia, a total of 436 EC cases were screened utilizing immunohistochemistry (IHC), MLH1 promoter methylation analysis and next-generation sequencing technology. A total of 53 of 436 (12.2%) ECs were classified as DNA mismatch repair-deficient (dMMR). MLH1 promoter hypermethylation was detected in 30 ECs (6.9%). Three ECs (0.7%) were found to be LS harboring germline pathogenic variants (PVs)/likely pathogenic variants (LPVs): two in the MSH2 gene and one in the MSH6 gene. Three ECs (0.7%) were Lynch-like syndrome (LLS) carrying double somatic MSH2 PVs/LPVs. Seven cases were found to have variants of uncertain significance in cancer-related genes other than MMR genes. Our results indicate that LS prevalence is low among Saudi EC patients and LLS is as common as LS in this ethnicity. Our findings could help in better understanding of the prevalence and mutational spectrum of this syndrome in Saudi Arabia, which may help in defining best strategies for LS identification, prevention and genetic counseling for EC patients.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias do Endométrio , Humanos , Feminino , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Proteína 2 Homóloga a MutS/genética , Reparo de Erro de Pareamento de DNA/genética , Arábia Saudita/epidemiologia , Mutação em Linhagem Germinativa/genética , Metilação de DNA , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Instabilidade de Microssatélites
10.
Proc Natl Acad Sci U S A ; 119(42): e2212870119, 2022 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-36215471

RESUMO

Eukaryotic DNA mismatch repair (MMR) depends on recruitment of the Mlh1-Pms1 endonuclease (human MLH1-PMS2) to mispaired DNA. Both Mlh1 and Pms1 contain a long unstructured linker that connects the N- and carboxyl-terminal domains. Here, we demonstrated the Mlh1 linker contains a conserved motif (Saccharomyces cerevisiae residues 391-415) required for MMR. The Mlh1-R401A,D403A-Pms1 linker motif mutant protein was defective for MMR and endonuclease activity in vitro, even though the conserved motif could be >750 Å from the carboxyl-terminal endonuclease active site or the N-terminal adenosine triphosphate (ATP)-binding site. Peptides encoding this motif inhibited wild-type Mlh1-Pms1 endonuclease activity. The motif functioned in vivo at different sites within the Mlh1 linker and within the Pms1 linker. Motif mutations in human cancers caused a loss-of-function phenotype when modeled in S. cerevisiae. These results suggest that the Mlh1 motif promotes the PCNA-activated endonuclease activity of Mlh1-Pms1 via interactions with DNA, PCNA, RFC, or other domains of the Mlh1-Pms1 complex.


Assuntos
Neoplasias , Proteínas de Saccharomyces cerevisiae , Trifosfato de Adenosina/metabolismo , DNA/metabolismo , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/metabolismo , Endonucleases/genética , Endonucleases/metabolismo , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteínas MutL , Proteína 2 Homóloga a MutS/metabolismo , Proteínas Mutantes/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
11.
Drugs ; 82(15): 1557-1564, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36308601

RESUMO

Pucotenlimab (Puyouheng™) is a humanised immunoglobulin (Ig) G4 monoclonal antibody (mAb) being developed by Lepu Biopharma for the treatment of solid tumours, including gastrointestinal cancer, metastatic melanoma, liver cancer, bladder cancer, non-small cell lung cancer and breast cancer. Pucotenlimab binds to PD-1 and blocks its interaction with its ligands, PD-L1 and PD-L2, thereby restoring the ability of immune cells to target cancer cells. In July 2022, pucotenlimab received conditional first approval in China for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumours, including patients with advanced colorectal cancer who have experienced disease progression after previous therapy with fluorouracil, oxaliplatin and irinotecan, as well as patients with other advanced solid tumours who have experienced disease progression after previous first-line therapy and have no satisfactory treatment alternatives. In September 2022, pucotenlimab was approved in China for the treatment of unresectable or metastatic melanomas after the failure of previous systemic therapy. This article summarizes the milestones in the development of pucotenlimab leading to the first approval for the treatment of MSI-H/dMMR advanced solid tumours.


Assuntos
Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Colorretais , Neoplasias Pulmonares , Humanos , Antineoplásicos Imunológicos/uso terapêutico , Reparo de Erro de Pareamento de DNA , Instabilidade de Microssatélites , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Progressão da Doença
12.
Biomolecules ; 12(10)2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-36291559

RESUMO

Colorectal cancer (CRC) in adolescents and young adults (AYA) is very rare. Known predisposition syndromes include Lynch syndrome (LS) due to highly penetrant MLH1 and MSH2 alleles, familial adenomatous polyposis (FAP), constitutional mismatch-repair deficiency (CMMRD), and polymerase proofreading-associated polyposis (PPAP). Yet, 60% of AYA-CRC cases remain unexplained. In two teenage siblings with multiple adenomas and CRC, we identified a maternally inherited heterozygous PMS2 exon 12 deletion, NM_000535.7:c.2007-786_2174+493del1447, and a paternally inherited POLD1 variant, NP_002682.2:p.Asp316Asn. Comprehensive molecular tumor analysis revealed ultra-mutation (&gt;100 Mut/Mb) and a large contribution of COSMIC signature SBS20 in both siblings' CRCs, confirming their predisposition to AYA-CRC results from a high propensity for somatic MMR deficiency (MMRd) compounded by a constitutional Pol δ proofreading defect. COSMIC signature SBS20 as well as SBS26 in the index patient's CRC were associated with an early mutation burst, suggesting MMRd was an early event in tumorigenesis. The somatic second hits in PMS2 were through loss of heterozygosity (LOH) in both tumors, suggesting PPd-independent acquisition of MMRd. Taken together, these patients represent the first cases of cancer predisposition due to heterozygous variants in PMS2 and POLD1. Analysis of their CRCs supports that POLD1-mutated tumors acquire hypermutation only with concurrent MMRd.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Adulto Jovem , Adolescente , Humanos , Reparo de Erro de Pareamento de DNA/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Síndrome , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Neoplasias Colorretais/genética , Carcinogênese/genética
13.
Pathol Res Pract ; 239: 154179, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36274380

RESUMO

OBJECTIVE: High stromal ratio of gastric cancer is associated with a poor prognosis. Fibronectin 1(FN1) is the main component of gastric cancer stroma. The focus of this research was to investigate the FN1 express pattern, the connection between FN1 expression, clinicopathological parameters, survival, and mismatch repair genes (MMR) or immune checkpoints in gastric cancer patients. METHODS: Eighty-six paired stomach cancer tissues, neighboring normal tissues, and eight independent gastric cancer tissues were used to create 180 points tissue microarrays. The association between epithelial fibronectin (E-FN1), stromal fibronectin (S-FN1) expression, and clinical characteristics was analyzed using the chi-square test or Fisher's exact test, and the survival analysis curve was analyzed using the log-rank test, followed by univariate and multivariate Cox regression. The correlation between FN1 and MMR or immune checkpoints was analyzed by Spearman correlation. RESULTS: FN1 is mainly expressed in gastric cancer tissues, with low or no expression in adjacent normal tissues. In tumor tissues, FN1 is mostly distributed in the stroma. High E-FN1 expression was associated with a decreased overall survival (OS), while S-FN1 expression did not. High S-FN1 expression correlated with older age (P<0.001), higher pathological grade (P<0.001), pathological type (P<0.001), vessel/lymphatic invasion (P<0.001), advanced T stage (P=0.001), N stage (P=0.01), and worse TNM stage(P = 0.033). FN1 expression was not associated with MMR or immune checkpoints (MLH1, MSH2, MSH6, PDL1, PD1, PMS2, and CD8). CONCLUSIONS: High E-FN1 expression predicted poor OS, while S-FN1 is associated with gastric cancer progression.


Assuntos
Neoplasias Gástricas , Humanos , Biomarcadores Tumorais/metabolismo , Reparo de Erro de Pareamento de DNA , Fibronectinas/genética , Prognóstico , Neoplasias Gástricas/patologia
14.
Nat Commun ; 13(1): 5808, 2022 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-36192430

RESUMO

Highly conserved MutS and MutL homologs operate as protein dimers in mismatch repair (MMR). MutS recognizes mismatched nucleotides forming ATP-bound sliding clamps, which subsequently load MutL sliding clamps that coordinate MMR excision. Several MMR models envision static MutS-MutL complexes bound to mismatched DNA via a positively charged cleft (PCC) located on the MutL N-terminal domains (NTD). We show MutL-DNA binding is undetectable in physiological conditions. Instead, MutS sliding clamps exploit the PCC to position a MutL NTD on the DNA backbone, likely enabling diffusion-mediated wrapping of the remaining MutL domains around the DNA. The resulting MutL sliding clamp enhances MutH endonuclease and UvrD helicase activities on the DNA, which also engage the PCC during strand-specific incision/excision. These MutS clamp-loader progressions are significantly different from the replication clamp-loaders that attach the polymerase processivity factors ß-clamp/PCNA to DNA, highlighting the breadth of mechanisms for stably linking crucial genome maintenance proteins onto DNA.


Assuntos
Reparo de Erro de Pareamento de DNA , Proteínas de Escherichia coli , Trifosfato de Adenosina/metabolismo , DNA/metabolismo , Reparo do DNA , Endonucleases/metabolismo , Proteínas de Escherichia coli/metabolismo , Proteínas MutL/genética , Proteínas MutL/metabolismo , Proteína MutS de Ligação de DNA com Erro de Pareamento/genética , Nucleotídeos , Antígeno Nuclear de Célula em Proliferação/metabolismo
16.
Gan To Kagaku Ryoho ; 49(10): 1130-1132, 2022 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-36281609

RESUMO

Deficient mismatch repair (dMMR)/microsatellite instability (MSI)-H colorectal cancer (CRC) has high immunogenicity. Although the cyclic GMP-AMP synthase( cGAS)-stimulator of interferon genes( STING) pathway activation has considerably contributed to the high number of CD8+ tumor-infiltrating lymphocytes (TILs), its role in dMMR/MSI-H CRC is largely unknown. In this study, we investigated the association between cGAS-STING expression and CD8+ TILs in CRC. Data analysis using the TCGA dataset CRC cohort showed that cGAS, STING, and CD8 gene expression levels were significantly higher in the MSI group. Immunohistochemistry examination of resected clinical CRC samples showed that cGAS-STING expression in tumor cells was high in the MSI CRC, and CD8+ TILs was also significantly infiltrated in the MSI group. Moreover, significant CD8+ TILs infiltration was observed in CRC with high cGAS and STING expression levels. The results suggest that dMMR/MSI -H CRC has maintained a high cGAS-STING expression, which may contribute to abundant CD8+ TILs.


Assuntos
Neoplasias Colorretais , Instabilidade de Microssatélites , Humanos , Reparo de Erro de Pareamento de DNA , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Neoplasias Colorretais/patologia , Interferons/genética
17.
Cancer Treat Rev ; 110: 102460, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36058142

RESUMO

Immune checkpoint inhibitors (ICIs) have marked a new era of cancer treatment, showing remarkable efficacy in a wide range of solid malignancies. In colorectal cancer (CRC), however, the therapeutic potential of ICIs is limited to the small group (≈5%) of patients with mismatch repair deficient (dMMR)/high microsatellite instable (MSI-H) tumours, which are characterised by high mutational/neo-antigen burden, and an inflammatory tumour microenvironment with abundant tumour-infiltrating lymphocytes. Over the last few years, research has focused on immuno-modulatory strategies that could overcome the inherent resistance to ICIs that is observed in the vast group (≈95%) of patients with mismatch repair proficient (pMMR)/microsatellite stable (MSS) tumours. Among these, the combination of ICIs with multi-kinase inhibitors has gained traction in preclinical studies and clinical trials. Thanks to their multiple targets and mechanisms of action, generally involving key cancer pathways such as oncogenesis, angiogenesis, metastasis, and tumour immunity, these agents can exert synergistic effects with ICIs, eventually turning inherently cold cancers into hot tumours, that can be efficiently recognised and targeted by an activated immune system. Regorafenib is routinely used for chemorefractory CRC with limited efficacy. Preliminary evidence, however, suggests that this multi-kinase inhibitor could be an optimal combination partner for ICIs. In this review article, we explain the biological rationale underlying the synergism between regorafenib and ICIs, discuss the available clinical data in CRC, and take a glance into future perspectives by presenting ongoing trials and possible research developments in this setting.


Assuntos
Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Instabilidade de Microssatélites , Repetições de Microssatélites , Compostos de Fenilureia , Piridinas , Microambiente Tumoral
18.
Expert Rev Mol Med ; 24: e32, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36059110

RESUMO

Roughly 3% of the human genome consists of microsatellites or tracts of short tandem repeats (STRs). These STRs are often unstable, undergoing high-frequency expansions (increases) or contractions (decreases) in the number of repeat units. Some microsatellite instability (MSI) is seen at multiple STRs within a single cell and is associated with certain types of cancer. A second form of MSI is characterised by expansion of a single gene-specific STR and such expansions are responsible for a group of 40+ human genetic disorders known as the repeat expansion diseases (REDs). While the mismatch repair (MMR) pathway prevents genome-wide MSI, emerging evidence suggests that some MMR factors are directly involved in generating expansions in the REDs. Thus, MMR suppresses some forms of expansion while some MMR factors promote expansion in other contexts. This review will cover what is known about the paradoxical effect of MMR on microsatellite expansion in mammalian cells.


Assuntos
Reparo de Erro de Pareamento de DNA , Instabilidade de Microssatélites , Animais , Reparo de Erro de Pareamento de DNA/genética , Instabilidade Genômica , Humanos , Mamíferos/genética , Repetições de Microssatélites
19.
Cancer Cell ; 40(9): 914-916, 2022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-36055229

RESUMO

Neoadjuvant treatment with immunotherapy using dostarlimab leads to impressive clinical responses and omission of surgery in patients with mismatch repair (MMR)-deficient rectal cancers, according to a study published in the New England Journal of Medicine.


Assuntos
Reparo de Erro de Pareamento de DNA , Neoplasias Retais , Anticorpos Monoclonais Humanizados , Reparo de Erro de Pareamento de DNA/genética , Humanos , Imunoterapia , Neoplasias Retais/genética , Neoplasias Retais/terapia
20.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(8): 1263-1266, 2022 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-36073228

RESUMO

Lynch syndrome (LS) is an autosomal dominant hereditary disease caused by deletion of such DNA mismatch repair (MMR) genes as MLH1, MSH2, MSH6, and PMS2. The functional loss of MMR genes results in instability of the highly repetitive DNA sequence, and may eventually leads to tumor occurrence. Here we report a case of LS- related endometrial cancer in a clustered LS family identified by genetic counseling and genetic testing. For patients with a family history of LSrelated tumors, the diagnosis of LS should be considered, and immunohistochemical testing of MMR and genetic testing for LS should be performed. A definite diagnosis of LS has important clinical significance for individuals and family members, and risk screening and preventive measures can minimize the overall risk of developing LS-related cancers.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias do Endométrio , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Testes Genéticos/métodos , Humanos
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