OBJECTIVE: To investigate the relationship between Ig class switch recombination (CSR) and mismatch repair (MMR) protein, microsatellite phenotype in extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). METHODS: Forty cases of MALT lymphoma archived in the Department of Pathology, Jiading District Central Hospital, Shanghai University of Medicine & Health Sciences were selected as the observation group, and twenty cases of benign lymphoid tissue hyperplasia were as the control group. The expressions of IgG, IgM, IgD, and IgA in both groups were detected by immunohistochemical double staining, and MMR proteins including MLH1, MSH2, MSH6, and PMS2 in both groups were detected by immunohistochemistry. Multiplex fluorescence PCR capillary electrophoresis was used to detect microsatellite phenotype in tumor and adjacent tissues of the experimental group. RESULTS: In the observation group, the proportions of single Ig heavy chain expression (modeⅠ), negative expression (modeⅡ), and multiple expression (mode Ⅲ) were 65% (26/40), 27.5% (11/40), and 7.5% (3/40), respectively, while in the control group were 0 (0/20), 5% (1/20), and 95% (19/20). The proportion of Ig heavy chain expression mode Ⅰ+Ⅱ in the observation group was 92.5%, which was significantly higher than 5% in the control group (P < 0.01). In the observation group, partial deletion of MMR protein was observed in 3 cases (7.5%), including 2 cases of MSH6 deletion and 1 case of both MSH6 and PMS2 deletion. In the control group, there was 1 case (5%) with PMS2 deletion. There was no significant difference in the deletion rate of MMR protein between the two groups ( P >0.05). A total of 5 cases of microsatellite instability (MSI) were detected in the observation group, including 1 case of low-frequency MSI (MSI-L), 4 cases of high-frequency MSI (MSI-H), and 2 cases of MSI-H with MSH6 deletion. When the loss expression of MSI-H or MMR protein was counted as a positive result, the MSI-H rate detected by PCR capillary electrophoresis was 10% (4/40), which was slightly higher than the MMR protein deletion rate detected by immunohistochemistry (7.5%, 3/40), but there was no statistically significant difference between the two groups (P >0.05). The MMR protein deletion rates among the Ig heavy chain protein expression mode Ⅰ, mode Ⅱ, and mode Ⅲ groups were 0 (0/26), 18.2% (2/11), and 33.3% (1/3), respectively. There was a statistically significant difference in the constituent ratios among the three groups (P < 0.05). The MMR protein deletion rates among the MSS, MSI-L, and MSI-H groups were 2.9% (1/35), 0 (0/1), and 50% (2/4), respectively. There was a statistically significant difference in the constituent ratios among the three groups (P < 0.05). MMR protein deficiency was positively correlated with Ig heavy chain expression pattern and MSI ( r =0.41, P < 0.05; r =0.48, P < 0.05), but Ig heavy chain expression pattern was not correlated with MSI ( r =0.02, P >0.05). CONCLUSION Ig heavy chain CSR detection is helpful for the differential diagnosis of MALT lymphoma. Low frequency MMR protein deletion and MSI-H phenotype exist in MALT lymphoma, which may be of certain value for the study of its occurrence, development and clinical treatment.
Humans ; Lymphoma, B-Cell, Marginal Zone/genetics* ; DNA Mismatch Repair ; Immunoglobulin Class Switching ; DNA-Binding Proteins/metabolism* ; MutS Homolog 2 Protein ; Microsatellite Repeats ; Phenotype ; MutL Protein Homolog 1 ; Mismatch Repair Endonuclease PMS2 ; Male

Rectal cancer is one of the most common malignant tumors in China, with more than half of patients diagnosed at the locally advanced stage. Currently, the standard treatment for locally advanced rectal cancer (LARC) primarily involves neoadjuvant chemoradiotherapy followed by radical surgery. The advent of immune checkpoint inhibitors has revolutionized the neoadjuvant treatment landscape for mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) rectal cancer. However, most rectal cancer patients exhibit mismatch repair-proficient/microsatellite stable (pMMR/MSS) status and show poor responsiveness to immunotherapy. In recent years, multiple studies have demonstrated that neoadjuvant short-course radiotherapy followed by chemotherapy and immunotherapy can improve the pathological complete response rate in pMMR/MSS LARC patients. Nevertheless, controversies persist regarding patient selection, efficacy evaluation, adverse event management, postoperative adjuvant therapy, and follow-up strategies. Considering the Colorectal Surgery Group of the Surgery Branch of the Chinese Medical Association, in collaboration with the Colorectal and Anal Surgery Committee of the Chinese Research Hospital Association, the Chinese Colorectal Cancer Clinical Research Collaborative Group, and related experts, has developed this consensus document by referencing domestic and international research advancements. The aim is to provide standardized guidance for the clinical application of this treatment approach.
Humans ; Rectal Neoplasms/genetics* ; Neoadjuvant Therapy ; Immunotherapy ; DNA Mismatch Repair ; Microsatellite Instability ; Consensus ; Combined Modality Therapy

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have emerged as critical agents for cancer therapy. By inhibiting the catalytic activity of PARP enzymes and trapping them in the DNA, PARPis disrupt DNA repair, ultimately leading to cell death, particularly in cancer cells with homologous recombination repair deficiencies, such as those harboring BRCA mutations. This review delves into the mechanisms of action of PARPis in anticancer treatments, including the inhibition of DNA repair, synthetic lethality, and replication stress. Furthermore, the clinical applications of PARPis in various cancers and their adverse effects as well as their combinations with other therapies and the mechanisms underlying resistance are summarized. This review provides comprehensive insights into the role and mechanisms of PARP and PARPis in DNA repair, with a particular focus on the potential of PARPi-based therapies in precision medicine for cancer treatment.
Humans ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use* ; Neoplasms/genetics* ; DNA Repair/drug effects* ; Animals ; Antineoplastic Agents/therapeutic use*

Oroxylin A (OA), a natural compound extracted from Scutellaria baicalensis, demonstrates preventive potential against ultraviolet B (UVB)-induced non-melanoma skin cancer (NMSC), the most prevalent cancer worldwide with increasing incidence. Utilizing SKH-1 hairless mice exposed to UVB, this study showed that OA delayed NMSC onset and alleviated acute skin damage. Mechanistic investigations revealed its dual action: inhibiting inflammation and enhancing nucleotide excision repair (NER) by stabilizing XPA, a crucial deoxyribonucleic acid (DNA) repair protein. This stabilization occurred through OA's interaction with glucose-regulated protein 94 (GRP94), which disrupted murine double minute 2 (MDM2)-mediated XPA ubiquitination and proteasomal degradation. By maintaining XPA levels, OA expedited photoproduct clearance and diminished genomic instability, ultimately impeding NMSC development. These findings suggest OA as a promising chemopreventive agent targeting the GRP94/MDM2-XPA axis to counteract UVB-induced carcinogenesis.
Animals ; Ultraviolet Rays/adverse effects* ; Skin Neoplasms/prevention & control* ; Flavonoids/pharmacology* ; Mice ; Xeroderma Pigmentosum Group A Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-mdm2/genetics* ; DNA Repair/drug effects* ; Scutellaria baicalensis/chemistry* ; Mice, Hairless ; Skin/radiation effects*

The accumulation of deoxyribonucleic acid (DNA) oxidative damage mediated by reactive oxygen species (ROS) is closely associated with liver diseases. 8-Oxoguanine (8-OxoG), a prevalent DNA oxidation product, plays a significant role in liver disease progression. The base excision repair (BER) pathway, comprising over 30 proteins including 8-OxoG DNA glycosylase1 (OGG1), MutY homolog (MUTYH), and MutT homolog protein 1 (MTH1), is responsible for the clearance and mismatch repair of 8-OxoG. Abnormally high levels of 8-OxoG and dysregulated expression and function of 8-OxoG repair enzymes contribute to the onset and development of liver diseases. Consequently, targeting the 8-OxoG production and repair system with agonists or inhibitors may offer a promising approach to liver disease treatment. This review summarizes the impact of 8-OxoG accumulation and dysregulated repair enzymes on various liver diseases, including viral liver disease, alcoholic liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), cholestatic liver disease (CLD), liver fibrosis, cirrhosis, and liver cancer. Additionally, we review natural constituents as potential therapeutic agents that regulate 8-OxoG production, repair enzymes, and repair system-related signal pathways in oxidative damage-induced liver diseases.
Humans ; Liver Diseases/genetics* ; Biological Products/pharmacology* ; DNA Repair/drug effects* ; Guanine/metabolism* ; Animals ; Disease Progression ; DNA Damage ; Oxidative Stress

Objective To study the pathological types,expression of mismatch repair protein,human epidermal growth factor receptor 2(HER2),and Pan-TRK,and Epstein-Barr virus(EBV)infection in patients with colorectal cancer resected in Tibet. Methods A total of 79 patients with colorectal cancer resected in Tibet Autonomous Region People's Hospital from December 2013 to July 2021 were enrolled in this study.The clinical and pathological data of the patients were collected.The expression of mismatch repair protein,HER2,and Pan-TRK was detected by immunohistochemical(IHC)staining,and detection of HER2 gene by fluorescence in situ hybridization(FISH)in the patients with HER2 IHC results of 2+ or above.EBV was detected by in situ hybridization with EBV-encoded small RNA. Results A total of 79 colorectal cancer patients were included in this study,with the male-to-female ratio of 1.26:1 and the mean age of(57.06±12.74)years(24-83 years).Among them,4 patients received preoperative neoadjuvant therapy.Colonic cancer and rectal cancer occurred in 57(57/79,72.15%,including 31 and 26 in the right colon and left colon,respectively)and 22(22/79,27.85%)patients,respectively.The maximum diameter of tumor varied within the range of 1-20 cm,with the mean of(6.61±3.33)cm.Among the 79 colorectal cancer patients,75(75/79,94.94%)patients showed adenocarcinoma.Lymph node metastasis occurred in 12(12/21,57.14%)out of the 21 patients with severe tumor budding,13(13/23,56.52%)out of the 23 patients with moderate tumor budding,and 2(2/31,6.45%)out of the 31 patients with mild tumor budding,respectively.The lymph node metastasis rate showed differences between the patients with severe/moderate tumor budding and the patients with mild tumor budding(all P<0.001).The IHC staining showed that mismatch repair protein was negative in 10(10/65,15.38%)patients,including 5 patients with both MSH2 and MSH6 negative,4 patients with both MLH1 and PMS2 negative,and 1 patient with MSH6 negative.Pan-TRK was negative in 65 patients.The IHC results of HER2 showed 0 or 1+ in 60 patients and 2+ in 5 patients.FISH showed no positive signal in the 5 patients with HER2 IHC results of 2+.The detection with EBV-encoded small RNA showed positive result in 1(1/65,1.54%)patient. Conclusions Non-specific adenocarcinoma of the right colon is the most common in the patients with colorectal cancer resected in Tibet,and 15% of the patients showed mismatch repair protein defects.EBV-associated colorectal carcer is rare,Pan-TRK expression and HER2 gene amplification are seldom.The colorectal cancer patients with moderate and severe tumor budding are more likely to have lymph node metastasis.
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Adenocarcinoma ; Biomarkers, Tumor/genetics* ; Colorectal Neoplasms/pathology* ; DNA Mismatch Repair ; DNA-Binding Proteins/genetics* ; Epstein-Barr Virus Infections/diagnosis* ; Herpesvirus 4, Human/metabolism* ; In Situ Hybridization, Fluorescence ; Lymphatic Metastasis ; Tibet ; Young Adult ; Aged, 80 and over

OBJECTIVES: To investigate the prevalence of pathogenic germline mutations of mismatch repair (MMR) genes in prostate cancer patients and its relationship with clinicopathological characteristics. METHODS: Germline sequencing data of 855 prostate cancer patients admitted in Fudan University Shanghai Cancer Center from 2018 to 2022 were retrospectively analyzed. The pathogenicity of mutations was assessed according to the American College of Medical Genetics and Genomics (ACMG) standard guideline, Clinvar and Intervar databases. The clinicopathological characteristics and responses to castration treatment were compared among patients with MMR gene mutation (MMR⁺ group), patients with DNA damage repair (DDR) gene germline pathogenic mutation without MMR gene (DDR⁺MMR^－ group) and patients without DDR gene germline pathogenic mutation (DDR^－ group). RESULTS: Thirteen (1.52%) MMR⁺ patients were identified in 855 prostate cancer patients, including 1 case with MLH1 gene mutation, 6 cases with MSH2 gene mutation, 4 cases with MSH6 gene mutation and 2 cases with PMS2 gene mutation. 105 (11.9%) patients were identified as DDR gene positive (except MMR gene), and 737 (86.2%) patients were DDR gene negative. Compared with DDR^－ group, MMR⁺ group had lower age of onset (P<0.05) and initial prostate-specific antigen (PSA) (P<0.01), while no significant differences were found between the two groups in Gleason score and TMN staging (both P>0.05). The median time to castration resistance was 8 months (95%CI: 6 months-not achieved), 16 months (95%CI: 12-32 months) and 24 months (95%CI: 21-27 months) for MMR⁺ group, DDR⁺MMR^－ group and DDR^－ group, respectively. The time to castration resistance in MMR⁺ group was significantly shorter than that in DDR⁺MMR^－ group and DDR^－ group (both P<0.01), while there was no significant difference between DDR⁺MMR^－ group and DDR^－ group (P>0.05). CONCLUSIONS MMR gene mutation testing is recommended for prostate cancer patients with early onset, low initial PSA, metastasis or early resistance to castration therapy.
Male ; Humans ; Prostate-Specific Antigen/genetics* ; Germ-Line Mutation ; Retrospective Studies ; DNA Mismatch Repair/genetics* ; DNA-Binding Proteins/metabolism* ; China ; Prostatic Neoplasms/pathology*

BACKGROUND: Microsatellite instability (MSI) is a key biomarker for cancer immunotherapy and prognosis. Integration of MSI testing into a next-generation-sequencing (NGS) panel could save tissue sample, reduce turn-around time and cost, and provide MSI status and comprehensive genomic profiling in single test. We aimed to develop an MSI calling model to detect MSI status along with the NGS panel-based profiling test using tumor-only samples. METHODS: From January 2019 to December 2020, a total of 174 colorectal cancer (CRC) patients were enrolled, including 31 MSI-high (MSI-H) and 143 microsatellite stability (MSS) cases. Among them, 56 paired tumor and normal samples (10 MSI-H and 46 MSS) were used for modeling, and another 118 tumor-only samples were used for validation. MSI polymerase chain reaction (MSI-PCR) was performed as the gold standard. A baseline was built for the selected microsatellite loci using the NGS data of 56 normal blood samples. An MSI detection model was constructed by analyzing the NGS data of tissue samples. The performance of the model was compared with the results of MSI-PCR. RESULTS: We first intersected the target genomic regions of the NGS panels used in this study to select common microsatellite loci. A total of 42 loci including 23 mononucleotide repeat sites and 19 longer repeat sites were candidates for modeling. As mononucleotide repeat sites are more sensitive and specific for detecting MSI status than sites with longer length motif and the mononucleotide repeat sites performed even better than the total sites, a model containing 23 mononucleotide repeat sites was constructed and named Colorectal Cancer Microsatellite Instability test (CRC-MSI). The model achieved 100% sensitivity and 100% specificity when compared with MSI-PCR in both training and validation sets. Furthermore, the CRC-MSI model was robust with the tumor content as low as 6%. In addition, 8 out of 10 MSI-H samples showed alternations in the four mismatch repair genes ( MLH1 , MSH2 , MSH6 , and PMS2 ). CONCLUSION MSI status can be accurately determined along the targeted NGS panels using only tumor samples. The performance of mononucleotide repeat sites surpasses loci with longer repeat motif in MSI calling.
Humans ; Microsatellite Instability ; Colorectal Neoplasms/diagnosis* ; Microsatellite Repeats/genetics* ; DNA Mismatch Repair

Objective: To explore the concordance and causes of different mismatch repair (MMR) and microsatellite instability (MSI) detection results in endometrial carcinoma (EC) molecular typing. Methods: A total of 214 EC patients diagnosed from January 2021 to April 2023 were selected at the Department of Pathology, Peking University Third Hospital. The immunohistochemistry (IHC) results of MMR protein were reviewed. Tumor specific somatic mutations, MMR germline mutations, microsatellite scores and tumor mutation burden (TMB) were detected by next-generation sequencing (NGS) with multi-gene panel. Methylation-specific PCR was used to detect the methylation status of MLH1 gene promoter in cases with deficient MLH1 protein expression. In cases with discrepant results between MMR-IHC and MSI-NGS, the MSI status was detected again by PCR (MSI-PCR), and the molecular typing was determined by combining the results of TMB and MLH1 gene promoter methylation. Results: (1) In this study, there were 22 cases of POLE gene mutation subtype, 55 cases of mismatch repair deficient (MMR-d) subtype, 29 cases of p53 abnormal subtype, and 108 cases of no specific molecular profile (NSMP). The median age at diagnosis of MMR-d subtype (54 years old) and the proportion of aggressive histological types (40.0%, 22/55) were higher than those of NSMP subtype [50 years old and 12.0% (13/108) respectively; all P<0.05]. (2) Among 214 patients, MMR-IHC test showed that 153 patients were mismatch repair proficient (MMR-p), 49 patients were MMR-d, and 12 patients were difficult to evaluate directly. MSI-NGS showed that 164 patients were microsatellite stable (MSS; equal to MMR-p), 48 patients were high microsatellite instability (MSI-H; equal to MMR-d), and 2 patients had no MSI-NGS results because the effective sequencing depth did not meet the quality control. The overall concordance between MMR-IHC and MSI-NGS was 94.3% (200/212). All the 12 discrepant cases were MMR-d or subclonal loss of MMR protein by IHC, but MSS by NGS. Among them, 10 cases were loss or subclonal loss of MLH1 and (or) PMS2 protein. Three discrepant cases were classified as POLE gene mutation subtype. In the remaining 9 cases, 5 cases and 3 cases were confirmed as MSI-H and low microsatellite instability (MSI-L) respectively by MSI-PCR, 6 cases were detected as MLH1 gene promoter methylation and 7 cases demonstrated high TMB (>10 mutations/Mb). These 9 cases were classified as MMR-d EC. (3) Lynch syndrome was diagnosed in 27.3% (15/55) of all 55 MMR-d EC cases, and the TMB of EC with MSH2 and (or) MSH6 protein loss or associated with Lynch syndrome [(71.0±26.2) and (71.5±20.1) mutations/Mb respectively] were significantly higher than those of EC with MLH1 and (or) PMS2 loss or sporadic MMR-d EC [(38.2±19.1) and (41.9±24.3) mutations/Mb respectively, all P<0.01]. The top 10 most frequently mutated genes in MMR-d EC were PTEN (85.5%, 47/55), ARID1A (80.0%, 44/55), PIK3CA (69.1%, 38/55), KMT2B (60.0%, 33/55), CTCF (45.5%, 25/55), RNF43 (40.0%, 22/55), KRAS (36.4%, 20/55), CREBBP (34.5%, 19/55), LRP1B (32.7%, 18/55) and BRCA2 (32.7%, 18/55). Concurrent PTEN, ARID1A and PIK3CA gene mutations were found in 50.9% (28/55) of MMR-d EC patients. Conclusions: The concordance of MMR-IHC and MSI-NGS in EC is relatively high.The discordance in a few MMR-d EC are mostly found in cases with MLH1 and (or) PMS2 protein loss or MMR protein subclonal staining caused by MLH1 gene promoter hypermethylation. In order to provide accurate molecular typing for EC patients, MLH1 gene methylation, MSI-PCR, MMR gene germline mutation and TMB should be combined to comprehensively evaluate MMR and MSI status.
Female ; Humans ; Middle Aged ; Class I Phosphatidylinositol 3-Kinases/metabolism* ; Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis* ; DNA Mismatch Repair/genetics* ; Endometrial Neoplasms/pathology* ; Microsatellite Instability ; Mismatch Repair Endonuclease PMS2/genetics* ; Molecular Typing

DNA ; DNA Damage ; DNA Repair ; Fanconi Anemia/genetics* ; Humans