Recorrência do ameloblastoma: análise de fatores clínicoradiográficos e imunoexpressão de hMSH2, hMLH1 e KI-67 / Ameloblastoma recurrence: analysis of clinical-radiographic factors and immunoexpression of hMSH2, hMLH1 and KI-67

Introdução: O ameloblastoma é uma neoplasia odontogênica benigna, que apresenta altas taxas de recorrência pós-operatória. Diversos estudos mostram a relação entre as características clínico-patológicas e as modalidades de tratamento na recorrência do ameloblastoma. Os mecanismos moleculares envolvidos com a etiopatogenia deste tumor são pouco conhecidos, e apesar de alterações no Sistema Mismatch favorecerem o desenvolvimento de diferentes neoplasias humanas, a importância destes no desenvolvimento do ameloblastoma ainda permanece pouco compreendido. Objetivo: Identificar os fatores clínico-patológicos associados à recorrência do ameloblastoma, bem como investigar o papel da imunoexpressão das proteínas hMLH1, hMSH2 e Ki-67 na recidiva desses tumores odontogênicos. Metodologia: Tratou-se de um estudo descritivo, transversal e restrospectivo, com uma amostra constituída por 22 casos de ameloblastomas recidivantes e 22 casos não-recidivantes. A análise imunoistoquímica foi realizada de forma quantitativa, considerando a localização celular (nuclear) das proteínas estudadas. O teste de McNemar foi utilizado para comparar as variáveis entre lesões da 1ª biópsia e recorrentes de AMB. A sobrevida livre de recorrência foi analisada pelo método de Kaplan-Meier e as funções de sobrevida foram comparadas de acordo com as variáveis pelo teste log-rank. Resultados: O gênero mais acometido foi o feminino (n=24; 54,5%), com média de idade de acometimento de 39,1 ± 19,8 anos, sendo 45,5% (n=20) leucodermas. A região posterior de mandíbula foi a mais frequente no grupo recidivante (n=18, 81,8%) e também para os casos que não apresentaram recidivas (n=16, 72,8%). O tempo livre de recorrência foi de 50,0 (34,5 ­ 63,6) meses. Foram fatores significativamente associadas à recorrência dos ameloblastomas: presença de expansão da cortical (p=0,0089), ausência de reconstrução óssea (p=0,018), tratamento conservador (p=0,021), perda de imunoexpressão de hMSH2 (p=0,006) e hMLH1 (p=0,038) e forte imunoexpressão de Ki-67 (p=0,029). Conclusão: Baseado nos achados desta pesquisa, aspecto radiográfico, modalidade do tratamento e imunoexpressão de proteínas do Sistema Mismatch e Ki-67 podem ser utilizados como indicadores para a recorrência em ameloblastomas (AU).

Introduction: Ameloblastoma is a benign odontogenic neoplasm, which has high rates of postoperative recurrence. Several studies show the relationship between clinicopathological characteristics and treatment modalities in ameloblastoma recurrence. The molecular mechanisms involved in the etiopathogenesis of this tumor are little known, and although changes in the Mismatch System favor the development of different human neoplasms, their importance in the development of ameloblastoma still remains poorly understood. Objective: To identify clinical and pathological factors associated with ameloblastoma recurrence, as well as to investigate the role of immunoexpression of hMLH1, hMSH2 and Ki-67 proteins in the recurrence of these odontogenic tumors. Methodology: This was a descriptive, cross-sectional and retrospective study, with a sample consisting of 22 cases of recurrent ameloblastoma and 22 non-recurrent cases. Immunohistochemical analysis was performed quantitatively, considering the cellular (nuclear) location of the studied proteins. McNemar's test was used to compare variables between 1st biopsy and recurrent AMB lesions. Recurrence-free survival was analyzed using the Kaplan-Meier method and survival functions were compared according to variables using the log-rank test. Results: The most affected gender was female (n=24; 54.5%), with a mean age of involvement of 39.1 ± 19.8 years, 45.5% (n=20) being white. The posterior region of the mandible was the most frequent in the relapsed group (n=18, 81.8%) and also for the cases that did not present recurrences (n=16, 72.8%). Recurrence-free time was 50.0 (34.5 ­ 63.6) months. Factors significantly associated with recurrence of AMBs were: presence of cortical expansion (p=0.0089), absence of bone reconstruction (p=0.018), conservative treatment (p=0.021), loss of hMSH2 immunoexpression (p=0.006) and hMLH1 (p=0.038) and strong Ki-67 immunoexpression (p=0.029). Conclusion: Based on the findings of this research, radiographic appearance, treatment modality and immunoexpression of proteins from the Mismatch System and Ki-67 can be used as indicators for recurrence in ameloblastomas (AU).

Association of status of mismatch repair protein expression and EB virus infection with clinicopathological parameters in 886 gastric adenocarcinoma patients / 中华胃肠外科杂志

Objective: To analyze the expression of mismatch repair (MMR) protein and the EB virus infection in gastric adenocarcinoma, and to examine the association of MMR expression and EB virus infection with clinicopathological parameters. Methods: A case-control study was performed. Clinicopathological data of patients who was pathologically diagnosed as gastric adenocarcinoma, received radical gastrectomy and had complete clinicopathological data from August 2017 to April 2020 in Tianjin Medical University Cancer Institute and Hospital were retrospectively collected and analyzed. The immunohistochemistry (IHC) of MMR proteins and in situ hybridization (ISH) of Epstein-Barr virus encoded RNA (EBER) were reviewed. The associations of MMR and EBER results with clinicopathological parameters were analyzed. The main observations of the study were MMR and EBER expression, and association of MMR and EBER results with clinicopathological parameters. Results: Eight hundred and eighty-six patients were enrolled, including 98 patients who received preoperative neoadjuvant chemoradiotherapy. Of 886 patients, 613 (69.2%) were males and the median age was 60 (22-83) years; 831 (93.8%) were mismatch repair proficiency (pMMR), and 55 (6.2%) were mismatch repair deficiency (dMMR). In dMMR group, 47 cases (85.5%) had the deficiency of both MLH1 and PMS2, 1 case (1.8%) had the deficiency of both MSH2 and MSH6, 4 cases (7.3%) had the deficiency only in PMS2, 2 cases (3.6%) had the deficiency only in MSH6, and 1 case (1.8%) had the deficiency only in MSH2. The deficiency rates of PMS2, MLH1, MSH6 and MSH2 were 5.8% (51/886), 5.3% (47/886), 0.3% (3/886) and 0.2% (2/886), respectively. Among the 871 cases with EBER results, 4.9% (43/871) were positive EBER. Univariate analysis showed that dMMR was more frequently detected in female patients (χ(2)=10.962, P=0.001), cancer locating in the antrum (χ(2)=9.336,P=0.020), Lauren intestinal type (χ(2)=9.718, P=0.018), stage T3 (χ(2)=25.866, P<0.001) and TNM stage II (χ(2)=15.470, P=0.002). The ratio of dMMR was not significantly associated with age, tumor differentiation, histological type, lymph node metastasis, distant metastasis or Her-2 immunohistochemical score (all P>0.05). Compared with negative EBER, positive EBER was more frequent in male patients (χ(2)=9.701, P=0.002), cancer locating in gastric fundus and corpus (χ(2)=17.964, P<0.001), gastric cancer with lymphoid stroma (χ(2)=744.073, P<0.001) and poorly differentiated cancer (χ(2)=13.739, P=0.010). Positive EBER was not significantly associated with age, depth of invasion, lymph node metastasis, distant metastasis, TNM stage or Her-2 immunohistochemical score (all P>0.05). In addition, all dMMR cases were EBER negative, and all cases of positive EBER were pMMR. Conclusions: The positive EB virus status is mutually exclusive with dMMR, indicating that different molecular subtypes of gastric adenocarcinoma are involved in different molecular pathways in tumorigenesis and progression. The overlapping of dMMR or positive EBER status and positive Her-2 expression is found in some cases of gastric adenocarcinoma. Patients with gastric adenocarcinoma after radical surgery should be tested for MMR status if they are female, the tumor locates in gastric antrum, the TNM staging is stage II or T3, or if the Lauren classification is intestinal type. And if patients are male, the tumor locates in the gastric fundus and corpus, the cancer is lymphoid stroma, or poor differentiated, the expression of EBER should be detected. Results of our study may provide evidence for further decision-making of clinical treatment.

Correlation between the expression of PD-L1 and dMMR related proteins in follicular thyroid carcinoma tissues and its clinical significance / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the correlation between PD-L1 expression and dMMR related proteins in follicular thyroid carcinoma tissues and its clinical significance. Methods: The postoperative paraffin-embedded tissue samples from 60 patients with thyroid follicular carcinoma were collected from the Second Affiliated Hospital of Fujian Medical University during January 2015 and June 2020. The collected samples were re-confirmed as thyroid follicular carcinoma tissues by Hematoxylin-eosin staining. The expression of PD-L1 and four homologous proteins encoded by four genes (MLH1, MSH2, MSH6, PMS2) in MMR system were detected by immunohistochemistry in the cancer and paracancerous tissues. The relationship between the expression of PD-L1 and depletion of MMR related proteins in thyroid follicular carcinoma tissues and its clinical significance were analyzed. Results: The positive expression rate of PD-L1 was significantly higher in the follicular thyroid carcinoma tissues than that in paracancerous tissues [63.3%(38/60) vs 11.7%(7/60), P<0.05]. The expression of PD-L1 was significantly correlated with tumor diameter, extrathyroidal infiltration, vascular invasion and recurrence (all P<0.05). In the cancer tissue specimens from 60 patients, 24 (40.0%) had expression of four MMR related proteins, which were pMMR tumors, and 36 (60.0%) had depletion of one or more MMR related proteins, which were dMMR tumors. The dMMR-type thyroid follicular carcinoma was significantly correlated with the status of lymph node metastasis and tumor staging (all P<0.05). PD-L1 was positively correlated with the incidence of dMMR, and PD-L1 was an independent risk factor for disease recurrence, while dMMR was associated with a better prognosis. Patients with PD-L1+/pMMR type were associated with higher tumor malignancy, while patients with PD-L1+/dMMR type were not associated with tumor pathological features but may easily benefit from immunotherapy. Conclusion: Positive PD-L1 expression and dMMR highly occur in follicular thyroid carcinoma. PD-L1 is associated with the increased tumor invasion and is an independent risk factor for disease recurrence, while dMMR is an early molecular event in the development of thyroid follicular carcinoma and is associated with better prognosis of patients.

Analysis of screening methods for DNA mismatch repair gene deletion in colorectal cancer / 中国肿瘤临床

Objective: Here, we aimed to analyze the two most commonly used methods for screening DNA mismatch repair (MMR) gene deletions in colorectal cancer to establish a more cost-effective strategy. Methods: A total of 223 patients with colorectal cancer were recruited from the First Affiliated Hospital of Xinjiang Medical University for this study from September 2018 to September 2019. Using the Ventana BenchMark ULTRA automatic immunohistochemistry platform, the expression levels of MLH1, MSH2, PMS2, and MSH6 proteins were assessed, and the microsatellite instability (MSI) status of the tumors was then determined through PCR capillary electrophoresis. Results: Among the 223 patients with colorectal cancer, 27 (12.1%) had MMR deficiency (dMMR) and 196 (87.9%) had MMR proficiency (pMMR). The missing rates of MLH1, MSH2, MSH6, and PMS2 were estimated as 9.0% (20/223), 1.8% (4/223), 2.7% (6/223), and 9.4% (21/223), respectively. The sensitivity and specificity of the two-antibody test employing antibodies against only PMS2 and MSH6 for screening dMMR colorectal cancer were the same as those of the four-antibody test. Twenty-seven cases exhibited high microsatellite instability (MSI-H) (12.1%) and 196 cases exhibited microsatellite stability (MSS) (87.9%). However, no case exhibited low microsatellite stability (MSI-L). The sensitivities of BAT-25, BAT-26, NR-21, NR-24, NR-27, and MONO-27 were 88.9%, 92.6%, 96.3%, 70.4%, 92.6%, and 77.8%, respectively. When MSI was defined using three markers, NR-21, NR-27, and BAT-26, with at least one of the three exhibiting instability, the results were the same as those obtained using the six-marker group. Conclusions: The proposed two-marker detection strategy provides a simple, reliable, and low-cost method for the identification of dMMR/MSI in colorectal cancer.

Clinicopathological characteristics and treatment of multiple primary colorectal carcinoma / 中华消化内镜杂志

Objective@#To investigate clinicopathological characteristics, diagnosis and treatment of multiple primary colorectal carcinoma (MPCC).@*Methods@#From January 2008 to March 2017, 42 patients diagnosed with MPCC underwent surgery at Beijing Shijitan Hospital, Capital Medical University. Their clinicopathological features, diagnosis and treatment were analyzed.@*Results@#These 42 MPCC patients accounted for 7.1% (42/592) colorectal cancer patients in the same period. There were 64 intestinal cancer lesions in 32 patients (76.2%) with synchronous carcinoma (SC), and 20 intestinal cancer lesions in 10 patients (23.8%) with metachronous carcinoma(MC), where the interval between the first and the recurrent was 18-105 months. The proportion of patients in the SC group with highly to moderately differentiated adenocarcinoma was significantly higher compared with that of the MC group (P<0.05), while the incidence of mucinous carcinoma was lower than that of the MC group(P<0.05). No significant differences were found with regard to tumor size, location, complications with adenoma, TNM stages, lymph nodes metastases or DNA mismatch repair between the SC group and the MC group(all P>0.05). Among 42 patients undergoing radical operation, 6 received colonic metallic stent implantation as a bridge to elective resection in 10 patients with colonic obstruction.@*Conclusion@#MPCC, mainly two-lesion cancer, is most commonly found in sigmoid colon and rectum. Those with poorly differentiated cancer, mucinous carcinoma and those complicated with adenoma should be closely followed up with colonoscopy. Colonic metallic stent implantation as a bridge to elective resection may improve the detection rate of SC.

Clinicopathological characteristics and treatment of multiple primary colorectal carcinoma / 中华消化内镜杂志

Objective To investigate clinicopathological characteristics,diagnosis and treatment of multiple primary colorectal carcinoma (MPCC). Methods From January 2008 to March 2017,42 patients diagnosed with MPCC underwent surgery at Beijing Shijitan Hospital,Capital Medical University. Their clinicopathological features,diagnosis and treatment were analyzed. Results These 42 MPCC patients accounted for 7. 1％ (42/ 592)colorectal cancer patients in the same period. There were 64 intestinal cancer lesions in 32 patients (76. 2％)with synchronous carcinoma (SC),and 20 intestinal cancer lesions in 10 patients (23. 8％)with metachronous carcinoma(MC),where the interval between the first and the recurrent was 18-105 months. The proportion of patients in the SC group with highly to moderately differentiated adenocarcinoma was significantly higher compared with that of the MC group (P<0. 05),while the incidence of mucinous carcinoma was lower than that of the MC group(P<0. 05). No significant differences were found with regard to tumor size,location,complications with adenoma,TNM stages,lymph nodes metastases or DNA mismatch repair between the SC group and the MC group(all P>0. 05). Among 42 patients undergoing radical operation,6 received colonic metallic stent implantation as a bridge to elective resection in 10 patients with colonic obstruction. Conclusion MPCC,mainly two-lesion cancer,is most commonly found in sigmoid colon and rectum. Those with poorly differentiated cancer, mucinous carcinoma and those complicated with adenoma should be closely followed up with colonoscopy. Colonic metallic stent implantation as a bridge to elective resection may improve the detection rate of SC.

Screening for microsatellite instability in colorectal carcinoma: practical utility of immunohistochemistry and PCR with fragment analysis in a diagnostic histopathology setting

@#Since 2014, the National Comprehensive Cancer Network (NCCN) has recommended that colorectal carcinoma (CRC) be universally tested for high microsatellite instability (MSI-H) which is present in 15% of such cancers. Fidelity of resultant microsatellites during DNA replication is contingent upon an intact mismatch repair (MMR) system and lack of fidelity can result in tumourigenesis. Prior to commencing routine screening for MSI-H, we assessed two commonly used methods, immunohistochemical (IHC) determination of loss of MMR gene products viz MLH1, MSH2, MSH6 and PMS2 against PCR amplification and subsequent fragment analysis of microsatellite markers, BAT25, BAT26, D2S123, D5S346 and D17S250 (Bethesda markers) in 73 unselected primary CRC. 15.1% (11/73) were categorized as MSI-H while deficient MMR (dMMR) was detected in 16.4% (12/73). Of the dMMR, 66.7% (8/12) were classified MSI-H, while 33.3% (4/12) were microsatellite stable/low microsatellite instability (MSS/MSI-L). Of the proficient MMR (pMMR), 95.1% (58/61) were MSS/MSI-L and 4.9% (3/61) were MSI-H. The κ value of 0.639 (standard error =0.125; p = 0.000) indicated substantial agreement between detection of loss of DNA mismatch repair using immunohistochemistry and the detection of downstream microsatellite instability using PCR. After consideration of advantages and shortcomings of both methods, it is our opinion that the choice of preferred technique for MSI analysis would depend on the type of laboratory carrying out the testing.

Associations of Genetic Variations in Mismatch Repair Genes MSH3 and PMS1 with Acute Adverse Events and Survival in Patients with Rectal Cancer Receiving Postoperative Chemoradiotherapy / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Mismatch repair (MMR) deficiency plays a critical role in rectal cancer. This study aimed to explore the associations between genetic variations in seven MMR genes and adverse events (AEs) and survival of patients with rectal cancer treated with postoperative chemoradiotherapy (CRT). MATERIALS AND METHODS: Fifty single nucleotide polymorphisms in seven MMR (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2) genes were genotyped by Sequenom MassARRAY method in 365 patients with locally advanced rectal cancer receiving postoperative CRT. The associations between genotypes and AEs were measured by odds ratios and 95% confidence intervals (CIs) by unconditional logistic regression model. The associations between genetic variations and survival were computed by the hazard ratios and 95% CIs by Cox proportional regression model. RESULTS: The most common grade ≥ 2 AEs in those 365 patients, in decreasing order, were diarrhea (44.1%), leukopenia (29.6%), and dermatitis (18.9%). Except 38 cases missing, 61 patients (18.7%) died during the follow-up period. We found MSH3 rs12513549, rs33013 and rs6151627 significantly associated with the risk of grade ≥ 2 diarrhea. PMS1 rs1233255 had an impact on the occurrence of grade ≥2 dermatitis. Meanwhile, PMS1 rs4920657, rs5743030, and rs5743100 were associated with overall survival (OS) time of rectal cancer. CONCLUSION: These results suggest that MSH3 and PMS1 polymorphisms may play important roles in AEs prediction and prognosis of rectal cancer patients receiving postoperative CRT, which can be potential genetic biomarkers for rectal cancer personalized treatment.

Correlation of mismatch repair protein expression and microsatellite instability with TNM staging in colorectal cancer / 肿瘤研究与临床

Objective To investigate the relationship between mismatch repair (MMR) protein expression and microsatellite instability (MSI) and tumor TNM staging in colorectal cancer. Methods The clinical data of 1351 patients who underwent radical resection of colorectal cancer at the Xijing Digestive Hospital of Air Force Military Medical University from January 2008 to December 2017 were retrospectively analyzed. The MMR and MSI status in patients with different gender, age and TNM staging were analyzed. Results Of the 1351 specimens, 291 (22％) didn't express MMR protein. Univariate analysis showed that there were significant differences in the deletion rates of MSH2, MSH6 and PMS2 between patients ≥60 years old and<60 years old (all P<0.05);there were significant differences in the deletion rates of MSH2 between stage T3 and the other stages (P<0.05); the deletion rates of MLH1, PMS2 among different N stages, and the deletion rates of MSH2 and MSH6 between stage N0 or N1 and the other N stages were significantly different (all P< 0.05); the deletion rates of PMS2 among different M stages were significantly different (P< 0.05). There were significant differences in PMS2 deletion rates among different TNM stages and MLH1, MSH2 and MSH6 deletion rates between stage Ⅱ or Ⅲ and the other stages (all P< 0.05). There was significant difference in MSI positive rates between patients ≥60 years old and<60 years old (P<0.05); there were significant differences in MSI positive rates between stage T3 or T4 and the other T stages, among different N or M stages, and between TNM stage Ⅱ, ⅢorⅣand the other TNM stages (all P<0.05). Conclusions The MMR protein expression and MSI in colorectal cancer patients are closely related to tumor TNM staging. Detection of MMR protein expression and MSI in colorectal cancer patients has certain reference value for judging TNM staging of colorectal cancer. To a certain extent, it can guide the diagnosis and treatment of patients with colorectal cancer and judge the prognosis.

Relationship between MLH1/MSH2 expression and prognosis of patients with sporadic colorectal cancer / 肿瘤

Objective: To investigate the expressions of mismatch repair gene MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2) in stage II-III sporadic colorectal adenocarcinoma tissues and their clinical signifiance. Methods: The specimens and follow-up data of 490 patients with sporadic colorectal cancer were collected after surgery from January 2014 to April 2016 in Nanjing Hospital of Chinese Medicine. The expressions of MLH1 and MSH2 in colorectal cancer were detected by immunohistochemistry. The relationships of MLH1 and MSH2 expressions with the clinical characteristics and prognosis of patients with colorectal cancer were analyzed. Results: The deletion rate of MLH1/MSH2 expression in colorectal cancer tissues was 20.41% (100/490). The MLH1/MSH2 deletion was correlated with tumor differentiation, location, mucus and lymph node metastasis (all P < 0.05). MLH1/MSH2 deletion mainly occurred in the patients with poorly differentiation, right colon, mucus, and 1-3 lymph nodes metastasis. The disease-free survival (DFS) time of patients with MLH1/MSH2 deletion was longer than that of patients with MLH1/MSH2 normal expression (33.9 months vs 30.4 months, P < 0.001). The prognosis of patients with right colon tumor, poor differentiation, TNM stage III, metastatic lymph nodes more than four, mucus, positive margin and MLH1/MSH2 normal expression was poor (all P < 0.05). The tumor differentiation, tumor location, mucus, surgical margin and expression of MLH1/MSH2 were independent prognostic factors for the patients with stage II - III sporadic colorectal cancer. Conclusion: There is MLH1/MSH2 deletion in stage II - III sporadic colorectal cancer tissues, and it is an independent prognostic factor in patients with colorectal cancer.

Correlation between the expression of four mismatch repair proteins and clinicopathological features of colorectal cancer in elderly patients / 中华老年医学杂志

Objective To investigate the correlation between the expression of four mismatch repair proteins and clinicopathological features of colorectal cancer in elderly patients. Methods The expression of four mismatch repair proteins,MLH1,PMS2,MSH2 and MSH6,in 85 specimens from elderly patients with colorectal cancer,who were treated at the Second Affiliated Hospital of Zhengzhou University from January 2012 to December 2016, was analyzed by immunohistochemistry.The correlation between the expression of these mismatch repair proteins and clinicopathological features of colorectal cancer was also analyzed. Results Of the 85 clinical specimens,76 showed positive expression of the mismatch repair proteins,yielding a positivity rate of 89.4% and a negative rate of 10.6%(9 cases).The negative expression rates of MLHl,PMS2,MSH2 and MSH6 were 7.1%(6 cases),7.1%(6 cases),3.5%(3 cases)and 1.4%(2 cases),respectively.In addition,4 cases(4.7%)had negative expression of MLHl and PMS2,1 case(1.2%)had negative expression of MSH2 and MSH6,and 1 case(1.2%)had negative expression of all four-proteins.Furthermore,univariate and multivariate Logistic regression analyses showed that negative expression rates of the mismatch repair proteins were closely associated with tumor size,tumor differentiation and lymph node metastasis in colorectal cancer(all P < 0.05). Conclusions Concurrent negative expression of MLHl and PMS2 and of MSH2 and MSH6 can be seen in colorectal cancer.Negative expression of mismatch repair proteins is closely related to clinicopathological features of colorectal cancer in elderly patients.

Analysis on clinicopathological features of 617 patients with colorectal cancer / 中国内镜杂志

Objective To summarize the clinicopathological features with 617 cases colorectal cancer and explore reliable clues for early diagnosis. Methods Retrospective analysis of clinical, endoscopic, pathological features and DNA mismatch repair of 617 cases of colorectal cancer was made from January 2008 to March 2017. Results The overall diagnostic yield of colorectal cancer was 2.35% (596/25 308). 18 patients were diagnosed as simultaneous multiple colorectal cancer (3.02%, 18/596). Males and females ratio is 1.34 : 1.00. The average age diagnosed was 66.8 years old. The proportion of colon cancer was 76.68% (457/596), while cancer located in right side of the colon was 39.17%. Occurrence rate of right colonic cancer were higher in female group (47.34%) than that in male group (33.46%) (P = 0.003). Well and moderately differentiated adenocarcinoma was observed in 84.60% (522/617) of the patients. The ratio of mucinous adenocarcinoma was 6.81% (42/617). Totally 230 patients received the DNA mismatch repair, and 57 patients were diagnosed as defective DNA mismatch repair (24.78%). Defective DNA mismatch repair (dMMR) was associated with right colonic cancer, poorly differentiated adenocarcinoma, signet-ring carcinoma and mucinous adenocarcinoma (P < 0.05). Conclusions Colonoscopy screening in the elderly patients deserves great attention. Raise awareness of simultaneous multiple colorectal cancer. Pay attention to the screening of right colon cancer in female. The DNA mismatch repair should be detected in right colonic cancer, poorly differentiated adenocarcinoma, signet-ring carcinoma and mucinous adenocarcinoma.

Endometrial cancer risk and survival by tumor MMR status / 부인종양

OBJECTIVE: The risk of developing endometrial cancer (EC) and/or survival following a diagnosis of EC might differ by tumor DNA mismatch repair (MMR) status. We assessed the association between tumor MMR status (classified as MMR-proficient, somatic MMR-deficient, germline MMR-deficient) and the risk of developing EC and survival following a diagnosis of EC. METHODS: We analyzed data from women who participated in the Australian National Endometrial Cancer Study (ANECS) conducted between 2005 and 2007. Risk analyses (698 cases/691 population controls) utilized sociodemographic and lifestyle information obtained from telephone interviews at recruitment. For survival analyses (728 cases), patients' clinical data was abstracted from medical records, and survival data were obtained via linkage with the Australian National Death Index. We used logistic regression analysis to evaluate the associations between tumor MMR status and EC risk, and proportional hazards models to perform survival analyses with adjustment of known prognostic factors. RESULTS: Established risk factors for EC did not differ significantly by tumor MMR status. In analyses including all EC subtypes, overall and EC-specific survival did not differ by tumor MMR status. Among women with the most common endometrioid subtype, EC-specific survival was worse for women with somatic MMR-deficient EC compared to women with MMR-proficient EC (hazard ratio [HR]=2.18; 95% confidence interval [CI]=1.19–4.01). CONCLUSION: The risk of EC is not associated with MMR status. Accurate separation of germline from somatic causes of MMR deficiency suggests that patients with endometrioid subtype somatic MMR-deficient tumors have poorer EC-specific survival than those with MMR-proficient tumors, after accounting for other prognostic factors.

Relationship between mismatch repair protein expression and clinicopathological features of endometrial cancer / 肿瘤研究与临床

Objective To screen out probable lynch syndrome (LS) associated endometrial cancer (EC) by investigating the expression of mismatch repair (MMR) protein in EC, and to analyze the disease traits combined with clinicopathologic characteristics. Methods The expressions of MSH2, MSH6, MLH1 and PMS2 were detected by using immunohistochemistry (IHC) in 443 EC patients. Results In 443 EC patients, 328 cases (74%) with all MMR proteins expression were classified as sporadic EC, and 115 cases (26%) cases with loss expression of at least one MMR protein were regarded as probable LS. MMR-deficient cases mostly showed a loss of MLH1/PMS2 expression (42%), followed by the absence of MSH2/MSH6 (23%), MSH6 (17%), PMS2 (17%) and MSH6/MLH1/PMS2 (3%). Compared with the sporadic EC group, obesity was not found in probable LS group (body mass index<28 kg/m2) (P=0.040), and high tumor grade was common (P=0.012); There was no significant difference between the two groups in age, the incidence of diabetes or hypertension, family history of cancer or histological type, tumor location, the International Federation of Gynecology and Obstetrics (FIGO) stage, myometrial invasion, lymph node metastasis, lymphatic or vascular invasion (all P> 0.05). A higher tumor grade was more common in the MSH6 and PMS2 deficient groups. Conclusions Compared with sporadic EC, the absence of obesity, a high grade tumor are more common in probable LS cases.

Relationship between mismatch repair protein expression and clinicopathological features of endometrial cancer / 肿瘤研究与临床

Objective To screen out probable lynch syndrome (LS) associated endometrial cancer (EC) by investigating the expression of mismatch repair (MMR) protein in EC, and to analyze the disease traits combined with clinicopathologic characteristics. Methods The expressions of MSH2, MSH6, MLH1 and PMS2 were detected by using immunohistochemistry (IHC) in 443 EC patients. Results In 443 EC patients, 328 cases (74%) with all MMR proteins expression were classified as sporadic EC, and 115 cases (26%) cases with loss expression of at least one MMR protein were regarded as probable LS. MMR-deficient cases mostly showed a loss of MLH1/PMS2 expression (42%), followed by the absence of MSH2/MSH6 (23%), MSH6 (17%), PMS2 (17%) and MSH6/MLH1/PMS2 (3%). Compared with the sporadic EC group, obesity was not found in probable LS group (body mass index<28 kg/m2) (P=0.040), and high tumor grade was common (P=0.012); There was no significant difference between the two groups in age, the incidence of diabetes or hypertension, family history of cancer or histological type, tumor location, the International Federation of Gynecology and Obstetrics (FIGO) stage, myometrial invasion, lymph node metastasis, lymphatic or vascular invasion (all P> 0.05). A higher tumor grade was more common in the MSH6 and PMS2 deficient groups. Conclusions Compared with sporadic EC, the absence of obesity, a high grade tumor are more common in probable LS cases.

The mechanism of 5-Fu-based drug resistance in DNA mismatch repair deficient colorectal cancer HCT-116 cells / 药学实践杂志

Objective To study the mechanisms of the drug resistance of DNA mismatch repair (MMR) deficient color-ectal cancer (CRC) HCT-116 to 5-fluorouracil (5-Fu) .Methods MLH1 deficiency HCT-116 cells were transfected with pcD-NA3 .1-MLH1 Vector .The expression of MLH1 was detected by Western blot .The change of resistance against 5-Fu was ex-amined by detecting the cell viability with CCK-8 kits .The expression of CD133 (cancer stem cell marker ) and CK8 & CK20 (cell differentiation marker) were detected by flow cytometry .Results Comparing to HCT-116 control group ,the viability of HCT-116 cells was markedly decreased (P<0 .01) after stable expressing MLH1 ,accompanied by the down-regulated expres-sion of CD133 on the cell surface .Moreover ,the up-regulation of cell differentiation marker CK8 and CK20 was observed in HCT-116 cells with stable expressing MLH1 .Conclusion Our data indicated that the expression of MLH1 was associated with down-regulated CD133+ stem-like cells in colorectal cancer HCT-116 with MLH1 deficiency .Therefore ,CD133+ stem-like cells may related to the drug resistance of MMR deficiency tumor .This study provides a possible theory to explain the 5-FU resist-ance in the colorectal cancer patients with MMR deficiency .

Comparison of the Mismatch Repair System between Primary and Metastatic Colorectal Cancers Using Immunohistochemistry

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide. Approximately 10%–15% of the CRC cases have defective DNA mismatch repair (MMR) genes. Although the high level of microsatellite instability status is a predictor of favorable outcome in primary CRC, little is known about its frequency and importance in secondary CRC. Immunohistochemical staining (IHC) for MMR proteins (e.g., MLH1, MSH2, MSH6, and PMS2) has emerged as a useful technique to complement polymerase chain reaction (PCR) analyses. METHODS: In this study, comparison between the MMR system of primary CRCs and paired liver and lung metastatic lesions was done using IHC and the correlation with clinical outcomes was also examined. RESULTS: Based on IHC, 7/61 primary tumors (11.4%) showed deficient MMR systems, while 13/61 secondary tumors (21.3%) showed deficiencies. In total, 44 cases showed proficient expression in both the primary and metastatic lesions. Three cases showed deficiencies in both the primary and paired metastatic lesions. In 10 cases, proficient expression was found only in the primary lesions, and not in the corresponding metastatic lesions. In four cases, proficient expression was detected in the secondary tumor, but not in the primary tumor. CONCLUSIONS: Although each IHC result and the likely defective genes were not exactly matched between the primary and the metastatic tumors, identical results for primary and metastatic lesions were obtained in 77% of the cases (47/61). These data are in agreement with the previous microsatellite detection studies that used PCR and IHC.

Hereditary Nonpolyposis Colorectal Cancer / 이화의대지

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary colorectal cancer syndrome and accounts for about 5% of colorectal cancer. It is inherited as autosomal dominant type and is caused by germline mutations in mismatch repair genes such as MLH1, MSH2, MSH6, and PMS2. Patients with HNPCC are characterized by a high level of microsatellite instability. They commonly develop colorectal cancer at young age and increase risk of extra-colic malignancies, especially endometrial cancer. They also show better oncologic outcomes compared to sporadic colorectal cancer. Several tools are used in diagnosis of HNPCC, including history taking, microsatellite instability test, immunohistochemistry for mismatch repair protein, and gene test. Affected patients and their families should get genetic counseling and regular surveillance for cancers, which can improve their survival rate.

Clinicopathological screening of Lynch syndrome：a report of 2 cases and literature review / 北京大学学报(医学版)

Lynch syndrome is an autosomal dominant genetic disease characterized by the early onset of colon cancer, endometrial cancer and other tumors caused by a genetic mutation within DNA mismatch repair (MMR) genes.A small subgroup (approximately 3% -5%) of endometrial cancer and colorectal cancer is related to Lynch syndrome .Identification of these patients in clinical practice will be of great benefit to the relatives and patients themselves .We reported two cases, and reviewed the literature and clinical diagnostic guideline.MMR protein was lost in the tumors.Meanwhile the two cases had different clinicopathological characteristics.Together with the literature, our findings may suggest that the MMR protein expression, associated molecular alterations and clinicopathological features and biological behavior of endometrial cancer and colorectal cancer related to Lynch syndrome are different .Thus the algorithm for detection the patients at highest risk is different .To detect the MMR loss by immunohisto-chemistry is a practicalscreening method.

Loss of ARID1A Expression in Gastric Cancer: Correlation with Mismatch Repair Deficiency and Clinicopathologic Features

PURPOSE: The AT-rich interactive domain 1A (ARID1A) gene encodes BRG1-associated factor 250a, a component of the SWItch/Sucrose NonFermentable chromatin remodeling complex, which is considered a tumor suppressor in many tumors. We aimed to investigate the prognostic significance of ARID1A expression in gastric cancers and explore its relationship with clinicopathologic parameters such as mismatch repair protein expression. MATERIALS AND METHODS: Four tissue microarrays were constructed from 191 resected specimens obtained at Soonchunhyang University Cheonan Hospital from 2006 to 2008. Nuclear expression of ARID1A was semiquantitatively assessed and binarized into retained and lost expression. RESULTS: Loss of ARID1A expression was observed in 62 cases (32.5%). This was associated with more frequent vascular invasion (P=0.019) and location in the upper third of the stomach (P=0.001), and trended toward more poorly differentiated subtypes (P=0.054). ARID1A loss was significantly associated with the mismatch repair-deficient phenotype (P=0.003). ARID1A loss showed a statistically significant correlation with loss of MLH1 (P=0.001) but not MSH2 expression (P=1.000). Kaplan-Meier survival analysis showed no statistically significant difference in overall survival; however, patients with retained ARID1A expression tended to have better overall survival than those with loss of ARID1A expression (P=0.053). In both mismatch repair-deficient and mismatch repair-proficient groups, survival analysis showed no differences related to ARID1A expression status. CONCLUSIONS: Our results demonstrated that loss of ARID1A expression is closely associated with the mismatch repair-deficient phenotype, especially in sporadic microsatellite instability-high gastric cancers.