Progress of Lynch syndrome associated endometrial cancer / 肿瘤研究与临床

Lynch syndrome (LS) is a common hereditary tumor syndrome. Gynecological malignancy is usually the first tumor of LS in women, and endometrial cancer (EC) is the most closely associated with LS. Most patients with LS are unaware of this risk, and it is possible to cause misdiagnosis. Thus, early diagnosis helps patients to start tumor surveillance timely, as well as a cascade of family surveillance. This paper reviews the progress of LS associated with EC.

The efficacy and safety comparison of radium-223 in the treatment of mCRPC patients with and without homologous recombination repair gene mutation / 中华泌尿外科杂志

Objective:To compare the efficacy and safety of radium-223 in the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients with and without homologous recombination repair (HRR) gene mutation.Methods:The clinical data of 27 patients with mCRPC bone metastases who received radium-223 therapy from April 2021 to November 2022 in Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine were retrospectively analyzed. Among the 27 mCRPC patients, 18 patients carrying HRR gene mutations belonged to the HRD(+ ) group, and 9 patients without HRR gene mutation belonged to the HRD(-) group. The age of patients in HRD(+ ) group was 69.5 (63.8, 77.0) years old, alkaline phosphatase (ALP) was 243.0 (82.8, 301.3) U/L, prostate specific antigen (PSA) was 71.6 (7.3, 329.8) ng/ml, pain score was 3.0 (1.0, 5.0) points. Eastern Cooperative Oncology Group (ECOG) score ranged from 0 to 1 points in 7 cases, and 2 points in 11 cases. In the HRD(-) group, the median age was 72.0 (64.5, 76.5) years old, ALP was 88.0 (67.5, 260.6) U/L, PSA was 19.1 (1.1, 117.8) ng/ml, and pain score was 2.0 (0, 4.5) points. The ECOG score ranged from 0 to 1 in 4 cases, and 2 in 5 cases in the HRD(-) group. There was no significant difference in the above general data between the two groups ( P>0.05). All patients received radium-223 treatment every 4 weeks, no more than 6 times. The changes of ALP, PSA, pain score and hematological adverse reactions were compared between the two groups. Results:In the HRD(+ ) group, the median number of radium-223 treatment was 4.5 (3.0, 5.3) couses, 4 patients (22.2%) completed 6 courses, and 6 patients died of prostate cancer during follow-up. In the HRD(-) group, the median number of radium treatment was 4.0 (2.5, 6.0) couses, 3 patients (33.3%) completed 6 courses, and 1 patient died of prostate cancer during follow-up. There was no significant difference in the number of radium treatment courses between the two groups ( P=0.320). ALP in HRD(+ ) group was 101.8 (61.3, 147.0) U/L after radium-223 treatment, which was significantly lower than that before treatment ( P=0.002). ALP in HRD(-) group was 73.0 (64.0, 113.5) U/L after radium-223 treatment, and it was not significantly different from that before treatment ( P=0.327). The rate of ALP response (ALP decrease >10%) in HRD(+ ) group was significantly higher than that in HRD(-) group [83.3% (15/18) vs. 44.4% (4/9), P=0.037]. PSA was 105.9(5.2, 798.4) ng/ml in HRD (+ ) group after radium-223 treatment, and was 25.6(0.8, 1 031.0) ng/ml in HRD(-) group, and they were not significantly different from that before treatment ( P=0.145, P=0.386). There were no significant differences in the rate of PSA response (PSA decrease>10%) between HRD(+ ) group and HRD(-) group [38.9% (7/18) vs. 22.2% (2/9), P=0.386]. The median pain score of HRD(+ ) group was 3.0 (0, 4.0) points after treatment, which was significantly lower than that before treatment ( P=0.028). The pain score of HRD(-) group was 1.0(0, 3.0) points after treatment, and it was not significantly different from that before treatment ( P=0.129). There was no significant difference in pain relief rate between HRD(+ ) group and HRD(-) group [66.7% (12/18) vs. 44.4% (4/9), P=0.411]. The incidence of at least one hematological adverse event during radium-223 treatment in the HRD(+ ) group was higher than that in the HRD(-) group [77.8% (14/18) vs. 33.3% (3/9), P=0.039]. There was no significant difference in the incidence of grade 1-2 hematological adverse events between the two groups [72.2%(13/18) vs. 33.3%(3/9), P=0.097]. Only 1 patient in the HRD(+ ) group experienced grade 3 anemia during treatment which was recovered after blood transfusion. Conclusions:Compared to mCRPC patients without HRR gene mutation, patients with HRR gene mutations had better ALP response and bone pain relief after radium-223 treatment. The overall incidence of adverse events in the HRD(+ ) group is higher than that in HRD(-) group, and there was no significant difference in grade 1-2 hematological adverse events between the two goups. It is necessary to expand the sample size to further verify the conclusion.

Value of DNA Repair Gene and TP53 Co-mutation in Predicting Effect of Immunotherapy on Lung Adenocarcinoma / 肿瘤防治研究

Objective To explore the value of DNA repair genes (DRGs) in predicting the effect of immunotherapy on lung adenocarcinoma based on second-generation sequencing technology. Methods The data of lung adenocarcinoma were obtained from the Cancer Genome Atlas, including the testing cohort and the validation cohort. In the testing set, according to the cut-off value of tumor mutational burden (TMB) score 15, the patients with lung adenocarcinoma were divided into two groups: the low TMB score group and the high TMB score group. And we analyzed the relation between TMB and the overall survival of lung adenocarcinoma patients. KRAS and TP53 co-mutation was used as the standard control, the differences in the mutation count and TMB score between only DRGs mutation group and KRAS or TP53 co-mutation groups were analyzed. In the validation cohort, the differences between DRGs and KRAS or TP53 co-mutation groups in TMB, tumor neoantigen burden and PFS were analyzed. Results The patients with TP53/DRGs co-mutation had higher mutation count and TMB score than those patients with only TP53 or DRGs mutation (P < 0.05). The patients with TP53/DRGs co-mutation had higher mutation count and TMB score than those patients with KRAS/TP53 co-mutation (P=0.037, P=0.044). In validation cohort analysis, the TP53/DRGs co-mutation patients also showed higher tumor neoantigens, higher TMB and longer progression-free survival than those patients with only TP53 or DRGs or KRAS/TP53 co-mutation groups. Conclusion TP53/DRGs co-mutation may be served as a pair of potential biomarkers for predicting the efficacy of immunotherapy on lung adenocarcinoma.

Síndrome de Lynch: impacto de la caracterización de familias en base a estudios genéticos / Lynch syndrome: impact of the characterization of families based on genetic studies

El objetivo de este trabajo fue caracterizar demográfica y molecularmente las familias con diagnóstico de síndrome de Lynch en base a estudios genéticos. Se utilizó la base prospectiva del Registro de Epidemiología Molecular de Cáncer Colorrectal (REM-CCR) del Hospital Italiano de Buenos Aires (Clinical trials.gov NCT02781337). El criterio de inclusión fue que tuvieran hecho un estudio genético entre 1996 y 2017 (secuenciación y/o determinación de grandes rearreglos de al menos un gen reparador de error de apareamiento). Se analizaron 50 familias con los criterios de Amsterdam. En 23 (46%) se identificaron variantes patogénicas (n=19) y probablemente patogénicas (n=2). El 28.6% de las variantes patogénicas fueron originalmente descritas en esta serie, entre ellas la variante c.1911del en el exón 12 de MSH2 identificada en una familia con agregación de cáncer de mama. Fue identificada una mutación fundadora de Piamonte, Italia (c.2252_2253del). Los genes afectados incluyeron MSH2 (13 variantes) MLH1 (9 variantes) y PMS2 (1 variante). La tasa de detección de mutaciones fue del 46%. Entre las familias con mutación identificada (n=23), se detectó una edad mediana de inicio del cáncer menor (46 vs. 50 años, p=0.02) y mayor incidencia de tumores extra-colorrectales (90.5% vs. 45.8%, p <0.01), que las 27 sin mutaciones. La implementación de estudios genéticos permitió caracterizar variables demográficas en base a la identificación de mutaciones germinales asociadas al síndrome de Lynch, identificándose dos grupos diferenciados por la edad de afectación y la incidencia de tumores extracolónicos (AU)

The aim of this study was to characterize demographically and molecularly families diagnosed with Lynch syndrome based on genetic studies. Families with a genetic study performed between 1996 and 2017 (sequencing and/or determination of large rearrangements of a mismatch repair gene at least) were selected from the prospective database REM-CCR of Hospital Italiano de Buenos Aires (Clinical trials. Gov NCT02781337). Fifty families fulfilled Amsterdam criteria were analyzed. Pathogenic variants were found in 23 out of 50 (46%) families, being 21 pathogenic and 2 likely pathogenic. The 28.6% of the pathogenic variants were originally described in this series. Among them, the variant c.1911del in MSH2 in a family with breast cancer aggregation and a founder MLH1 mutation from Piedmont, Italy (c.2252_2253del) were identified. Affected genes include MSH2 (13 variants), MLH1 (9 variants), PMS2 (1 variant). Mutations detection rates was 46%. Those families with an identified mutation (n=23) had a lower median age of cancer onset (46 vs. 50 years, p=0.02) and a higher incidence of extra-colorectal tumors (90.5% vs. 45.8%, p<0.01) than those without identified mutations (n=27). The implementation of genetic studies allowed characterizing demographic variables based on the identification of germline mutations associated with Lynch syndrome. Two groups, Síndrome de Lynch: impacto de la caracterización de familias en base a estudios genéticos 3 differentiated by the age of cancer onset and the incidence of extracolonic tumors were characterized (AU)

Expression and clinical significance of mismatch repair gene in colorectal cancer / 中国肿瘤临床

Objective: To investigate the expression and clinical significance of mismatch repair genes (MMR) MLH1, MSH2, MSH6, and PMS2 in colorectal carcinoma. Methods: Colorectal cancer tissues, collected from 607 patients enrolled in Sichuan Provincial People's Hospital from January 2015 to September 2016, were assigned into two groups based on whether the samples were positive or nega-tive for MMR expression to determine the relationship between MMR expression and clinicopathology. We then evaluated the diag-nostic value of MMR expression in the screening of Lynch syndrome and sporadic colorectal cancer. Results: The deletion rate of MMR protein was 35.58%. No statistically significant difference in age, sex, tumor size, P53, CD34, and D2-40 expression was detected be-tween the negative group with MMR protein deficiency and the positive group with normal expression (P>0.05). Differences in tumor location, differentiation, TNM stage, lymph node metastasis, and VEGF and Ki-67 expression between the two groups were statistically significant (P<0.05). The combined detection of MLH1, MSH2, PSM2, and MSH6 proteins may serve as a simple and economical meth-od for screening patients with Lynch syndrome. Conclusions: The risk of colorectal cancer can be reduced by MMR detection of surgi-cal specimens from colorectal cancer patients, screening of patients with Lynch syndrome and their family members, and assisting with proper management and intervention.

Germline Variants in MLH1, MSH2, and MSH6 in Korean Patients with Lynch Syndrome

BACKGROUND: The phenotypic and genetic spectrum of Lynch syndrome (LS) seems to differ according to ethnicity. The aim of this study was to investigate the clinical, pathological, and genetic features of LS in a large sample of Korean patients. METHODS: We enrolled a total of 232 patients who fulfilled the revised Bethesda criteria (81%, 232/286) from 286 individuals who underwent genetic screening for LS (MLH1, MSH2, and MSH6 sequencing) in the Samsung Medical Center in Korea from 2004 to 2015. Histopathologic findings, microsatellite instability data, and clinical information were collected. RESULTS: We identified 61 different pathogenic or likely pathogenic variants (39 in MLH1, 20 in MSH2, and 2 in MSH6), including 4 novel variants, in 101 unrelated Korean patients (101/232, 44%). When multiple tumor manifestations in a single patient were individually considered, there were 285 cancers recorded from 232 cases. A diverse spectrum of tumors, including colorectal cancer, endometrial cancer, stomach cancer, and ovary cancer, was observed. Patients with genetic alterations were more closely associated with a family history of cancers, double primary cancers, and the development of secondary neoplasms than patients without genetic alterations (P < 0.0001, P=0.0052, and P=0.0010, respectively). CONCLUSIONS: We report the distribution of pathogenic variants in MLH1, MSH2, and MSH6, as well as the tumor spectrum, in a large sample of Korean patients with LS. Genetic testing could be an effective stratification strategy for surveillance of LS. This study sheds light on the genetic features of Asian patients with LS.

Role of H4K20me1 and base excision repair-related genes in repairing DNA damage induced by arsenic pollution through coal burning / 中华地方病学杂志

Objective To investigate the global level of histone 4 lysine 20 monomethylation (H4K20me1) and expression of base excision repair related mRNA in coal-burning-borne endemic arsenism patients and to analyze its relationship with DNA damage,in order to provide a scientific basis in deepening the interpretation of the role of arsenic in inhibiting repair of DNA damage.Methods In 2014,47 hair samples,blood samples and skin tissue samples of the cases in Xingren County Guizhou Province were collected from the voluntary surgical treatment patients with endemic arsenism (15 general pathological change cases,14 precancerous cases and 18 cancerous cases) and 12 controls.The hair arsenic content was tested via the inductively coupled plasma-mass spectrometry method.The expression of histone H4K20me1 in skin tissues was detected via the immunohistochemistry method;quantitative real-time polymerase chain reaction was used to detect the mRNA levels of poly (ADP-ribose) polymerase (PARP1),N-methylation of purine-DNA-glycosylation (MPG) and X-ray repair cross complementary gene 1 (XRCC1);and DNA damage in peripheral blood was detected by single cell gel electrophoresis test,the level of H4K20me1 in peripheral blood cells was detected by using a sandwich enzyme-linked immunosorbent assay.Results Compared with the control group [median (25 ～ 75 percentile):0.15 (0.07-0.23) μg/L],the hair arsenic content in the case group [0.34 (0.17-0.51) μg/L] was significantly increased (Z =6.037,P ＜ 0.05).Compared with the control group (0.32 ± 0.13,0.17 ± 0.12),the modification level of H4K20me1 in peripheral blood with cancerous group (0.62 ± 0.11) was significantly increased,the modification levels of H4K20me1 (0.54 ± 0.20,0.83 ± 0.10) in skin tissues were increased in the precancerous group and cancerous group (P ＜ 0.05).Compared with the control group [0.95 (0.50-1.49),1.12 (0.98-1.48),0.96 (0.67-1.17)],the mRNA expression levels of PARP1 and MPG in cancerous group [0.37 (0.30-0.44),0.38 (0.15-0.48)] were significantly decreased;the mRNA expression levels of XRCC1 [0.48 (0.38-0.89),0.32 (0.20-0.55)] were significantly decreased in the precancerous group and cancerous group (P ＜ 0.05).Compared with the control group (1.19 ± 0.55,1.27 ± 0.51),Tail DNA％ and Tail moment were significantly increased in the general pathological change group (6.49 ± 0.98,6.60 ± 1.11),the precancerous lesion group (11.22 ± 1.40,10.07 ± 1.11),and the cancerous group (20.38 ± 1.72,27.01 ± 1.78,P ＜ 0.05).There was a positive correlation between the degree of skin lesion and modification level of H4K20me1 in peripheral blood and skin tissues and DNA damage levels (TailDNA％,OTM,r =0.885,0.855,0.806,0.883,P ＜ 0.05).There was a positive correlation between modification level of H4K20me1 in peripheral blood and level of DNA damage (TailDNA％,OTM),the level of H4K20me1 protein expression in skin (r =0.535,0.804,0.754,P ＜ 0.05),and a negative correlation with mRNA expression of MPG,XRCC1 and PARP1 (r =-0.563,-0.514,-0.550,P ＜ 0.05).There was a positive correlation between the modification level of H4K20me1 in skin and DNA damage levels (TailDNA％,OTM,r =0.602,0.875,P ＜ 0.05),and a negative correlation with mRNA expression of MPG,XRCC1 and PARP1 (r =-0.492,-0.502,-0.552,P ＜ 0.05).Conclusion The arsenic pollution of coal burning may affect the level of H4K20me1 modification,inhibit mRNA transcriptional expression of PARP1,MPG and XRCC1 genes related with base excision repair,which may lead to increased DNA damage and participate in the occurrence and development of arsenic poisoning skin lesions.

Research of berberine to proliferation and apoptotic mechanism of human ovarian cancer cell line SKOV3 / 中国免疫学杂志

Objective:To investigate the effect of berberine on the proliferation and apoptosis of human ovarian cancer cell (SKOV3). Methods:Cell proliferation was detected by MTT method. The cell apoptosis was detected by FCM Annexin V/PI double staining and transmission electron microscopy. The methylation status of hMLH1 gene promoter CpG island was analyzed by methylation specific PCR. The expression of Bcl-2, Bax, Survivin and hMLH1 gene mRNA were detected by real-time fluorescent quantitative RT-PCR. Results:The berberine could significantly inhibit the proliferation of ovarian cancer SKOV3 cells(P<0. 05) in dose-and time-de-pendent manner. When combined with cisplatin, berberine showed synergistic anticancer effects. Berberine could induce SKOV3 cells apoptosis significantly, it might lower the expression of Bcl-2 and Survivin gene and enhance the expression of Bax gene. In addition, berberine could restore the hMLH1 promoter methylation status and increase the expression of hMLH1 mRNA. Conclusion:Berberine can inhibit the proliferation of ovarian cancer cells and induce apoptosis, which show that the synergistic enhancement anticancer effects with cisplatin.

Research of berberine to proliferation and apoptotic mechanism of human ovarian cancer cell line SKOV3 / 中国免疫学杂志

Objective:To investigate the effect of berberine on the proliferation and apoptosis of human ovarian cancer cell (SKOV3). Methods:Cell proliferation was detected by MTT method. The cell apoptosis was detected by FCM Annexin V/PI double staining and transmission electron microscopy. The methylation status of hMLH1 gene promoter CpG island was analyzed by methylation specific PCR. The expression of Bcl-2, Bax, Survivin and hMLH1 gene mRNA were detected by real-time fluorescent quantitative RT-PCR. Results:The berberine could significantly inhibit the proliferation of ovarian cancer SKOV3 cells(P<0. 05) in dose-and time-de-pendent manner. When combined with cisplatin, berberine showed synergistic anticancer effects. Berberine could induce SKOV3 cells apoptosis significantly, it might lower the expression of Bcl-2 and Survivin gene and enhance the expression of Bax gene. In addition, berberine could restore the hMLH1 promoter methylation status and increase the expression of hMLH1 mRNA. Conclusion:Berberine can inhibit the proliferation of ovarian cancer cells and induce apoptosis, which show that the synergistic enhancement anticancer effects with cisplatin.

Expression of ERCC-1 protein and its clinical implication in locally advanced cervical cancer / 中华放射肿瘤学杂志

Objective To examine the protein expression of the nucleotide excision repair gene (ERCC-1) in patients with locally advanced cervical cancer and its relationship with the efficacy of radiotherapy and chemotherapy.Methods The expression of ERCC-1 protein in 88 patients with locally advanced cervical cancer treated in our hospital between 2007-2011 was measured using immunohistochemistry (IHC).The patients were divided into high-expression group (n=48) and low-expression group (n=40) based on the fluorescence intensity on the IHC staining.All patients received cisplatin (40 mg/m2 per week) during radiotherapy.The relationship between ERCC-1 protein expression and the clinicopathological factors of cervical cancer was analyzed using the chi-square test.Survival was calculated using the Kaplan-Meier method and compared by the log-rank test.Multivariate prognostic analysis was performed using the Cox model.Results The overall response rate (CR+PR) was 81%(39/48) in the high-ERCC-1 expression group and 85%(34/40) in the low-ERCC-1 expression group (P=0.641).ERCC-1 protein expression was associated with recurrence and metastasis (P=0.043,0.043).The 5-year survival rate was significantly higher in the low-ERCC-1 expression group than in the high-ERCC-1 expression group (65% vs.42%, P=0.029).Conclusions Patients with high ERCC-1 protein expression are more likely to have local recurrence and distant metastasis than those with low ERCC-1 protein expression.ERCC-1 protein expression may be a clinically significant biomarker for predicting the prognosis of cervical cancer patients.

Expression of MLH1, MSH2, MSH6 and PMS2 in colorectal cancer and their role in the screening of Lynch syndrome / 临床与实验病理学杂志

Purpose To investigate the expression of mismatch repair proteins MLH1,MSH2,MSH6 and PMS2 and their clinical significance in colorectal cancer.Methods Immunohistochemical analysis was used to detect MLH1,MSH2,MSH6 and PMS2 protein expression in formalin-fixed paraffin-embedded tissues from 102 colorectal cancer patients,and microsatellite instability (MSI) was tested in 20 cases.The relationship between MMR protein expression and clinical pathological features was also analyzed.Results 15 cases (14.7％) had MMR protein loss.The loss rate of MLH1,MSH2,MSH6 and PMS2 protein was 12.7％ (13/102),3.9％ (4/102),4.9％ (5/102) and 10.8％ (11/102),respectively.MLH1,MSH2,MSH6 and PMS2 protein losses were not related with gender,age,tumor size,depth of invasion and lymph node metastasis (P ＞ 0.05).MLH1 and PMS2 protein losses were related to histological differentiation (P ＜0.05).MSI was detected in 10 Lynch syndrome candidates.2 cases (2.0％)of high-frequency microsatellite instability (MSI-H) were identified,and the remaining 8 cases were MSS.However,10 cases without MMR expression abnormality all showed MSI-L/MSS.Conclusion Immunohistochemical detection of MLH1,MSH2,MSH6 and PMS2 can be used as primary screening for Lynch syndrome and its combination with MSI test can effectively increase the diagnostic rate in Lynch syndrome.

Associação da imunoexpressão das proteínas XRCC1, TFIIH E XPF com características clinicopatológicas e sobrevida em carcinoma epidermoide de língua oral / Association of immunoexpression of XRCC1, TFIIH and XPF proteins with clinicopathological characteristics and survival in oral tongue squamous cell carcinoma

Sistemas de reparo do DNA, genes e proteínas, são essenciais para manutenção da integridade do genoma, evitando graves doenças como o câncer. Desrregulação na expressão destas proteínas vem sendo associado tanto ao risco do desenvolvimento, como na evolução de variados cânceres humanos com destaque para o carcinoma epidermoide oral. O objetivo deste trabalho foi analisar a imunoexpressão das proteínas de reparo do DNA, XRCC1, THIIF e XPF em carcinoma epidermoide de língua oral (CELO) e investigar associação com parâmetros clínicos, histopatológicos, de desfecho e sobrevida em cinco anos. Setenta e quatro casos de CELO foram analisados por meio da técnica da imuno-histoquímica de forma semiquantitativa. Observou-se alta expressão das proteínas pesquisadas nas células parenquimatosas, identificando associação significativa da elevada expressão de XRCC1 com melhor estadiamento clínico (p=0,02). A regressão de Cox revelou tamanho do tumor (p<0,01), comprometimento linfonodal (p=0,04), estágio do tumor (p=0,02) e profundidade de invasão >4mm (p=0,05) como fatores prognósticos para CELO. Os resultados deste experimento sugerem que as proteínas XRCC1, TFIIH e XPF participam do processo de tumorigênese, entretanto a imunoexpressão das mesmas não pode ser utilizada como indicador independente de prognóstico para CELO (AU).

DNA repair systems, genes and proteins are essential for genome integrity maintenance, avoiding serious diseases such as cancer. Deregulation in the expression of those proteins has been associated with both the risk of development and evolution of various human cancers, including oral squamous cell carcinoma. The purpose of this study was to analyze the immunoreactivity of the DNA repair proteins XRCC1, THIIF and XPF in oral tongue squamous cell carcinoma (OTSCC) and to investigate its association with clinical and histopathological parameters, outcome and 5-year survival rate. Seventy-four cases of OTSCC were analyzed semi-quantitatively through immunohistochemistry. We observed that DNA repair proteins were highly expressed in parenchymal cells; however, we only observed a significant association between XRCC1 high expression and better clinical staging (p=0,02). Cox regression showed that tumor size (p<0,01), lymph node involvement (p=0,04), tumor stage (p=0,02) and depth of invasion> 4mm (p=0,05) were prognostic factors. The results of this experiment suggest that XRCC1, TFIIH and XPF participate in the tumorigenic process, however, their immunoexpression may not be used as an independent prognostic indicator for OTSCC (AU).

Progress on the diagnosis, treatment, and family management of Lynch syndrome / 中国肿瘤临床

Lynch syndrome is the most common type of genetically determined colon-cancer predisposition syndrome, accounting for 5%of all colorectal cancer (CRC) cases. This hereditary syndrome is characterized by the germline mutation of human mismatch repair genes and microsatellite instability. Recent studies have shown that Lynch syndrome and sporadic CRC differ in diagnosis and treat-ment;these results are especially relevant for the clinical management of Lynch syndrome. In this review, we reverted to the original characterization of Lynch syndrome, and the developments in its screening and diagnosis were summarized. Furthermore, the manage-ment of families with this disorder was discussed.

Validation of Prediction Models for Mismatch Repair Gene Mutations in Koreans / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Lynch syndrome, the commonest hereditary colorectal cancer syndrome, is caused by germline mutations in mismatch repair (MMR) genes. Three recently developed prediction models for MMR gene mutations based on family history and clinical features (MMRPredict, PREMM1,2,6, and MMRPro) have been validated only in Western countries. In this study, we propose validating these prediction models in the Korean population. MATERIALS AND METHODS: We collected MMR gene analysis data from 188 individuals in the Korean Hereditary Tumor Registry. The probability of gene mutation was calculated using three prediction models, and the overall diagnostic value of each model compared using receiver operator characteristic (ROC) curves and area under the ROC curve (AUC). Quantitative test characteristics were calculated at sensitivities of 90%, 95%, and 98%. RESULTS: Of the individuals analyzed, 101 satisfied Amsterdam criteria II, and 87 were suspected hereditary nonpolyposis colorectal cancer. MMR mutations were identified in 62 of the 188 subjects (33.0%). All three prediction models showed a poor predictive value of AUC (MMRPredict, 0.683; PREMM1,2,6, 0.709; MMRPro, 0.590). Within the range of acceptable sensitivity (> 90%), PREMM1,2,6 demonstrated higher specificity than the other models. CONCLUSION: In the Korean population, overall predictive values of the three models (MMRPredict, PREMM1,2,6, MMRPro) for MMR gene mutations are poor, compared with their performance in Western populations. A new prediction model is therefore required for the Korean population to detect MMR mutation carriers, reflecting ethnic differences in genotype-phenotype associations.

Avaliação de polimorfismos funcionais nos genes de reparo XRCC1, APEX1, XPD e XPF em carcinomas de células escamosas orais / Evaluation of functional polymorphisms in the repair genes XRCC1, APEX1, XPD and XPF in oral squamous cell carcinomas

As vias de reparo por excisão de base (BER) e por excisão de nucleotídeo (NER) desempenham um papel crucial na manutenção da integridade genômica. Polimorfismos em genes das vias BER e NER, que modulam a capacidade de reparo do DNA, podem estar relacionados ao risco de desenvolvimento e prognóstico do câncer oral. O presente trabalho teve como objetivo investigar a frequência de polimorfismos de nucleotídeos simples, em dois genes da via de reparo do DNA por excisão de base (XRCC1 ­ rs25487 e APEX1 ­ rs1130409) e dois genes da via de reparo por excisão de nucleotídeo (XPD ­ rs13181 e XPF ­ rs1799797), em pacientes com carcinoma de células escamosas oral (CCEO), buscando associações com o risco de desenvolver esta neoplasia maligna e o seu prognóstico. Um total de 92 amostras de DNA de pacientes com CCEO e 130 controles foram genotipadas utilizando o método da reação em cadeia da polimerase em tempo real. O software estatístico GraphPad Prism version 6.0.1. foi utilizado para a aplicação dos testes apropriados. Odds ratio (OR) e hazard ratio (HR), e seus intervalos de confiança (IC) de 95%, foram calculados pela regressão logística. A avaliação do prognóstico foi realizada por meio da curva de Kaplan-Meier e análise multivariada de Cox. A presença das variantes polimórficas nos genes XRCC1, APEX1, XPD, e XPF não foram associadas ao risco de desenvolver CCEO. A interação da presença da variante polimórfica com o hábito de fumar não foi significativa para nenhum dos polimorfismos analisados. Já a presença do polimorfismo em XPD, somada ao hábito de beber, aumentou o risco de desenvolver CCEO (OR 1,86, 95% IC: 0,86 ­ 4,01, p=0,03). Apenas o SNP do APEX1 (rs1130409) esteve associado a uma diminuição da sobrevida específica (HR 3,94, 95% IC: 1,31 ­ 11,88, p=0,01). O presente estudo sugere uma interação entre o consumo de álcool e a presença do polimorfismo estudado no gene XPD. Além disso, indica um pior prognóstico para pacientes que possuem o polimorfismo estudado em APEX1 (AU).

Base excision repair (BER) and nucleotide excision repair (NER) pathways play critical role in maintaining genome integrity. Polymorphisms in BER and NER genes which modulate the DNA repair capacity may affect the susceptibility and prognosis of oral cancer. This study was conducted with genomic DNA from 92 patients with oral squamous cell carcinomas (OSCC) and 130 controls. The cases were followed up to explore the associations between BER and NER genes polymorphisms and the risk and prognosis of OSCC. Four single-nucleotide polymorphisms (SNPs) in XRCC1 (rs25487), APEX1 (rs1130409), XPD (rs13181) and XPF (rs1799797) genes were tested by polymerase chain reaction ­ quantitative real time method. The GraphPad Prism version 6.0.1 statistical software was applied for statistical analysis of association. Odds ratio (OR), hazard ratio (HR), and their 95 % confidence intervals (CIs) were calculated by logistic regression. Kaplan-Meier curve and Cox proportional hazard model were used for prognostic analysis. The presence of polymorphic variants in XRCC1, APEX1, XPD and XPF genes were not associated with an increased risk of OSCC. Gene-environment interactions with smoking were not significant for any polymorphism. The presence of polymorphic variants of the XPD gene in association with alcohol consumption conferred an increased risk of 1.86 (95% CI: 0.86 ­ 4.01, p=0.03) for OSCC. Only APEX1 was associated with decreased specific survival (HR 3.94, 95% CI: 1.31 ­ 11.88, p=0.01). These results suggest an interaction between polymorphic variants of the XPF gene and alcohol consumption. Additionally APEX1 may represent a prognostic marker for OSCC (AU).

Clinical significance of mismatch repair genes immunohistochemical expression of complex endometrial hyperplasia

OBJECTIVE: Women with Lynch syndrome have an increased risk of developing colorectal and gynecologic malignancies such as endometrial cancer. Complex hyperplasia has about a 30% risk of developing into endometrial cancer. The aim of this study was to determine the genetic risk for developing endometrial cancer by immunohistochemical staining of premalignant lesions for mutL homolog 1, mutS homolog 2, mutS homolog 6, and postmeiotic segregation increased 2. METHODS: Twenty cases (n=20) were selected from among patients with available sample blocks for analysis. Clinical information was obtained from medical chart review. Immunohistochemical staining was performed for all of the tumor blocks. Staining was scored based on the intensity (intensity score 0-3) . RESULTS: Among the 20 cases of complex endometrial hyperplasia, 11 (55%) patients showed loss of expression of at least one of the following proteins: mutL homolog 1, mutS homolog 2, mutS homolog 6, or postmeiotic segregation increased 2. Seven (35%) patients were negative for the expression of two or more proteins, and one patient (5%) was negative for the expression of all four proteins. CONCLUSION: More than half of the patients showed loss of expression of at least one mismatch repair protein in our study population. Genetic risk counseling and further tests are recommended for these patients.

Polymorphism of XRCC1 gene and its relation with genetic susceptibility of nasopharyngeal carcinoma in chinese living in jiangsu, zhejiang province and shanghai / 第二军医大学学报

Objective To study the polymorphism of XRCC1 gene and its relation with genetic susceptibility of the nasopharyngeal carcinoma (NPC) in Chinese living in Jiangsu, Zhejiang Province and Shanghai. Methods A case-control study was performed with 87 NPC patients and 94 healthy controls ofHan nationality in Chinese living in Jiangsu, Zhejiang Province and Shanghai. The two groups were matched by sex and age. PCR-RFLP technique was used to explore the relation of different XRCC1 polymorphismswith the susceptibility of NPC. Results The frequencies of the genotypes of XRCC1 Argl94Trp and Arg399Gln were similar between NPC andcontrol groups. The risk of NPC individuals with the Trp194Trp genotype was reduced compared with that in those with Argl94Arg genotype, but with no significant differences (0R = 0. 41, 95% CI:0. 081. 65, P = 0. 21). No association was observed between the genetic susceptibility ofNPC and other Argl94Trp variants or all Arg399Gln variants. Conclusion Our findings suggest that the polymorphism of XRCC1 has no association with the risk of nasopharyngeal carcinoma inChinese living in Jiangsu, Zhejiang Province and Shanghai, but the Trp194Trp variant genotype may be associated with a reduced risk of NPC.

Expression of mismatch repair gene in endometrioid adenocarcinoma and its prognostic significance / 肿瘤研究与临床

Objective To explore the expression of mismatch repair gene (MMR) (MLH1,MSH2,PMS2 and MSH6) in endometrioid adenocarcinoma,and to analyze its clinical pathological significance.Methods Inmunohistochemical EnVision method was used to detect the expressions of DNA mismatch repair proteins (MLH1,MSH2,PMS2 and MSH6) in 101 cases of endometrial adenocarcinoma.The phenotypes of tumor microsatellite instability (MSI) and microsatellite stable were determined,and its relationship with onset age,differentiation,depth of myometrial invasion,lymphatic metastasis and prognosis of tumor were analyzed.Results There were 67 cases of hysterectomy and 34 cases of endometrial biopsy in 101 cases of endometrial adenocarcinoma.52 cases of surgical specimens and 14 cases of biopsy specimens were included in 66 cases that had complete follow-up data.Rates of negative expression were as follows:MLH1 31.6 ％ (32/101),MSH228.7 ％ (29/101),PMS2 16.8 ％ (17/101),MSH6 8.9 ％ (9/101).MSI phenotype 53.5 ％ (54/101),MSS phenotype 46.5 ％ (47/101).Univariate analysis showed that prognoses of MSI-L&MSS group (34 cases) were better than those of MSI-H group (18 cases) in hysterectomy organization (P =0.041).The differences between depth of myometrial invasion,degree of differentiation,age and prognosis of endometrial adenocarcinoma were statistically significant (P ＜0.05).Cox multivariate analysis showed that differences between depth of myometrial invasion,age and prognosis of endometrial adenocarcinoma were statistically significant (P =0.034,P =0.009),while there was no significant difference between MSI-L&MSS group and MSI-H group in prognosis (P ＞ 0.05).Conclusions MSI is one of the molecular events that occur in the endometrioid adenocarcinoma.Age and depth of tumor invasion are independent prognostic factors of endometrioid adenocarcinoma.In view of inconsistency between univariate analysis and multivariate analysis,whether MSI can be used as deterministic accordance for endometrioid adenocarcinoma prognostic evaluation requires further verification.

Effects of baicalin on the apoptosis and cell cycle of colorectal cancer cells in orthotopic transplantation mice model with mismatch repair gene deficient / 中华消化外科杂志

Objective To study the effect of baicalin on the apoptosis and cell cycle of colorectal cancer cells in orthotopic transplantation mice model with mismatch repair gene hMLH1 deficient.Methods Sixty orthotopic transplantation mice models of human colorectal cancer cell line HCT1 16 expressing green fluorescent protein (GFP) were established,and were randomly divided into the control group and the 50,100,200 mg/kg baicalin groups according to the random number table.Mice in the 50,100,200 mg/kg baicalin groups received intragastric infusion of baicalin at the corresponding dosages twice a day,while mice in the control group received intragastric infusion of 5％ NaHCO3.Cell cycles and apoptotic rates of the HCT116-GFP cells were detected by flow cytometry and TUNEL method respectively.Differences between the 2 groups were analyzed using the analysis of variance or chi-square test,and differences within each group were analyzed using the LSD-t test.Results The orthotopic transplantation mice models of human colorecta] cancer were successfully constructed,and there was no significant difference in the body weight of the mice and tumor size among the 4 groups (F =0.343,0.107,P ＞0.05).The proportion of HCT116-GFP cells in the G2/M phase in the 50,100,200 mg/kg baicalin groups were 22％±6％,18％±7％ and 19％±6％,which were significantly higher than 7％ ±5％ of the control group (t =5.421,3.483,3.575,P ＜0.05).There were no significant differences in the proportion of HCT116-GFP cells in the G2/M phase among the 50,100,200 mg/kg baicalin groups (F =1.291,P ＞ 0.05).The apoptotic rates of HCT116-GFP cells in the 50,100,200 mg/kg baicalin groups were significantly higher than the control group (t =7.163,3.703,2.688,P ＜0.05).The apoptotic rate of the 50 mg/kg baicalin group was significantly higher than that of the 200 mg/kg baicalin group (t =2.259,P ＜ 0.05).Conclusions Baicalin significantly inhibits tumor growth in the orthotopic transplantation mice model with mismatch repair gene hMLH1 deficient.After treated with baicalin,the cell cycle is arrested at the G2/M phase,thus the tumor growth is inhibited.

Polymorphisms in base-excision & nucleotide-excision repair genes & prostate cancer risk in north Indian population.

Background & objectives: Genetic variation in the DNA repair genes might be associated with altered DNA repair capacities (DRC). Reduced DRC due to inherited polymorphisms may increase the susceptibility to cancers. Base excision and nucleotide excision are the two major repair pathways. We investigated the association between two base excision repair (BER) genes (APE1 exon 5, OGG1 exon 7) and two nucleotide excision repair (NER) genes (XPC PAT, XPC exon 15) with risk of prostate cancer (PCa). Methods: The study was designed with 192 histopathologically confirmed PCa patients and 224 age matched healthy controls of similar ethnicity. Genotypes were determined by amplification refractory mutation specific (ARMS) and PCR-restriction fragment length polymorphism (RFLP) methods. Results: Overall, a significant association in NER gene, XPC PAT Ins/Ins (I/I) genotype with PCa risk was observed (Adjusted OR- 2.55, 95%CI-1.22-5.33, P=0.012). XPC exon 15 variant CC genotypes presented statistically significant risk of PCa (Adjusted OR- 2.15, 95% CI-1.09-4.23, P=0.026). However, no association was observed for polymorphism with BER genes. Diplotype analysis of XPC PAT and exon 15 revealed that the frequency of the D-C and I-A diplotype was statistically significant in PCa. The variant genotypes of NER genes were also associated with high Gleason grade. Interpretation & conclusions: The results indicated that there was a significant modifying effect on the association between genotype XPC PAT and exon 15 polymorphism and PCa risk which was further confirmed by diplotype analysis of XPC PAT and exon 15 in north Indian population.