Relationship between mismatch repair protein, RAS, BRAF, PIK3CA gene expression and clinicopathological characteristics in elderly colorectal cancer patients

BACKGROUND Colorectal cancer(CRC)is common in elderly patients.Mismatch repair(MMR)protein deletion is one of the causes of CRC.The RAS(KRAS/NRAS),BRAF,and PIK3CA genes are important gene targets in CRC treatment and are closely related to the prognosis and survival of patients.However,little is known regarding the relationship between the expression of MMR,RAS,BRAF,PIK3CA and the clinicopathological features in CRC patients.AIM To analyze the relationship between the expression of MMR,RAS,BRAF,PIK3CA and the clinicopathological features in CRC.METHODS A total of 327 elderly patients with CRC were enrolled,and immunohistochemistry was used to detect the MMR protein.Real-time quantitative polymerase chain reaction was used to detect the RAS(KRAS/NRAS),BRAF,and PIK3CA genes.The clinicopathological data of the patients were recorded and analyzed by SPSS 19.0 statistical software.RESULTS In 327 elderly patients with CRC,the rate of MMR protein loss was 9.79%(32/327),and the deletion rate of four MMR proteins(MSH2,MSH6,MLH1,PMS2)was 1.83%(6/327),3.06%(10/327),7.65%(25/327),and 7.65%(25/327),respectively.There were no significant differences between MMR protein deletion and sex,pathological type,tumor morphology,differentiation degree or lymph node metastasis(P>0.05),but there was a significant difference between MMR protein deletion and tumor diameter and tumor location(P=0.048/P=0.000).The mutation rates of the KRAS,NRAS,BRAF and PIK3CA genes in elderly CRC patients were 44.95%(147/327),2.45%(8/327),3.36%(11/327)and 2.75%(9/327),respectively;the KRAS gene mutation was closely related to tumor morphology(P=0.002)but not to other clinicopathological features(P>0.05),and there were no significant differences between NRAS gene mutation and clinicopathological features(P>0.05).The BRAF gene mutation showed a significant difference in pathological type,tumor location,differentiation degree and lymph node metastasis(P<0.05),but was not correlated with sex,tumor size and tumor morphology(P>0.05).The PIK3CA gene mutation showed no significant differences in the above clinicopathological characteristics(P>0.05).Significant differences were observed between MMR protein deletion and KRAS,BRAF,and PIK3CA gene mutations in elderly CRC patients(P=0.044,P=0.000,P=0.003,respectively),but there was no significant difference between MMR protein deletion and NRAS mutation(P>0.05).CONCLUSION In elderly CRC patients,the tumor is mainly located in the right colon,and the deletion rate of MMR protein is higher when the tumor diameter is greater than or equal to 5 cm;the deletion rate of MLH1 and PMS2 is more common;the mutation rate of KRAS gene is higher than that of the NRAS,BRAF and PIK3CA genes,the BRAF gene mutation has different degrees of correlation with clinicopathological characteristics;when the MMR protein is deleted,the BRAF and PIK3CA gene mutations are often present,and the KRAS gene mutation rate is low.

Unusual immunohistochemical“null”pattern of four mismatch repair proteins in gastric cancer:A case report

BACKGROUND Immunohistochemical(IHC)staining for mismatch repair(MMR)proteins is useful for gastric cancer treatment and prognosis.Different IHC staining patterns reflect the complex biological phenomena underlying MMR deficiency.We herein report a rare IHC staining pattern of four MMR-related proteins in gastric cancer.CASE SUMMARY A“null”IHC staining pattern of four MMR-related proteins,including MLH1,PMS2,MSH2,and MSH6,in a 67-year-old male patient with gastric cancer pT3N3aM0 revealed promoter hypermethylation of MLH1.Next-generation sequencing showed that these four genes exhibited changes.One of these was the somatic mutation of the missing copy number in exon 14 of MSH2.Mutation analysis using peripheral blood showed no germline mutations in these four genes.The patient had no history of personal or family tumor history.We classified this case as sporadic.The patient returned to normal after operation,and there were no signs of tumor metastasis and recurrence.After six cycles of adjuvant chemotherapy,the patient was discharged in a stable condition.The patient had a mild reaction to chemotherapy and a good prognosis.At present,16 mo after the operation,the patient's condition is stable.CONCLUSION Abnormal MMR protein expression,helpful for individualized follow-up care,helped identify a sporadic case lacking familial clinical management implications.

Positive Correlation between PMS2 Deficiency and PD-L1 Expression in Pancreatic Cancer

Background: Pancreatic cancer is one of the most lethal types of cancer, and immunotherapy has become a promising remedy with advancements in tumor immunology. However, predicting the clinical response to immunotherapy in pancreatic cancer remains a dilemma for clinicians. Methods: GEPIA database was used to analyze the differential expression of MMR and PD-L1 genes in 33 common cancer types including pancreatic cancer. The expression levels of MMR and PD-L1 genes were downloaded from the GEPIA and GEO databases to analyze the correlation between MMR genes and PD-L1, and the clinicopathological and survival information were downloaded from the TCGA databases to analyze the relationship between the expression of MMR, PD-L1 and clinicopathological characteristics, prognosis. Meanwhile, the tumor tissue samples of 41 patients with pancreatic cancer were collected, and the protein expression levels of MMR and PD-L1 were detected by immunohistochemical assay. Furthermore, we analyzed the correlation between MMR and PD-L1, and the correlation between the expression of MMR, PD-L1 and clinicopathological characteristics, prognosis of pancreatic cancer patients. Results: Bioinformatics analysis showed that MLH1, MLH3, MSH2, MSH3, and PMS2 were highly expressed in most cancer types including pancreatic cancer (P P = 0.012), clinical stage (I vs II: P = 0.016), MSH2 expression was related to clinical stage (P < 0.05), T stage (T3 vs T4: P = 0.039), and MSH3 expression was related to T stage (P < 0.05). Besides, both MSH2 expression (P P = 0.044) were significantly associated with prognosis. GEPIA data also showed that MSH2 expression was related to prognosis (P = 0.008). The correlation analysis revealed that the expressions MSH2, MLH1, PMS2 had strong correlations with PD-L1 both in GEPIA and GEO databases. Real-world data indicated that of the 41 pancreatic cancer patients, 5 cases had MLH1 deletion, 5 cases had MSH2 deletion, 4 cases had PMS2 deletion, and 12 cases had PD-L1 positive expression. Notably, PMS2 deletion was associated with PD-L1 positive expression (P = 0.035). In addition, MLH1 was related to clinical stage (P = 0.033), age (P = 0.048), and MSH2 was related to clinical stage (P = 0.033). However, MLH1 (P = 0.697), MSH2 (P = 0.956), PMS2 (P = 0.341), and PD-L1 (P = 0.734) appeared to have no impact on overall survival among patients with pancreatic cancer. Conclusion: Both bioinformatics and real-world data showed that there were correlation between PMS2 deletion and PD-L1 expression, and correlation between MLH1, MSH2 and clinical stage.

A biomarker study in Peruvian males with breast cancer

BACKGROUND Breast cancer(BC)frequency in males is extremely low and tumor features vary from its female counterpart.Breast cancer clinical and pathological features differ by race in women.Tumor infiltrating lymphocyte(TIL)levels,mismatch repair(MMR)protein loss,androgen receptor(AR)expression,and PIK3CA gene mutations are predictive biomarkers of response to biological therapy in female BC.There is limited information about clinical and pathological features as well as predictive biomarkers in males of non-Caucasian races with BC.AIM To investigate clinicopathological features and biomarkers of BC tumors in males and their prognostic value in Peruvian population.METHODS This study looked at a single-institution series of 54 Peruvian males with invasive BC who were diagnosed from Jan 2004 to June 2018.Standard pathological features,TIL levels,MMR proteins,AR immunohistochemistry staining,and PIK3CA gene mutations were prospectively evaluated in cases with available paraffin material.Percentage of AR and estrogen receptor(ER)positive cells was additionally calculated by software after slide scanning.Statistical analyses included association tests,intraclass correlation test and Kaplan Meier overall survival curves.RESULTS The median age was 63 years and most cases were ER-positive(85.7%),HER2 negative(87.2%),Luminal-A phenotype(60%)and clinical stage II(41.5%)among our male breast tumors.Median TIL was 10%and higher levels tended to be associated with Luminal-B phenotype and higher grade.AR-positive was found in 85.3%and was correlated with ER(intraclass index of 0.835,P<0.001).Loss of MMR proteins was found in 15.4%and PIK3CA mutation(H1047R)in 14.3%(belonged to the Luminal-A phenotype).Loss of MMR proteins was associated with AR-negative(P=0.018)but not with ER(P=0.43)or TIL(P=0.84).Early stages(P<0.001)and lower grade(P=0.006)were associated with longer overall survival.ER status,phenotype,AR status,TIL level,MMR protein loss nor PIK3CA mutation was not associated with survival(P>0.05).CONCLUSION Male BC is usually ER and AR positive,and Luminal-A.MMR loss and PIK3CA mutations are infrequent.Stage and grade predicted overall survival in our South American country population.