Incidence and molecular characteristics of deficient mismatch repair conditions across nine different tumors and identification of germline variants involved in Lynch-like syndrome.

BACKGROUND: Based on molecular characteristics, deficient DNA mismatch repair (dMMR) solid tumors are largely divided into three categories: somatically MLH1-hypermethylated tumors, Lynch syndrome (LS)-associated tumors, and Lynch-like syndrome (LLS)-associated tumors. The incidence of each of these conditions and the corresponding pathogenic genes related to LLS remain elusive. METHODS: We identified dMMR tumors in 3609 tumors from 9 different solid organs, including colorectal cancer, gastric cancer, small-bowel cancer, endometrial cancer, ovarian cancer, upper urinary tract cancer, urinary bladder cancer, prostate cancer, and sebaceous tumor, and comprehensively summarized the characterization of dMMR tumors. Characterization of dMMR tumors were performed as loss of at least one of MMR proteins (MLH1, MSH2, MSH6, and PMS2), by immunohistochemistry, followed by MLH1 promotor methylation analysis and genetic testing for MMR genes where appropriate. Somatic variant analysis of MMR genes and whole exome sequencing (WES) were performed in patients with LLS. RESULTS: In total, the incidence of dMMR tumors was 5.9% (24/3609). The incidence of dMMR tumors and the proportion of the three categorized dMMR tumors varied considerably with different tumor types. One to three likely pathogenic/pathogenic somatic MMR gene variants were detected in 15 out of the 16 available LLS tumors. One patient each from 12 patients who gave consent to WES demonstrated non-MMR germline variants affect function (POLQ or BRCA1). CONCLUSIONS: Our data regarding the LS to LLS ratio would be useful for genetic counseling in patients who are suspected to have LS, though the genetic backgrounds for the pathogenesis of LLS need further investigation.

[Development of Cancer of the Remnant Colorectal Segment after Ileal-Pouch Anal Anastomosis/Ileorectal Anastomosis in Patients with Familial Adenomatous Polyposis].

PURPOSE: This retrospective study was performed to investigate the recent trend of occurrence of cancer of the remnant colorectal segment(RCRS)after ileal-pouch anal anastomosis(IPAA)/ileorectal anastomosis(IRA)and to consider the optimal surveillance methods in patients with familial adenomatous polyposis(FAP)undergoing(procto)colectomy. PATIENTS AND METHODS: The subject was a total of patients with FAP undergoing IPAA or IRA between 2005 and 2022. Clinicopathological data were extracted from medical charts and analyzed. Cumulative incidence of cancer in the RCRS and overall survival after treatment of such tumors were calculated by the Kaplan-Meier method. RESULTS: There were 45 male and 56 female. IPAA was performed in 49 patients(hand-sewn; n=33, stapled; n=16)and IRA was performed in 52 patients. The median age at initial colorectal surgery was 32 years old(range, 13-66 years old). Median postoperative follow-up was 11 years(range, 1-48 years). Eighty-one patients were confirmed to have pathogenic variant of APC by genetic test. The cumulative incidence of cancer of the RCRS did not differ between patients undergoing IPAA and those undergoing IRA(p= 0.73, 4.1% versus 1.9% at 10 years). The cumulative 5-year overall survival rate after additional surgery for the tumor of RCRS was 82%. CONCLUSION: This study has several limitations due to single institutional retrospective study with small cases and non-standardized postoperative endoscopic surveillance. However, our results seem to show satisfactory oncological outcomes of patients with FAP in terms of the control of cancer of the RCRS under postoperative periodic surveillance, regardless of the type of colorectal resection.

[A Case of Transverse Colon Cancer Associated with Lynch Syndrome with Excellent Response to Pembrolizumab].

A 47-year-old woman diagnosed with transverse colon cancer with liver, peritoneal, and lymph node metastases was admitted. Modified FOLFOX6(mFOLFOX6)regimen was given as a first line chemotherapy and was followed by pembrolizumab after 1 cycle of the mFOLFOX6, because microsatellite instability(MSI)test of the tumor showed high-frequency MSI. Because of the transverse colon obstruction after 2 cycles of pembrolizumab, she underwent right hemicolectomy. Histological examination of the resected specimen revealed no residual tumor cells in the primary tumor and reginal lymph nodes. Immunohistochemistry for mismatch repair proteins(IHC-MMR)showed loss of MSH2 and MSH6 expression. Genetic test identified a MSH2 pathogenic variant leading to the diagnosis of Lynch syndrome. The present case shows the importance of MSI test or IHC-MMR before the treatment of metastatic colorectal cancer.

[Complete Response to Immune Checkpoint Inhibitors in Unresectable Gastric Cancer-A Report of Five Cases].

Immune checkpoint inhibitors(ICIs)are widely used for the treatment of unresectable gastric cancer. We treated approximately 70 patients with ICIs. ICI treatment with pembrolizumab was administered for MSI-high cases and nivolumab for MSS cases in the second- or third-line chemotherapy. We observed 5 cases of complete response. Among these, 2 patients presented with liver metastases, 2 with peritoneal disseminations, and 1 with pulmonary metastasis. In 1 patient, the primary tumor invaded the diaphragm and descending aorta; whereas, in another patient the primary tumor invaded the pancreas and liver. All patients had progressive disease after first-line chemotherapy.

Concordance between microsatellite instability testing and immunohistochemistry for mismatch repair proteins and efficient screening of mismatch repair deficient gastric cancer.

Microsatellite instability (MSI) testing, an established technique that has gained prominence in recent years for its predictive potential regarding the efficacy of immune checkpoint inhibitors, is used to evaluate DNA mismatch repair (MMR) deficiency (dMMR). As with other methods, the immunohistochemistry (IHC) of MMR proteins is also widely adopted. Although both techniques have been validated, their concordance rate remains unknown, particularly regarding non-colorectal cancer. Therefore, the aim of the present study was to explore and elucidate their concordance in the context of gastric cancer (GC). A total of 489 surgically resected primary GC tissues were analyzed to compare the results yielded by the MSI test and those from IHC. Of 488 GC cases, 56 (11.5%) exhibited a loss of MMR proteins, whereas 52 (10.7%) were classified as high-frequency MSI (MSI-H). The concordance rate between these two categories was 99.2%. The microsatellite markers BAT26 and MONO27 demonstrated 100% sensitivity and 99.5% specificity in detecting dMMR GC. In addition, histopathological analysis revealed that MSI-H was more prevalent in GCs exhibiting coexisting Tub2 and Por1 subtypes. However, four discordant cases were observed. All four cases were microsatellite-stable cases but exhibited loss of MLH1 protein expression with hypermethylation of the MLH1 promoter. The results of the present study highlight that while there is a strong concordance between MSI and IHC testing results for determining dMMR status, IHC testing may offer superior efficacy in detecting dMMR.

Clinical predominance of whole-exome sequencing to evaluate microsatellite instability status.

The microsatellite instability (MSI)/mismatch repair (MMR) status is one of the critical genomic biomarkers for predicting patient response to immune checkpoint inhibitors (ICIs). In this study, we aimed to investigate the concordance among the MSIsensor score obtained from whole-exome sequencing (WES), which could be a futuristic clinical cancer sequencing method, using only tumor tissues, MSI-PCR results, and immunohistochemistry (IHC) results to analyze various solid cancer types. We first endeavored to set the cut-off value of MSIsensor to determine functional deficient mismatch repair (f-dMMR) status. The MSI status of 1054 patients analyzed using WES was evaluated using MSIsensor. In addition, 87 of these patients were further analyzed using MSI-PCR and MMR IHC to calculate the sensitivity and specificity of the MSIsensor cut-off score. Our results showed that score 12.5 was an adequate cut-off score equivalent to PCR-confirmed MSS/MSI-low and MSI-high statuses, with sensitivity, specificity, and area under the curve values of 95.2%, 100%, and 0.998, respectively. Moreover, we identified false-positive cases of tumors with high mutational burden with an MSIsensor score <12.5, and optional IHC examination could rescue these cases. In conclusion, the MSIsensor score obtained using WES with tumor tissue showed a high clinical validity, with a cut-off value of 12.5 for f-dMMR detection, in combination with optional IHC analysis for MMR. Our novel algorithm will provide insights into the development of ICIs for cancer treatment, particularly when WES becomes a more common cancer genomic test in the near future.

Gastric Emptying is Accelerated in Patients With Gastric Tube Reconstruction Following Laparoscopic Proximal Gastrectomy.

BACKGROUND: Laparoscopic proximal gastrectomy (LPG) is an attractive option for the treatment of early gastric cancer in the upper third of the stomach. No optimal method of reconstruction after LPG has been established because of problems associated with postoperative reflux. Gastric tube reconstruction, a type of esophagogastrostomy, is a simple procedure, but it is associated with a high frequency of reflux esophagitis (RE). We investigated the relationship between RE and gastric emptying, along with nutritional parameters. SUBJECTS AND METHODS: We compared gastric emptying in patients who had undergone curative LPG with gastric tube reconstruction for gastric cancer with that of patients after total gastrectomy (TG), distal gastrectomy (DG) and of healthy volunteers and patients after DG. The LPG group was divided into an RE LPG-RE (+) group and a non-reflux esophagitis (non-RE) an LPG-RE (-) group, and we compared gastric emptying and indices of nutrition, such as body weight and laboratory findings, between those among LPG-RE (+), LPG-RE (-), and TG groups. RESULTS: The time lag between ingestion and peak 13 CO 2 expiration (T lag) in the healthy volunteer group was significantly shorter in the LPG group longer than those in the healthy volunteer LPG group and TG group. The T lag was significantly shorter in the RE LPG-RE (+) group than in the non-RE LPG-RE (-) group. The percentage change in body weight percentage in the non-RE LPG-RE (-) group was significantly larger than that in the RE LPG-RE (+) group at 12 months after surgery. Both the serum albumin and hemoglobin levels in the non-RE LPG-RE (-) tended to be preserved compared with those in the RE LPG-RE (+) group and TG group. CONCLUSIONS: Gastric emptying was accelerated after LPG, and was associated with RE. Our data suggest that RE could be associated with body weight loss after LPG.

Recent trends in the morbidity and mortality in patients with familial adenomatous polyposis: a retrospective single institutional study in Japan.

BACKGROUND: This study aimed to assess current trends in morbidity and mortality among patients with familial adenomatous polyposis (FAP). These data can be used for optimal surveillance and management of such patients. METHODS: Data (November 2001 and April 2020) of genetically confirmed patients with FAP (n = 87) and their first-degree relatives with FAP phenotype (n = 20) were extracted from the Saitama Medical Center database. Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) were estimated using indirect method. RESULTS: Overall, 46 men and 61 women were included; the median age at FAP diagnosis was 28.0 years for both. The SMR for all causes of death was 47.7 (95% confidence interval [CI] 19.1-98.2) in women and 26.5 (95% CI 9.73-57.8) in men. The SIR for colorectal cancer (CRC) was 860 (95% CI 518-1340) in women and 357 (95% CI 178-639) in men. The SMR for CRC was 455 (95% CI 93.7-1330) in women and 301 (95% CI 62.0-879) in men. Thirteen patients died during the observation period, and CRC was the leading cause of death (46%). Other causes of death included desmoid tumor (n = 2), small intestinal cancer (n = 2), ovarian cancer (n = 1), duodenal cancer (n = 1), and sepsis (n = 1). CONCLUSIONS: The mortality ratio, estimated using SMR, remained high. CRC was the leading cause of death, whereas almost half of the causes of deaths were extra-colonic tumors. Life-long management of extra-colonic diseases may improve the prognosis in these patients.

[Report of Multidisciplinary Treatment for Sisters with Li-Fraumeni Syndrome].

Li-Fraumeni syndrome(LFS)is a hereditary cancer disorder caused by germline variant in TP53 and characterized by various malignancies. Multidisciplinary treatment is needed for tumors of LFS, however, radiation therapy is a relative contraindication because of frequent development of secondary malignancy such as sarcoma in the irradiated field. Case 1: A 22- year-old woman who was diagnosed with LFS by genetic test when she developed upper rectal cancer. Her rectal tumor with marked bilateral lateral lymph node dissection was successfully removed by low anterior resection with extensive lateral lymph node dissection. She underwent resection for ovarian metastasis followed by chemotherapy and radiotherapy but subsequently died by the disease 32 months postoperatively. Case 2(elder sister of Case 1): A brain tumor was identified in the left high frontal lobe to the parietal lobe because of consciousness disorder, after the genetic diagnosis of LFS. The brain tumor was successfully resected. Histological examination revealed diffuse astrocytoma(WHO grade Ⅱ). Local recurrence was observed 46 months later, and radiation therapy was performed. Six months have passed since radiation therapy, no exacerbation of local recurrence has been observed.

Identification of Lynch syndrome-associated DNA mismatch repair-deficient bladder cancer in a Japanese hospital-based population.

BACKGROUND: The prevalence of Lynch syndrome (LS)-associated DNA mismatch repair (MMR)-deficient bladder cancer (BC) has scarcely been investigated. METHODS: Immunohistochemistry for four MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed in formalin-fixed paraffin-embedded (FFPE) sections prepared from the resected specimens of 618 consecutive newly diagnosed BC cases. Genetic/epigenetic analyses were performed in patients displaying the loss of any MMR proteins in the tumor. RESULTS: Of the 618 patients, 9 (1.5%) showed the loss of MMR protein expression via immunohistochemistry; specifically, 3, 3, 2, and 1 patients displayed the loss of MLH1/PMS2, PMS2, MSH6, and MSH2/MSH6, respectively. All nine patients were male with a median age of 68 years (63-79 years). One had been previously diagnosed as having LS with an MSH2 variant. Genetic testing demonstrated the presence of a pathogenic PMS2 variant (n = 1), a variant of uncertain significance in MSH2 (n = 1), and no pathogenic germline variants of the MMR genes (n = 1). One patient with MSH6-deficient BC did not complete the genetic testing because of severe degradation of DNA extracted from the FFPE specimen, but the patient was strongly suspected to have LS because of their history of colon cancer and MSH6-deficient upper urinary tract cancer. There remained a possibility that the remaining four patients who refused genetic testing had LS. CONCLUSIONS: The prevalence of LS-associated MMR-deficient BC was estimated to be 0.6-1.1% among unselected BC cases.

Comprehensive analysis of DNA mismatch repair-deficient gastric cancer in a Japanese hospital-based population.

BACKGROUND: The attention on mismatch repair-deficient (dMMR) gastric cancer has increased in this era of anti-PD-1 blockade therapy; however, the prevalence and molecular genetics of patients with dMMR gastric cancer have not been completely investigated. METHODS: Immunohistochemistry of MMR proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary gastric cancers of 513 consecutive patients. Genetic and/or epigenetic alterations of the MMR genes were also investigated. RESULTS: Loss of expression of one or more MMR proteins was observed in 58 patients (11.3%); 54 patients showed loss of MLH1/PMS2, 3 patients showed loss of MLH1/PMS2/MSH6 and 1 patient showed loss of PMS2 alone. Among these 58 patients, 55 showed hypermethylation of the promoter region of MLH1. Genetic testing revealed that the remaining three patients had Lynch syndrome (n = 1) or Lynch-like syndrome (n = 2). A total of 15 patients (25.9% of all patients with dMMR gastric cancer and 2.9% of all patients with gastric cancer), including 11 patients with stage I-III dMMR gastric cancer who had recurrence and 4 patients with stage IV dMMR gastric cancer, are potential candidates for the use of anti-PD-1 blockades. CONCLUSIONS: This is the first study to investigate the frequency and molecular genetic mechanisms of dMMR gastric cancer comprehensively, focusing on the benefit of using PD-1 blockades. Our observations will be beneficial in the clinical practice of metastatic gastric cancer.

Clinical outcomes of gastric tube reconstruction following laparoscopic proximal gastrectomy for early gastric cancer in the upper third of the stomach: experience with 100 consecutive cases.

BACKGROUND: Gastric tube reconstruction is a form of esophagogastrostomy performed after laparoscopic proximal gastrectomy (LPG). It is a simple and safe technique, but it may cause reflux esophagitis (RE) and impair postsurgical QOL. For several years, we have developed the gastric tube reconstruction and performed it on more than 100 patients. This study aimed to determine whether gastric tube reconstruction can be a feasible choice after LPG in regard to surgical safety and postoperative nutritional status. METHODS: The subjects consisted of 171 patients who underwent LPG (n = 102) or laparoscopic total gastrectomy (LTG) (n = 69). We compared the two groups in terms of surgical outcomes, incidence rate of RE, and nutritional status including postoperative weight loss and hemoglobin levels. RESULTS: There were no significant differences with regard to the surgical duration and blood loss between the two groups. The incidence of RE was not significantly higher with LPG than with LTG (16.7% vs. 10.1%, respectively; P = 0.07). Later than 2 years and 6 months after surgery, the body weight percentage of preoperative body weight in the LPG group was significantly higher than that in the LTG group. Hemoglobin and ferritin levels in the LPG group were significantly higher than those in the LTG group, later than one after surgery. The overall survival rates were similar between the two groups (5-year survival rates: 97.1% vs. 94.2% in the LPG and LTG groups, respectively; P = 0.69). CONCLUSIONS: Gastric tube reconstruction after LPG is simple and had better outcomes than LTG in terms of postoperative nutritional status.

Prediction Model for Gastric Cancer With DNA Mismatch Repair Deficiency.

BACKGROUND/AIM: DNA mismatch repair (MMR) deficiency has received increasing attention as a biomarker of anti-PD-1 treatments of solid tumors including gastric cancer (GC). However, efficient screening has not been established. PATIENTS AND METHODS: A total of 513 patients were tested for the expression of MMR proteins by immunohistochemistry to identify MMR deficient GC. Development of a prediction model was attempted using the common clinicopathological features. RESULTS: In total, 11% (57/513) of the patients showed loss of expression of either one or more MMR proteins (MMR protein deficiency; MMR-D). Multivariate analysis demonstrated that age (≥70 years), sex (female), tumor location (lower 1/3), depth invasion (low, T1/T2/T3), and absence of distant metastasis were significantly independent predictive factors of MMR-D GCs. The MMR-D GC probability estimated by the prediction model ranged from 0.4% to 62.2%, and the area under the curve of the receiver operating characteristics curve was 0.82 (95% confidence interval=0.75-0.87). CONCLUSION: Our prediction model can sufficiently and efficiently identify MMR-D GCs using clinical features.

Prevalence and molecular characteristics of DNA mismatch repair deficient endometrial cancer in a Japanese hospital-based population.

BACKGROUND: The prevalence and molecular characteristics of defective DNA mismatch repair endometrial cancers in the Japanese population have been underexplored. Data supporting clinical management of patients with Lynch-like syndrome and germline variant of uncertain significance of mismatch repair genes are still lacking. METHODS: Immunohistochemistry of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary endometrial cancers in 395 women with a median age of 59 years. Genetic and/or epigenetic alterations of the mismatch repair genes were also investigated. RESULTS: Loss of expression of one or more mismatch repair proteins was observed in 68 patients (17.2%). A total of 17 out of 68 patients (25%, 4.3% of all cases) were identified as candidates for genetic testing for Lynch syndrome after excluding 51 patients with MLH1 hypermethylated cancer. Fourteen of these 17 patients subjected to genetic testing were found to have Lynch syndrome (n = 5), germline variant of uncertain significance (n = 2) or Lynch-like syndrome (n = 7). Compared with patients with Lynch syndrome, those with germline variant of uncertain significance and Lynch-like syndrome tended to demonstrate an older age at the time of endometrial cancer diagnosis (P = 0.07), less fulfillment of the revised Bethesda guidelines (P = 0.09) and lower prevalence of Lynch syndrome-associated tumors in their first-degree relatives (P = 0.01). CONCLUSIONS: This study provides useful information for management in patients with DNA mismatch repair endometrial cancer. Specifically, cancer surveillance as recommended in patients with Lynch syndrome might not be necessary in patients with germline variant of uncertain significance and Lynch-like syndrome and their relatives.

[Two Cases of Esophageal Neuroendocrine Carcinoma That Were Successfully Controlled by Multi-Modality Therapy].

Esophageal neuroendocrine carcinoma is extremely rare, and its treatment strategy has not been established. We report 2 cases esophageal neuroendocrine carcinoma. Case 1: A 74-year-old man was diagnosed as having esophageal neuroendocrine carcinoma(clinical T3N4M0, Stage Ⅳa). He received 60 Gy of radiation therapy with etoposide(100 mg/m2)plus cisplatin(80 mg/m2). No recurrence has been detected 1 year after treatment. Case 2: A 78-year-old man was diagnosed as esophageal neuroendocrine carcinoma(clinical T3N0M0, Stage Ⅱ). He underwent esophagectomy with 3 field lymph nodes dissection. Adjuvant chemotherapy was administered with irinotecan(60 mg/m2)plus cisplatin(60 mg/m2). After chemotherapy, he survived 1 year without recurrence.

[Changes in Renal Function and Feasibility of Adjuvant Chemotherapy for Colorectal Cancer Patients with Diverting Ileostomy after Ileal Pouch-Anal Anastomosis].

We investigated changes in estimated glomerular filtration rate(eGFR)in 11 colorectal cancer patients(6 familial adenomatous polyposis, 5 ulcerative colitis)who underwent restorative proctocolectomy with ileal pouch-anal anastomosis(IPAA) and diverting ileostomy(DI), the tolerability and adverse events of adjuvant chemotherapy(ACT)in 4 cases. After IPAA, eGFR decreased significantly(p=0.02)and did not return to the preoperative level even after stoma closure(p<0.01). mFOLFOX6 was selected as the regimen in 4 candidates, and no significant changes in eGFR after ACT were observed. The relative dose intensity of oxaliplatin was 91.7%, and no gastrointestinal adverse events of Grade 3 or higher were observed. Although in a small number of cases, mFOLFOX6 as ACT after IPAA and DI may be feasible.

[A Case of Carcinoma of the Ileostomy Site Associated with Familial Adenomatous Polyposis-Report of a Case].

We report a rare carcinoma of the permanent ileostomy site developing 20 years or more after total proctocolectomy (TPC)in a 65-year-old woman with familial adenomatous polyposis(FAP). She underwent TPC for rectal cancer associated with FAP in her 40th at other institution. She also underwent pancreas-sparing total duodenectomy for duodenal mucosal cancer associated with severe duodenal polyposis at 59 years at our institution. She was referred to our hospital again complaining of the mass of the ileostomy site, 10 cm in diameter. Though biopsy revealed no definite malignancy, serum CA19-9 was elevated(98 U/mL), leading to a preoperative diagnosis to be ileal carcinoma. The involved bowel was widely resected. Histological examination demonstrated Stage ⅡA ileal carcinoma. Postoperative course was uneventful and she is well without recurrence 7 months after the ileal resection. This case seems valuable in that long-term surveillance including ileal carcinoma is important in the management of FAP patients whose colorectal cancer and duodenal cancer have been already well controlled.

Prevalence and clinicopathological/molecular characteristics of mismatch repair protein-deficient tumours among surgically treated patients with prostate cancer in a Japanese hospital-based population.

BACKGROUND: The prevalence and molecular characteristics of deficient mismatch repair prostate cancer in the Japanese population have scarcely been investigated. METHODS: Immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from resected primary prostate cancers in patients who underwent prostatectomy at our institution between January 2001 and May 2016. Genetic and/or epigenetic alterations of mismatch repair genes were investigated in patients with any loss of mismatch repair protein expression in the tumour. RESULTS: Of the 337 patients, four (1.2%) showed loss of mismatch repair protein expression on immunohistochemistry. All four patients showed loss of both MSH2 and MSH6 protein expression. Genetic testing was performed in two of the four patients, demonstrating no pathogenic germline alterations were present. In each of these two patients, at least one somatic alteration inactivating MSH2 without MSH2 hypermethylation was identified, leading to the diagnosis of supposed 'Lynch-like syndrome'. Patients with deficient mismatch repair prostate cancer were at a significantly higher stage (pT2pN0 vs. pT3-4pN0/pTanypN1, P = 0.02) and had a greater Gleason score (<8 vs. ≥8, P < 0.01) than those with proficient mismatch repair prostate cancer. CONCLUSIONS: The prevalence of deficient mismatch repair prostate cancer in the Japanese hospital-based prostatectomized population was extremely low. To improve screening efficacy for deficient mismatch repair prostate cancer, screening candidates can be limited to patients with locally advanced, node-positive and/or Gleason score of 8 or greater prostate cancer. Universal tumour screening for Lynch syndrome seems ineffective in patients with prostate cancer.

Prevalence and Molecular Characterization of Defective DNA Mismatch Repair in Small-bowel Carcinoma in a Japanese Hospital-based Population.

OBJECTIVES: To investigate the prevalence and molecular characteristics of defective DNA mismatch repair (dMMR) in small-bowel carcinoma (SBC) in a Japanese-hospital population. METHODS: Immunohistochemistry was performed to evaluate the expression of MMR proteins (MLH1, MSH2, MSH6, and PMS2) in formalin-fixed paraffin-embedded sections prepared from surgically resected primary SBCs from 30 patients during March 2002 to March 2017. Genetic testing for Lynch syndrome was performed in patients who demonstrated MMR protein loss. RESULTS: Two of 30 patients (6.7%) demonstrated concomitant loss of MSH2/MSH6 protein expression. Further genetic testing identified a pathogenic MSH2 variant in one of these patients. CONCLUSIONS: The prevalence of dMMR SBCs in a Japanese hospital-based population seems lower than that reported in previous studies. To determine whether dMMR SBCs might be strongly linked to Lynch syndrome, there is a need for further investigation with a larger sample size.