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.

Predictive modeling for the germline pathogenic variant of the APC gene in patients with adenomatous polyposis: proposing a new APC score.

BACKGROUND: The precise diagnosis and medical management of patients with suspected familial adenomatous polyposis should be based on genetic testing, which may not always be available. Therefore, establishing a new model for predicting the likelihood of a germline pathogenic variant (GPV) of APC based on its clinical manifestations could prove to be useful in clinical practice. METHODS: The presence of GPVs of APC gene was investigated in 162 patients with adenomatous polyposis (≥ 10 polyps) using a multigene panel or single-gene testing. To generate a predictive model for GPV of the APC gene, a logistic regression analysis was performed using the clinicopathological variables available at the time of the diagnosis of adenomatous polyposis. RESULTS: Ninety (55.6%) patients had GPV of the APC gene. According to a multivariate logistic regression analysis, age < 40 years, polyps ≥ 100, fundic gland polyposis, and a family history of colorectal polyposis were found to be independent predictors of the GPV of APC and were used to establish a formula for predicting the GPV of APC using the four predictors. The prediction model had an area under the curve of 0.91 (0.86-0.96) according to a receiver operating characteristic analysis. CONCLUSION: The model for predicting the GPV of APC will help patients with adenomatous polyposis and physicians make decisions about genetic testing.

[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.

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.

[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.

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.

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.

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.

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.

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.

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.

[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.

[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.

Clinically applicable cases of anti-programmed cell death protein 1 immunotherapy for colorectal cancer patients.

We investigated the prevalence and characteristics of defective mismatch repair (dMMR) in colorectal cancer (CRC) patients who would potentially benefit from anti-programmed cell death protein 1 (PD-1) immunotherapy. Medical records were obtained and reviewed for 1147 patients who underwent surgical resection of stage I-IV CRC, in whom universal screening for Lynch syndrome using immunohistochemistry for MMR proteins had been undertaken. The molecular characteristics of dMMR CRCs were also investigated. Defective MMR accounted for 5.2% of stage I-IV CRC patients, including 12 (1.0% of all CRC patients) who had stage IV disease or recurrence after curative resection (n = 6 each). These 12 patients included patients with LS (n = 3) and Lynch-like syndrome (n = 1). Defective MMR tumors were predominantly located in the right-sided colon (P < 0.01). Approximately 1% of stage I-IV CRC patients could potentially benefit from anti-PD-1 immunotherapy, while one-third would require genetic counseling and/or MMR gene testing.

[A Family of Attenuated Familial Adenomatous Polyposis].

The proband was a 49-year-old woman who had undergone total colectomy, ileorectostomy, and bilateral ovariectomy for the treatment of cecal(T3N0)and sigmoid colon(T4a, N2b, M1c2[Ova], Stage Ⅳc)cancers. Pathological findings revealed 6 adenomas and 2 adenocarcinoma-in-adenomas in the right colon, other than advanced colon cancers. She had a family history of colorectal cancer meeting the Amsterdam Criteria I, but none of her relatives had definite polyposis. Considering the possibility of Lynch syndrome, the microsatellite-instability test and immunohistochemistry(IHC)examination of the mismatch repair protein were performed, leading to the results of microsatellite stable and proficient mismatch repair protein expression. Therefore, we performed the multigene panel test containing 26 genes using the next-generation sequencing technology. In the APC(5q22.2)gene, a pathogenic variant(exon 12 c.994C>T/p.Arg332*)was identified, leading to a diagnosis of attenuated familial adenomatous polyposis(AFAP). After disclosure of the results to the proband, the single-site variant analysis was performed on her 3 daughters. In her second and third daughters, the same variant was confirmed, and laparoscopic total colectomy was performed 23 and 35 months after the disclosure of the genetic analysis results, respectively. Currently, we are conducting periodical surveillance for the residual rectum.

[A Family with Lynch Syndrome Diagnosed after a Proband of Elderly Multiple Colorectal Cancers].

The proband was a 77-year-old man who had been admitted to a local hospital for fecal occult blood. He was diagnosed with descending colon carcinoma, T4a, N1, M0, Stage Ⅲb, and rectal adenoma. He had undergone surgeries for rectal cancer at 52 years of age and cecum colon cancer at 57 years of age. Regarding his family history, 5 first-degree and 3 second- degree relatives had a history of gastrointestinal and gynecological cancers, thus meeting 2 of the 5 criteria of the revised Bethesda guidelines. The microsatellite-instability(MSI)test performed using preoperative biopsy tissues demonstrated high-frequency MSI(MSI-H). Hartmann's procedure was performed for MSI-H colon cancer under a strong suspicion of Lynch syndrome. Pathological findings were consistent with descending colon carcinoma, tub2, pT3, pN0, M0, pStage Ⅱa. He was then referred to our hospital. We performed the immunohistochemistry(IHC)analysis of the mismatch repair protein using surgical specimens. The IHC analysis revealed defective expression of the MSH2/MSH6 protein. We found a pathogenic variant in the mismatch repair gene, MSH2(c.1510+2T>G), through genetic testing and finally diagnosed the patient with Lynch syndrome. After disclosure of the results to the proband, 7 relatives underwent genetic testing for the MSH2 variant. Four relatives had the same variant and were also diagnosed with Lynch syndrome. They subsequently underwent surveillance for Lynch syndrome-associated cancers. In 2 variant carriers with a history of early colorectal cancer, an early colon cancer was identified and successfully resected endoscopically. Surveillance for Lynch syndrome-associated cancer is ongoing for the proband and variant carriers.

[Cancer Risk in Lynch Syndrome-Associated Endometrial Cancer Patients and Their Relatives].

Endometrial cancer(EC)is often the sentinel cancer in women with Lynch syndrome(LS), but the actual incidence of EC as the sentinel cancer in patients with LS is not well-known in Japan. We investigated the history of malignancies and incidence of sentinel cancers in patients with LS-associated EC and their relatives. We examined 8 patients with LS-associated EC between 2005 and 2019. Five of them(63%)had suffered from a cancer other than EC, while 5(63%)had developed a cancer after EC. Seven patients(88%)had EC as the sentinel cancer, while 1(13%)developed colorectal cancer before EC. Among first-degree relatives(15 men and 23 women), 15(40%)had a history of cancer, of whom 7 were women (30%). Five women(22%)had EC, all sentinel. Among second-degree relatives(40 men, 44 women, 14 unknown), 16 (16%)had cancer. Four women(9%)had a history of cancer, of whom 2(5%)had EC, all sentinel. Although we only investigated a few LS cases, the importance of EC as the sentinel cancer was highlighted in Japanese women with LS.