Objective: To explore the concordance and causes of different mismatch repair (MMR) and microsatellite instability (MSI) detection results in endometrial carcinoma (EC) molecular typing. Methods: A total of 214 EC patients diagnosed from January 2021 to April 2023 were selected at the Department of Pathology, Peking University Third Hospital. The immunohistochemistry (IHC) results of MMR protein were reviewed. Tumor specific somatic mutations, MMR germline mutations, microsatellite scores and tumor mutation burden (TMB) were detected by next-generation sequencing (NGS) with multi-gene panel. Methylation-specific PCR was used to detect the methylation status of MLH1 gene promoter in cases with deficient MLH1 protein expression. In cases with discrepant results between MMR-IHC and MSI-NGS, the MSI status was detected again by PCR (MSI-PCR), and the molecular typing was determined by combining the results of TMB and MLH1 gene promoter methylation. Results: (1) In this study, there were 22 cases of POLE gene mutation subtype, 55 cases of mismatch repair deficient (MMR-d) subtype, 29 cases of p53 abnormal subtype, and 108 cases of no specific molecular profile (NSMP). The median age at diagnosis of MMR-d subtype (54 years old) and the proportion of aggressive histological types (40.0%, 22/55) were higher than those of NSMP subtype [50 years old and 12.0% (13/108) respectively; all P<0.05]. (2) Among 214 patients, MMR-IHC test showed that 153 patients were mismatch repair proficient (MMR-p), 49 patients were MMR-d, and 12 patients were difficult to evaluate directly. MSI-NGS showed that 164 patients were microsatellite stable (MSS; equal to MMR-p), 48 patients were high microsatellite instability (MSI-H; equal to MMR-d), and 2 patients had no MSI-NGS results because the effective sequencing depth did not meet the quality control. The overall concordance between MMR-IHC and MSI-NGS was 94.3% (200/212). All the 12 discrepant cases were MMR-d or subclonal loss of MMR protein by IHC, but MSS by NGS. Among them, 10 cases were loss or subclonal loss of MLH1 and (or) PMS2 protein. Three discrepant cases were classified as POLE gene mutation subtype. In the remaining 9 cases, 5 cases and 3 cases were confirmed as MSI-H and low microsatellite instability (MSI-L) respectively by MSI-PCR, 6 cases were detected as MLH1 gene promoter methylation and 7 cases demonstrated high TMB (>10 mutations/Mb). These 9 cases were classified as MMR-d EC. (3) Lynch syndrome was diagnosed in 27.3% (15/55) of all 55 MMR-d EC cases, and the TMB of EC with MSH2 and (or) MSH6 protein loss or associated with Lynch syndrome [(71.0±26.2) and (71.5±20.1) mutations/Mb respectively] were significantly higher than those of EC with MLH1 and (or) PMS2 loss or sporadic MMR-d EC [(38.2±19.1) and (41.9±24.3) mutations/Mb respectively, all P<0.01]. The top 10 most frequently mutated genes in MMR-d EC were PTEN (85.5%, 47/55), ARID1A (80.0%, 44/55), PIK3CA (69.1%, 38/55), KMT2B (60.0%, 33/55), CTCF (45.5%, 25/55), RNF43 (40.0%, 22/55), KRAS (36.4%, 20/55), CREBBP (34.5%, 19/55), LRP1B (32.7%, 18/55) and BRCA2 (32.7%, 18/55). Concurrent PTEN, ARID1A and PIK3CA gene mutations were found in 50.9% (28/55) of MMR-d EC patients. Conclusions: The concordance of MMR-IHC and MSI-NGS in EC is relatively high.The discordance in a few MMR-d EC are mostly found in cases with MLH1 and (or) PMS2 protein loss or MMR protein subclonal staining caused by MLH1 gene promoter hypermethylation. In order to provide accurate molecular typing for EC patients, MLH1 gene methylation, MSI-PCR, MMR gene germline mutation and TMB should be combined to comprehensively evaluate MMR and MSI status.
Female ; Humans ; Middle Aged ; Class I Phosphatidylinositol 3-Kinases/metabolism* ; Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis* ; DNA Mismatch Repair/genetics* ; Endometrial Neoplasms/pathology* ; Microsatellite Instability ; Mismatch Repair Endonuclease PMS2/genetics* ; Molecular Typing

Hereditary colorectal cancer accounts for approximately 5% of all colorectal cancer cases, mainly including familial adenomatous polyposis and Lynch syndrome. Total proctocolectomy plus ileal pouch-anal anastomosis and total colectomy plus ileorectal anastomosis are two major procedures for familial adenomatous polyposis, however, the exact impact of these two procedures on surgical efficacy, oncologic efficacy as well as functional results still remains uncertain. Segmental colectomy and total colectomy are two major procedures for Lynch syndrome, each of them both has advantages and disadvantages, and there still lacks a consensus about the optimal strategy because of the nature of retrospective study with a relatively insufficient evidence support. As a result, we would make a review about the current surgical treatment status and future perspectives of hereditary colorectal cancer.
Adenomatous Polyposis Coli/surgery* ; Anastomosis, Surgical/methods* ; Colectomy ; Colorectal Neoplasms, Hereditary Nonpolyposis/surgery* ; Humans ; Proctocolectomy, Restorative/methods* ; Retrospective Studies

Lynch syndrome (LS) is an autosomal dominant hereditary disease caused by deletion of such DNA mismatch repair (MMR) genes as MLH1, MSH2, MSH6, and PMS2. The functional loss of MMR genes results in instability of the highly repetitive DNA sequence, and may eventually leads to tumor occurrence. Here we report a case of LS- related endometrial cancer in a clustered LS family identified by genetic counseling and genetic testing. For patients with a family history of LSrelated tumors, the diagnosis of LS should be considered, and immunohistochemical testing of MMR and genetic testing for LS should be performed. A definite diagnosis of LS has important clinical significance for individuals and family members, and risk screening and preventive measures can minimize the overall risk of developing LS-related cancers.
Colorectal Neoplasms, Hereditary Nonpolyposis/pathology* ; DNA Mismatch Repair ; Endometrial Neoplasms/pathology* ; Female ; Genetic Testing/methods* ; Humans

Objective: To investigate the molecular classification and clinicopathological features of endometrial carcinoma(EC). Methods: One hundred cases of EC diagnosed in the Department of Pathology, Tianjin Central Hospital of Gynecology and Obstetrics from November 2020 to November 2021 were selected. Sanger sequencing and immunohistochemical staining were used for molecular classification according to the 5th WHO classification. The clinicopathological characteristics of each molecular subtype was analyzed. Results: The 100 EC patients had a mean age of 53 years (range 26 to 72 years). There were 10 cases of POLE mutation (POLE mut), including two cases (2/10) of "binary-classifier" EC, two cases (2/10) of FIGO Grade 3 endometrioid endometrial carcinoma (G3-EEC), and three cases (3/10) of other high-grade subtypes. There were 38 cases of mismatch repair deficiency (dMMR), including one case (1/38, 2.6%) of "binary-classifier" EC and 36 cases (36/38, 94.7%) were EEC. Twenty-one cases (21/38, 55.3%) showed simultaneous loss of expression of MLH1 and PMS2, and 20 cases (20/21, 95.2%) were positive for MLH1 methylation, indicating that they were sporadic EC. Six patients (6/38, 15.8%) were tested for germline detection of Lynch syndrome (LS) related genes, and one patient was LS-related EC. There were 44 cases of non-specific molecular profile (NSMP), including 34 cases (34/44, 77.3%) of G1-2 EEC and seven cases (7/44, 15.9%) of G3-EEC. There were eight cases of p53 abnormality (p53 abn), including four cases (4/8) of G3-EEC, two cases (2/8) of other high-grade subtypes, and one patient had hereditary breast cancer and ovarian cancer syndrome. Conclusions: Correct interpretation of POLE mutation, MMR and p53 immunohistochemistry is the key of molecular classification. The interpretation must strictly follow standard diagnostic procedures and specifications to ensure the accuracy of molecular classification.
Adult ; Aged ; Carcinoma, Endometrioid/genetics* ; Colorectal Neoplasms, Hereditary Nonpolyposis/pathology* ; DNA Mismatch Repair ; Endometrial Neoplasms/pathology* ; Female ; Humans ; Middle Aged ; Mismatch Repair Endonuclease PMS2/metabolism* ; MutL Protein Homolog 1/metabolism* ; Tumor Suppressor Protein p53/metabolism*

OBJECTIVE: To determine the ratio of deficient mismatch repair (dMMR) proteins and Lynch syndrome among patients undergoing colorectal cancer resection. METHODS: From June 2014 to May 2016, immunohistochemistry for mismatch repair proteins including mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and PMS1 homolog 2 (PMS2) were carried out on 207 surgically resected specimens. Samples with lost expression of MMR proteins underwent genetic testing. RESULTS: Loss of expression of MMR proteins were found among 21 patients and accounted for 10.14% of the colorectal cancers. dMMR was more common in patients ≤50 years old, or with proximal tumor at splenic flexure and mucinous adenocarcinoma. Ten patients underwent genetic testing, with three pathogenic mutations (MSH6 c.3013C>T, MLH1 c.199G>A and a novel MSH6 c.584delT) and four ambiguous mutations identified. At least 1.4% of the colorectal cancers were diagnosed as Lynch syndrome. CONCLUSION Routine screening for Lynch syndrome among patients with colorectal cancer with MMR protein immunohistochemistry as preliminary screening method and MMR gene sequencing as diagnostic method is effective and feasible. It can reduce missed diagnosis of Lynch syndrome and bring lifelong benefit to patients and their families.
Adolescent ; Colorectal Neoplasms, Hereditary Nonpolyposis ; Early Detection of Cancer ; Humans ; Immunohistochemistry ; Middle Aged ; Mismatch Repair Endonuclease PMS2 ; MutS Homolog 2 Protein

Lynch syndrome (LS), an autosomal dominantly inherited disease previously known as hereditary non-polyposis colorectal cancer (HNPCC), leads to a high risk of colorectal cancer (CRC) as well as malignancy at certain sites including endometrium, ovary, stomach, and small bowel (Hampel et al., 2008; Lynch et al., 2009). Clinically, LS is considered the most common hereditary CRC-predisposing syndrome, accounting for about 3% of all CRC cases (Popat et al., 2005). LS is associated with mutations of DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, PMS2, and EPCAM (Ligtenberg et al., 2009; Lynch et al., 2009), which can trigger a high frequency of replication errors in both microsatellite regions and repetitive sequences in the coding regions of various cancer-related genes. Immunohistochemistry (IHC) tests followed by genetic analysis of these mutations play a significant role in diagnosis, treatment determination, and therapeutic response prediction of LS (Lynch et al., 2009; Alex et al., 2017; Ryan et al., 2017). Here, we report substitution of one base-pair in exon 1 of MLH3 (c.1397C>A) and a frameshift mutation in exon 19 of MLH1 (c.2250_2251ins AA) in a 43-year-old Chinese male with an LS pedigree.
Adult ; Asian People/genetics* ; China ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics* ; Exons ; Female ; Frameshift Mutation ; Germ-Line Mutation ; Humans ; Male ; MutL Protein Homolog 1/genetics* ; MutL Proteins/genetics* ; Pedigree

In 2017, 10 topics were selected as major clinical research advances in gynecologic oncology. For cervical cancer, efficacy and safety analysis results of a 9-valent human papillomavirus (HPV) vaccine and long-term impact of reduced dose of quadrivalent vaccine were updated. Brief introduction of KEYNOTE trials of pembrolizumab, a monoclonal antibody that blocks the interaction between programmed death (PD)-1 and its ligands, PD-L1 and PD-L2, followed. Tailored surveillance programs for gynecologic cancer related with Lynch syndrome and update on sentinel lymph node mapping were reviewed for uterine corpus cancer. For ovarian cancer, 5 topics were selected including poly(ADP-ribose) polymerases inhibitors and immunotherapy. The other potential practice changers covered in this review were lymphadenectomy in advanced disease, secondary cytoreductive surgery in recurrent disease, weekly dose-dense regimen for first-line chemotherapy, incorporation of bevacizumab maintenance in platinum-sensitive recurrent disease, and effect of platinum-free interval prolongation. Conflicting opinions of academic societies on periodic pelvic examination were introduced in conjunction with relevant literature review. For the field of radiation oncology, results of 2 big trials, The Postoperative Radiation Therapy in Endometrial Carcinoma-3 and Gynecologic Oncology Group-258, for endometrial cancer and recent advance in high-dose-rate brachytherapy for cervical cancer were reported. Topics for breast cancer covered adjuvant capecitabine after preoperative chemotherapy, adjuvant pertuzumab and trastuzumab in early human epidermal growth factor receptor 2-positive disease, olaparib for metastatic cancer in patients with a germline BRCA mutation, 20-year risks of recurrence after stopping endocrine therapy at 5 years, and contemporary hormonal contraception and the risk of breast cancer.
Bevacizumab ; Brachytherapy ; Breast Neoplasms ; Capecitabine ; Chemotherapy, Adjuvant ; Colorectal Neoplasms, Hereditary Nonpolyposis ; Contraception ; Drug Therapy ; Endometrial Neoplasms ; Female ; Gynecological Examination ; Humans ; Immunotherapy ; Ligands ; Lymph Node Excision ; Lymph Nodes ; Molecular Targeted Therapy ; Ovarian Neoplasms ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases ; Radiation Oncology ; Receptor, Epidermal Growth Factor ; Recurrence ; Trastuzumab ; Uterine Cervical Neoplasms

OBJECTIVE: Lynch syndrome is a cancer predisposition syndrome caused by germline mutation of DNA mismatch repair (MMR) genes. Lynch syndrome only causes about 0.4% of cases of ovarian cancer, which suggests that universal screening may not be cost-efficient. However, the frequency of Lynch syndrome in ovarian cancer is unclear in the Asian population. The goal of the study was to investigate a screening strategy using family history. METHODS: The subjects were 129 patients with ovarian cancer. Clinical and family history were collected using a self-administered questionnaire, and Society of Gynecologic Oncology (SGO) criteria 2007 and PREMM5 were used for risk assessment. Microsatellite instability, immunohistochemistry, and methylation of MMR genes were analyzed. RESULTS: Of the 129 cases, 25 (19.4%) met the SGO criteria, and 4 of these 25 had MSI-high and MMR deficiency. Two cases had loss of MSH2 and MSH6, indicating MSH2 mutation, and the other two had loss of MLH1 and PMS2, including one without MLH1 methylation indicating MLH1 mutation. These results show that screening using family history can detect Lynch syndrome in 12.0% (3/25) of ovarian cancer cases. The 3 cases were positive for PREMM5, but negative for Amsterdam II criteria and revised Bethesda guidelines. Genetic testing in one case with MSH2 and MSH6 deficiency confirmed the diagnosis of Lynch syndrome with MSH2 mutation. CONCLUSION: This is the first study of screening for Lynch syndrome in ovarian cancer using clinical and family history in an Asian population. This approach may be effective for diagnosis in these patients.
Asian Continental Ancestry Group ; Colorectal Neoplasms, Hereditary Nonpolyposis* ; Diagnosis ; DNA Mismatch Repair ; Genetic Testing ; Germ-Line Mutation ; Humans ; Immunohistochemistry ; Mass Screening* ; Medical History Taking ; Methylation ; Microsatellite Instability ; Ovarian Neoplasms* ; Risk Assessment*

No abstract available.
Colorectal Neoplasms, Hereditary Nonpolyposis*

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.
Asian Continental Ancestry Group ; Colorectal Neoplasms ; Colorectal Neoplasms, Hereditary Nonpolyposis* ; Endometrial Neoplasms ; Female ; Genetic Testing ; Humans ; Korea ; Microsatellite Instability ; Ovarian Neoplasms ; Stomach Neoplasms