Mismatch Repair Protein Deficiency Research Articles

Factors associated with the efficacy of first-line nivolumab plus chemotherapy in advanced gastric cancer patients with deficient mismatch repair.

We aimed to investigate clinicopathologic factors leading to different clinical outcomes in patients with deficient mismatch repair protein (d-MMR) gastric cancer (GC) treated with nivolumab plus chemotherapy (nivolumab chemotherapy). This retrospective study included 28 patients with d-MMR advanced GC treated with first-line nivolumab chemotherapy. As a control group, 68 treated with first-line chemotherapy alone were included. Clinicopathological factors, including the neutrophil-to-lymphocyte ratio (NLR) and PD-L1 combined positive score (CPS), were analyzed with regards to the efficacy outcomes. Progression-free survival (PFS) was longer (median PFS; not reached [NR] vs. 5.2months, hazard ratio [HR] 0.28, P < 0.001), and overall survival (OS) tended to be longer (median OS; NR vs. 17.9months, HR 0.43, P = 0.057) in patients treated with nivolumab chemotherapy than those treated with chemotherapy. The PFS benefit of nivolumab chemotherapy over chemotherapy was pronounced in the subgroup with a lower NLR (< 3.80 [median NLR]) (HR 0.10), whereas it was less prominent in patients with a high NLR (≥ 3.80) (HR 0.58). Among patients treated with nivolumab chemotherapy, PFS was worse in patients with a higher NLR (≥ 3.80) than in those with a lower NLR (< 3.80), and survival outcomes were similar between those with PD-L1 CPS ≥ 5 and < 5. Nivolumab chemotherapy was associated with better efficacy outcomes than chemotherapy alone among patients with d-MMR GC, but survival outcomes were poor even with nivolumab chemotherapy for those with a high NLR. Survival outcomes were not different according to PD-L1 CPS among d-MMR patients treated with nivolumab chemotherapy.

Microsatellite instability and mismatch repair protein deficiency: equal predictive markers?

Current clinical guidelines recommend mismatch repair (MMR) protein immunohistochemistry (IHC) or molecular microsatellite instability (MSI) tests as predictive markers of immunotherapies. Most of the pathological guidelines consider MMR protein IHC as the gold standard test to identify cancers with MMR deficiency and recommend molecular MSI tests only in special circumstances or to screen for Lynch syndrome. However, there are data in the literature which suggest that the two test types may not be equal. For example, molecular epidemiology studies reported different rates of deficient MMR (dMMR) and MSI in various cancer types. Additionally, direct comparisons of the two tests revealed relatively frequent discrepancies between MMR IHC and MSI tests, especially in non-colorectal and non-endometrial cancers and in cases with unusual dMMR phenotypes. There are also scattered clinical data showing that the efficacy of immune checkpoint inhibitors is different if the patient selection was based on dMMR versus MSI status of the cancers. All these observations question the current dogma that dMMR phenotype and genetic MSI status are equal predictive markers of the immunotherapies.

Mismatch repair protein deficiency and its implications on distant metastasis in colorectal cancer: A comprehensive analysis.

While previous studies have indicated variability in distant metastatic potential among different mismatch repair (MMR) states in colorectal cancer (CRC), their findings remain inconclusive, especially considering potential differences across various ethnic backgrounds. Furthermore, the gene regulatory networks and the underlying mechanisms responsible for these variances in metastatic potential across MMR states have yet to be elucidated. We collected 2058 consecutive primary CRC samples from the South West of China and assessed the expression of MMR proteins (MLH1, MSH2, MSH6, and PMS2) using immunohistochemistry. To explore the inconsistencies between different MMR statuses and recurrence, we performed a meta-analysis. To delve deeper, we employed Weighted Gene Co-expression Network Analysis (WGCNA), ClueGo, and iRegulon, pinpointing gene expression networks and key regulatory molecules linked to metastasis and recurrence in CRC. Lastly, both univariate and multivariate Cox regression analyses were applied to determine the impact of core regulatory molecules on metastasis. Of the samples, 8.2% displayed deficient MMR (dMMR), with losses of MLH1 and PSM2 observed in 40.8% and 63.9%, respectively. A unique 24.3% isolated loss of PMS2 without concurrent metastasis was identified, a result that diverges from established literature. Additionally, our meta-analysis further solidifies the reduced recurrence likelihood in dMMR CRC samples compared to proficient MMR (pMMR). Two gene expression networks tied to distant metastasis and recurrence were identified, with a majority of metastasis-related genes located on chromosomes 8 and 18. An IRF1 positive feedback loop was discerned in the metastasis-related network, and IRF1 was identified as a predictive marker for both recurrence-free and distant metastasis-free survival across multiple datasets. Geographical and ethnic factors might influence peculiarities in MMR protein loss. Our findings also highlight new gene expression networks and crucial regulatory molecules in CRC metastasis, enhancing our comprehension of the mechanisms driving distant metastasis.

Gastrointestinal tumors with SWI/SNF complex deficiency: a clinicopathological analysis of 36 cases

Objective: To investigate the clinicopathological characteristics of gastrointestinal tumors with SWI/SNF complex deficiency and to perform a prognostic analysis of the patients. Methods: Gastrointestinal tumor cases with SWI/SNF complex deficiency expression diagnosed at the Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China from August 2021 to May 2023 were collected. Hematoxylin and eosin (HE) stained slides were reviewed, and immunohistochemical results were analyzed. Clinical and pathological information was recorded, and relevant literature was reviewed. Results: A total of 36 cases of gastrointestinal tumor with loss of SWI/SNF complex expression were identified, including 28 males (77.8%) and 8 females (22.2%). The average age at diagnosis was 70 years (range 48-85 years). Clinical staging showed 3 cases in stage Ⅰ (8.3%), 12 cases in stage Ⅱ (33.3%), 19 cases in stage Ⅲ (52.8%), and 2 cases in stage Ⅳ (5.6%). Complete or partial loss of ARID1A expression was observed in 20 cases (55.6%); complete or partial loss of SMARCA2 expression was observed in 24 cases (66.7%). SMARCA4 exhibited complete loss of expression in 4 cases (11.1%). Eleven cases (30.6%) showed concurrent complete or partial losses of both ARID1A and SMARCA2 expression. Twelve cases (33.3%) had mismatch repair protein deficiency, all of which were characterized by MLH1/PMS2 absence. Mismatch repair protein deficiency was associated with loss of ARID1A expression (P<0.01). Patients with mismatch repair protein deficiency were also associated with earlier clinical stage and a lower risk of lymph node metastasis compared to the ones with intact mismatch repair proteins (P<0.05). Conclusions: SWI/SNF complex deficiency in gastrointestinal tumors is associated with dedifferentiation and often accompanied by mismatch repair protein deficiency. Compared to the cases with intact mismatch repair proteins, the cases with defective mismatch repair protein have an earlier clinical stage and a lower risk of lymph node metastasis.

Ring Finger 43 Hot-spot Frameshift Mutation G659V in Colorectal Cancer Patients: Report from a Tertiary Cancer Care Hospital in North India.

The Ring Finger 43 (RNF43) is a tumor suppressor gene that negatively regulates the Wnt/β-catenin signaling. The p.G659fs is a recurrent RNF43 C-terminal truncating variant frequent in colorectal cancer (CRC) patients. We aimed to identify this hotspot variant in CRC patients and assessed the relationship between the mutation, clinical characteristics, and tumor β-catenin localization. Formalin-fixed, paraffin-embedded tissue samples of upfront, surgically resected, sporadic colorectal adenocarcinoma cases were selected. The p.G659fs mutation was determined by capillary sequencing with sequence-specific primers. Tissue microarray and immunohistochemistry were employed to analyze nuclear β-catenin expression and the expression of mismatch repair (MMR) proteins, respectively. In addition, clinical details were retrieved from the hospital medical records and data were analyzed. The RNF43 p.G659fs mutation was observed in 8% of CRC patients. In total, 25% of tumors showed a loss of immunostaining for one or more MMR proteins and 14.6% of tumors showed positive nuclear β-catenin staining. The p.G659fs variant was significantly enriched in MMR-deficient tumors (P = 0.04). Importantly, no correlation was observed between the variant and nuclear β-catenin localization (P = 0.48), indicating a Wnt-independent role of this variant in CRC tumors. To the best of our knowledge, this is the first study from North India to show the involvement of RNF43 p.G659fs variant in CRC patients. The mutation correlated with MMR protein deficiency and seems to be conferring tumorigenicity independent of the Wnt pathway.

Clinicopathological characteristics of multiple-classifier endometrial cancers: a cohort study and systematic review.

Endometrial cancers with more than one molecular feature-POLE mutations (POLEmut), mismatch repair protein deficiency (MMRd), p53 abnormality (p53abn)-are called 'multiple classifiers'. To describe our cohort of multiple classifiers and to report the results of a review on their incidence and the techniques used to identify them. Multiple classifiers identified at the European Institute of Oncology, Milan, between April 2019 and Decmber 2022, were included. Clinicopathological, molecular characteristics, and oncologic outcomes were summarized and compared between single and multiple classifiers sharing common features. Studies on molecular classification of endometrial cancer were searched in the PubMed Database to collect data on the incidence of multiple classifiers and the techniques used for classification. Among 422 patients, 48 (11.4%) were multiple classifiers: 15 (3.6%) POLEmut-p53abn, 2 (0.5%) POLEmut-MMRd, 28 (6.6%) MMRd-p53abn, and 3 (0.7%) POLEmut-MMRd-p53abn. MMRd-p53abn and MMRd differed in histotype (non-endometrioid: 14.8% vs 2.0%, p=0.006), grade (high-grade: 55.6% vs 22.2%, p=0.001), and MMR proteins expression, whereas they differed from p53abn in histotype (non-endometrioid: 14.8% vs 50.0%, p=0.006). POLEmut-p53abn and POLEmut differed only in grade (high-grade: 66.7% vs 22.7%, p=0.008), while they differed from p53abn in age (56.1 vs 66.7 years, p=0.003), stage (advanced: 6.7% vs 53.4%, p=0.001), and histotype (non-endometrioid: 6.7% vs 50.0%, p=0.002). Two (7.1%) patients with MMRd-p53abn, 4 (4.0%) with MMRd, and 25 (34.3%) with p53abn had a recurrence. No recurrences were observed in POLEmut-p53abn and POLEmut. TP53 sequencing allowed the detection of additional 7 (18.9%) multiple classifiers with normal p53 immunostaining. The incidence of multiple classifiers ranged from 1.8% to 9.8% in 10 published studies including >100 patients. When only p53 immunohistochemistry was performed, the highest incidence was 3.9%. The characteristics of POLEmut-p53abn resembled those of POLEmut, whereas MMRd-p53abn appeared to be intermediate between MMRd and p53abn. The high proportion of multiple classifiers may be related to the methods used for molecular classification, which included both p53 immunohistochemistry and TP53 sequencing.

Mismatch Repair Protein Deficiency in Triple Negative Breast Carcinomas: Clinicopathological Features

Abstract Introduction/Objective Female breast cancer has now surpassed lung cancer as the most commonly diagnosed cancer worldwide. Triple-negative breast cancer (TNBC) accounts for approximately 10–15% of all breast cancers. Chemotherapy remains the mainstay of systemic treatment for patients with TNBCs. Studies of mismatch repair (MMR) deficiency in TNBC reported variable prevalence ranging, from 0.2% to 18.6%. Recent studies described an excellent response in a patient with metastatic breast cancer treated with anti-PD1 illustrating the urgent need to test for MMRP deficiency as a predictive biomarkers to select those patients who could benefit from immunotherapy. The aim of the study is to detect MMRP deficiency in a cohort of TNBC Jordanian patients using the immunohistochemical methods. Methods/Case Report This study targeted cases of TNBC diagnosed and treated at King Hussein Cancer Center from 2015 until 2021. Clinicopathological data was obtained from 152 patients’ records. Immunohistochemistry for MLH1, MSH2, MSH6 and PMS2 proteins were performed on paraffin embedded tissue containing carcinoma. Results (if a Case Study enter NA) The median age of patients at diagnosis was 49 years. A total of 14 out of 152 (9.2%) cases showed deficient MMR (dMMR) expression. Loss of expression of PMS2 was seen in 13 cases, 5 of which showed also loss of MLH1 expression. Loss of expression of both MSH6 and MSH2 was seen in one case. Positive family history of cancer was present in 5 of 12 patients with available data, three of whom had isolated loss of PMS2 and two had combined loss of PMS2 and MLH1. One pt. with loss of MSH6 and MSH2, had a personal history of a second malignancy (Lung cancer). The median duration of follow-up was 27 months. The overall (OS) and event- free survival (EFS) were better for dMMR despite the lack of statistically significant differences. At 24 months EFS and OS were 77.9% and 85.7% for dMMR and 63.9% and 56.9% for pMMR respectively. Conclusion The prevalence of dMMR in TNBC is 9% with most of the cases apparently related to Lynch syndrome. dMMR tumors tend to be associated with better outcomes compared to pMMR cases. dMMR can serve as a biomarker for better prognosis. These results are of value in directing the clinical management.

Microsatellite instability screening in colorectal carcinoma: immunohistochemical analysis of MMR proteins in correlation with clinicopathological features and Ki-67 protein expression

BackgroundDefects in mismatch repair (MMR) system or microsatellite instability (MSI) and detected in colorectal carcinoma (CRC), both in sporadic and more frequently in hereditary cases. Immunohistochemistry (IHC) is the most frequent method for MMR protein deficiency screening in CRCs. In this study, we aimed to evaluate immunohistochemical expression of MMR and Ki-67 in colorectal carcinoma with clinicopathological features.MethodsIn this study, we evaluated the immunohistochemical expression of MMR proteins including MSH6, MSH2, PMS2 and MLH1 in 50 resection materials with colorectal carcinoma. Their expression is correlated with clinicopathological features of patients together, with Ki-67 protein expression in attempt to screen the most significant predictor of microsatellite instability.ResultsOf the 50 cases of cancer colon, 28% were classified as MSI-H, 20% were MSI-L, and 52% were MSS. The most frequent pattern in MSI-H tumors was concurrent loss of MSH6 and PMS2 proteins. There was a significant correlation between MMR protein expression pattern with tumor size, grade, T-classification and stage (0.015, 0.0515, 0.0162 and 0.0391), respectively. MSI-H tumors were located more frequently in right colon, early TNM stage and poorly differentiated and infrequent distant metastases. There was a significant correlation between Ki-67 high expression and MSI status patterns in their common biological aspects distinct from MSI-negative tumors.ConclusionsMismatch repair defective colorectal carcinoma has characteristics clinicopathological features different from MSS tumors. The role of immunohistochemistry (IHC) for MSI evaluation is the easiest and effective way for evaluation of MMR deficiency in colorectal carcinoma.

The prevalence of lynch syndrome (DNA mismatch repair protein deficiency) in patients with primary localized prostate cancer using immunohistochemistry screening

BackgroundProstate cancer is one of the most heritable human cancers. Lynch syndrome is an autosomal dominant inheritance caused by germline mutations in DNA mismatch repair (MMR) genes, which are also associated with an increased incidence of prostate cancer. However, prostate cancer has not been defined as a Lynch syndrome-associated cancer. The proportion of Lynch syndrome patients in primary prostate cancers is unclear. In this study, we investigated MMR protein loss using universal immunohistochemical screening to determine the prevalence of Lynch syndrome in patients with localized prostate cancer who underwent radical prostatectomy.MethodsOne hundred twenty-nine surgical specimens from radical prostatectomy performed at Toranomon Hospital between 2012 and 2015 were retrospectively tested using universal screening with immunohistochemistry staining for expression of the MMR proteins MLH1, PMS2, MSH2, and MSH6. For all suspected MMR-deficient patients, germline genetic tests focusing on MMR genes were performed.ResultsMMR protein loss was found in only one patient (0.8%) who showed dual MSH2/MSH6 loss. This patient showed a single nucleotide pathogenic germline mutation from c.1129 C to T (p.Gln377*) at exon 7 in the MSH2 gene. He was diagnosed with a primary prostate cancer at 66 years of age. He had a documented history of Lynch syndrome (Muir–Torre syndrome) with previous colon cancer, sebaceous tumor, and keratoacanthoma as well as subsequent bladder cancer, all of which also showed dual MSH2/MSH6 loss. He also had a strong family history of colorectal and other Lynch syndrome-associated cancers. The pathological stage was pT3aN0M0, and the pathological grade was Gleason 7(4 + 3) with tertiary pattern 5.ConclusionsIn this study, immunohistochemical screening of MMR proteins for Lynch syndrome was performed in a series of prostate cancer cases. The prevalence of Lynch syndrome in localized prostate cancer was 0.8%, which is low compared with other Lynch syndrome-associated cancers.

Mismatch Repair Deficiency Is a Prognostic Factor Predicting Good Survival of Opisthorchis viverrini-Associated Cholangiocarcinoma at Early Cancer Stage.

The mismatch repair (MMR) system prevents DNA mutation; therefore, deficient MMR protein (dMMR) expression causes genetic alterations and microsatellite instability (MSI). dMMR is correlated with a good outcome and treatment response in various cancers; however, the situation remains ambiguous in cholangiocarcinoma (CCA). This study aims to evaluate the prevalence of dMMR and investigate the correlation with clinicopathological features and the survival of CCA patients after resection. Serum and tissues were collected from CCA patients who underwent resection from January 2005 to December 2017. Serum OV IgG was examined using ELISA. The expression of MMR proteins MLH1, MSH2, MSH6 and PMS2 was investigated by immunohistochemistry; subsequently, MMR assessment was evaluated as either proficient or as deficient by pathologists. The clinicopathological features and MMR status were compared using the Chi-square test. Univariate and multivariate analyses were conducted to identify prognostic factors. Among the 102 CCA patients, dMMR was detected in 22.5%. Survival analysis revealed that dMMR patients had better survival than pMMR (HR = 0.50, p = 0.008). In multivariate analysis, dMMR was an independent factor for a good prognosis in CCA patients (HR = 0.58, p = 0.041), especially at an early stage (HR = 0.18, p = 0.027). Moreover, subgroup analysis showed dMMR patients who received adjuvant chemotherapy had better survival than surgery alone (HR = 0.28, p = 0.012). This study showed a high prevalence of dMMR in cholangiocarcinoma with dMMR being the independent prognostic factor for good survival, especially in early-stage CCA and for patients who received adjuvant chemotherapy. dMMR should be the marker for selecting patients to receive a specific adjuvant treatment after resection for CCA.

Mutational Landscape of ER Receptor Negative Endometrial Cancer Patients Categorized as No Specific Molecular Profile (NSMP)

The endometrial cancer (EC) molecular classification introduced by The Cancer Genome Atlas (TCGA) has initiated molecular-based classification with clear prognostic value. Four major tumor subtypes exist: 1) TP53 mutation (p53abn); 2) POLE mutation (POLEmut); 3) mismatch repair protein deficient (MMRd); and 4) no specific molecular profile (NSMP). Of these subtypes, p53abn patients exhibited the worst prognosis. Recently, a prognostic refinement of NSMP EC using estrogen receptor (ER) status, from PORTEC-III trial data, showed that (ER-) NSMP patients had a strikingly poor prognosis, similar to p53abn patients. Currently, drivers of NSMP (ER-) disease are unknown and require genomic characterization. In this study, we perform an integrated molecular analysis to characterize this aggressive and poorly understood cohort. RNAseq and mutational data was downloaded from the TCGA, PanCancer Atlas, Uterine Endometrial Carcinoma dataset via the genomic data commons (GDC). All patients in this cohort demonstrated endometrioid histology. P53abn, and POLE mutated patients were filtered using mutational data. MMRd and NSMP ESR1 gene low expressors (ER Low) were filtered using Z-score cutoffs of RNAseq expression data. Survival analysis was performed using the Survival R-package. Gene expression testing was performed using the EdgeR R-package. Pathway Enrichment analysis was conducted using EnrichR software. Forty-two patients out of 529 samples met our GDC NSMP (ER low) filtering criteria (7%), similar to the 5% of PORTEC-III patients classified as NSMP (ER -). Strikingly 83% percent of GDC NSMP (ER low) patients harbored a mutation in the PI3K-AKT-mTOR signaling pathway, with 48% of GDC NSMP (ER low) patients carrying a mutation in the p110 alpha (PIK3CA) gene. Interestingly, of the patients with PIK3CA mutant tumors, 2/20 patients died in 5 years (10%), compared to 9/22 patients whose tumors were PIK3CA WT (41%) (p = 0.02). Among GDC NSMP (ER low) patients with PIK3CA WT tumors gene expression signatures were enriched for MYC target genes (p = 1.1e-51), DNA replication (p = 4.3e-30), cell cycle (p = 9.32e-20), and cell cycle checkpoints (p = 6.4e-20) pathways. Additionally, strongly in PIK3CA WT tumors are mitochondrial membrane proteins (p = 1.63e-37) and ribosomal proteins (2.9e-24). In this analysis, we show that GDC NSMP (ER low) tumors nearly all harbor a mutation in the PI3K-AKT-mTOR signaling pathway. Further we demonstrate that the most common gene mutation in the cohort, PIK3CA, is counterintuitively a marker of improved survival. Additionally, we show that within that this subpopulation, PIK3CA WT patients exhibit robustly upregulated gene expression programs dedicated to energy production, cell cycling, and division.

Clear cell carcinoma of the uterine cervix; an unusual HPV-independent tumor: Clinicopathological features, PD-L1 expression, and mismatch repair protein deficiency status of 16 cases.

Endocervical clear cell carcinoma (c-CCC) is a rare and HPV-independent adenocarcinoma type of cervix. Being usually resistant to conventional chemotherapy. Immunotherapy has recently been added as a preferred regimen as a second-line treatment option for programed cell death-ligand 1 (PD-L1)-positive or mismatch repair (MMR) deficient cervical carcinomas. In this study, clinicopathological features, PD-L1 expression, and MMR deficiency status of c-CCCs were investigated. Sixteen c-CCC diagnosed cases were included in this study. PD-L1 expression was evaluated using two different PD-L1 clones (22C3 and SP263). MMR deficiency status of the cases was evaluated using four MMR proteins (MLH1, PMS2, MSH2, and MSH6). Most of the c-CCC cases were presented as FIGO Stage I (68.75%). PD-L1 expression in either tumoral or tumor-infiltrating immune cells (TILs) was present in 62.5% (10/16) and 69% (11/16) of the 22C3 and SP263 clones, respectively. Most of the cases with high TIL density were also positive for PD-L1. The PD-L1 expression rate was less than 50% in most of the cases and 12.5% of the cases shared extensive PD-L1 staining. Overall, MMR deficiency was observed in 31.25% of the cases. Most of the MMR-deficient cases (80%) were PD-L1 positive. Although our study cohort is limited, we have shown that PD-L1 expression and MMR deficiency can be found in c-CCCs in variable degrees. These findings suggest that accompanying TIL density and MMR deficiency could be used as candidates for predicting PD-L1 positivity for c-CCCs. However, to indicate the clinical importance of these findings, objective treatment outcomes of cases treated with immunotherapy should be seen.

Loss of SATB2 and CDX2 expression is associated with DNA mismatch repair protein deficiency and BRAF mutation in colorectal cancer.

The relationship between the expression of the SATB2 and CDX2 proteins and common molecular changes and clinical prognosis in colorectal cancer (CRC) still needs further clarification. We collected 1180 cases of CRC and explored the association between the expression of SATB2 and CDX2 and clinicopathological characteristics, molecular alterations, and overall survival of CRC using whole-slide immunohistochemistry. Our results showed that negative expression of SATB2 and CDX2 was more common in MMR-protein-deficient CRC than in MMR-protein-proficient CRC (15.8% vs. 6.0%, P = 0.001; 14.5% vs. 4.0%, P = 0.000, respectively). Negative expression of SATB2 and CDX2 was more common in BRAF-mutant CRC than in BRAF wild-type CRC (17.2% vs. 6.1%, P = 0.003; 13.8% vs. 4. 2%; P = 0.004, respectively). There was no relationship between SATB2 and/or CDX2 negative expression and KRAS, NRAS, and PIK3CA mutations. The lack of expression of SATB2 and CDX2 was associated with poor histopathological features of CRC. In multivariate analysis, negative expression of SATB2 (P = 0.030), negative expression of CDX2 (P = 0.043) and late clinical stage (P = 0.000) were associated with decreased overall survival of CRC. In conclusion, the lack of SATB2 and CDX2 expression in CRC was associated with MMR protein deficiency and BRAF mutation, but not with KRAS, NRAS and PIK3CA mutation. SATB2 and CDX2 are prognostic biomarkers in patients with CRC.

Clinicopathological characteristics of endometrial carcinomas according to DNA mismatch repair protein status

DNA mismatch repair protein deficiency (MMRd) in endometrial carcinoma is associated with the risk of Lynch syndrome and response to immune checkpoint inhibitors. It is also related to microsatellite instability and corresponds to a molecular subtype of endometrial tumor with an unclear prognosis. Here, we evaluated the clinicopathological characteristics and prognosis of 312 consecutive endometrial carcinoma cases submitted to complete surgical staging at a single institution. We compared MMRd and mismatch repair protein–proficient (MMRp) tumors and examined the effects of the MMR protein loss type (MLH1/PMS2 vs. MSH2/MSH6) and influence of L1CAM and p53 expression. The median follow-up period was 54.5 (range, 0–120.5) months. No difference was observed between MMRd [n = 166 (37.2%)] and MMRp [n = 196 (62.8%)] cases in terms of age, body mass index, FIGO stage, tumor grade, tumor size, depth of myometrial infiltration, or lymph node metastasis. More MMRd than MMRp tumors had endometrioid histology (87.9% vs. 75.5%) and despite MMRd had more lymphovascular space invasion (LVSI; 27.2% vs. 16.9%), they presented fewer recurrences and no difference in lymph node metastasis and disease-related death. Relative to those with MLH1/MSH6 loss, tumors with MSH2/MSH6 loss were diagnosed at earlier FIGO stages, were smaller, and had less ≥50% myometrial invasion, LVSI and lymph node metastasis. Outcomes, however, did not differ between these groups. L1CAM positivity and mutation-type p53 expression were more common in MMRp than in MMRd tumors and did not differ between the MLH1/PMS2 and MSH2/MSH6 loss groups. In the entire cohort, L1CAM and mutation p53 expression were associated with worse prognosis, but only non-endometrioid histology, FIGO stage III/IV, and deep myometrial infiltration were significant predictors. In the subgroup of endometrioid carcinomas, only FIGO stage III/IV was associated with poor outcomes. The risk of lymph node metastasis was associated with tumor size, non-endometrioid histology, and multifocal LVSI. For MMRd tumors, only tumor size and myometrial invasion depth were predictive of lymph node involvement. In our cohort, MMRd tumors were associated with greater recurrence-free, but not overall, survival. The precise identification of MMRd status, present in a substantial proportion of endometrial cancer cases, is a challenge to be overcome for proper patient management. MMRd status serves as a marker for Lynch syndrome, and a significant number of these tumors are high risk and candidate to immunotherapy.

Nectin-4 as a Predictive Marker for Poor Prognosis of Endometrial Cancer with Mismatch Repair Impairment.

The adhesion molecule Nectin-4 is a new potential therapeutic target for different types of cancer; however, little is known about its diagnosis significance in endometrial cancer (EC). We found that Nectin-4 expression was significantly higher in EC tissues than in nonadjacent normal tissue. The area under the receiver operating characteristic curve value of 0.922 indicated good diagnostic accuracy for Nectin-4 expression in EC. Furthermore, Nectin-4 expression was associated with DNA mismatch repair (MMR) protein deficiency. Notably, the high Nectin-4 expression group of patients with MSH2/6-deficient EC had shorter progression-free survival than that of the low Nectin-4 expression group. The number of lymphovascular space invasion-positive patients in groups with MMR deficiency and high Nectin-4 expression was also increased compared with that in the low Nectin-4 expression group. Bioinformatics analysis revealed that alteration in Nectin-4 and MMR genes is associated with Nectin-4 expression in EC. To the best of our knowledge, this is the first study to show that Nectin-4 expression may be a potential biomarker for EC diagnosis and that high Nectin-4 expression in MMR-deficient patients with EC can predict short progression-free survival, thus providing clues to identify patients for adjuvant therapy.

An Expanded Series of Pilomatrix-like High-grade Endometrioid Carcinoma (PiMHEC), Including Both MMR Deficient and MMR Proficient Cases.

An Expanded Series of Pilomatrix-like High-grade Endometrioid Carcinoma (PiMHEC), Including Both MMR Deficient and MMR Proficient Cases.

Locally advanced rectal cancer patients with mismatch repair protein deficiency can obtain better pathological response after regional chemoembolization.

Preoperative transcatheter rectal arterial chemoembolization (TRACE) can enhance the pathological response rate in some patients with locally advanced rectal cancer (LARC). However, how to accurately identify patients who can benefit from this neoadjuvant modality therapy remains to be further studied. Deficient mismatch repair (dMMR) protein plays a crucial role in maintaining genome stability. A proportion of patients with rectal cancer are caused by the loss of mismatch repair (MMR) protein. Given the role of MMR in guiding the efficacy in patients with colorectal carcinoma (CRC), this study is designed to evaluate the effect of dMMR status on the response to neoadjuvant therapy through a retrospective analysis. We launched a retrospective study. First, we selected patients with LARC from the database, and these patients had received preoperative TRACE combined with concurrent chemoradiotherapy. Then, the tumor tissue biopsied by colonoscopy before intervention was taken for immunohistochemistry. According to the expression of MLH-1, MSH-2, MSH-6 and PMS-2, these patients were divided into dMMR protein group and proficient MMR (pMMR) protein group. All patients underwent pathological examination at the end of neoadjuvant therapy, either surgically excised tissue or colonoscopically biopsied tissue. The end point was the pathologic complete response (pCR) after TRACE combined with concurrent chemoradiotherapy. From January 2013 to January 2021, a total of 82 patients with LARC received preoperative TRACE combined with concurrent chemoradiotherapy, and the treatment was well tolerated. Among 82 patients, there were 42 patients in the pMMR group and 40 patients in the dMMR group. 69 patients returned to the hospital for radical resection. In 8 patients, the colonoscopy showed good tumor regression grade after 4 weeks of interventional therapy and refused surgery. The remaining five patients were neither surgically treated nor reexamined by colonoscopy. 77 patients were eventually enrolled in the study. Individually, the pCR rates of these two groups (10%, 4/40 vs. 43%, 16/37) showed significant difference (P < 0.05). Biomarker analysis indicated that patients with dMMR protein had a better propensity for pCR. In patients with LARC, preoperative TRACE combined with concurrent chemoradiotherapy showed good pCR rates, especially in patients with dMMR. Patients with MMR protein defects have a better propensity for pCR.

Universal screening for Lynch syndrome in operated colorectal cancer by immunohistochemistry: a cohort of patients in Liaoning province, China.

Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome worldwide. Due to the decreasing family size in Liaoning province. The Bethesda and Amsterdam II criteria have lower sensitivity and specificity and are not suitable for the local population. Immunohistochemistry screening for mutations in DNA mismatch repair (MMR) in newly diagnosed colorectal cancer can improve the detection rate of LS. All newly diagnosed colorectal cancer patients who underwent surgery between January 2018 and June 2020 at Cancer Hospital of China Medical University and Shengjing Hospital of China Medical University from Liaoning China were included retrospectively, and the ratio of universal LS screening by immunohistochemistry, MMR protein deficiency (dMMR) ratio, MLH1 loss, MSH2 loss, MSH6 loss, and PMS2 loss was analyzed. The clinicopathological characteristics of patients with pMMR and dMMR were analyzed. A total of 7019 colorectal cancer patients underwent surgery and 4802 (68.41%) patients were screened by immunohistochemistry for MMR, 258 (5.37%) cases were reported to have a loss of MMR expression. In the dMMR group, a higher number of patients were under 50 years old, more tumors were located at the right colon, less patients have lymph node metastasis, more tumors were stage II, and histological types of mucinous carcinoma or signet ring carcinoma were more common, compared with the pMMR group. Only 2.71% dMMR patients meet Amsterdam criteria II, 2.71% of patients meet Revised Bethesda guidelines, and 17.83% meet Chinese LS criteria. Twenty-five dMMR patients were confirmed by next-generation sequencing and five families were confirmed as Lynch family. These data imply that universal screening for LS by immunohistochemistry may be effective in Liaoning province.

Impact of DNA mismatch repair proteins deficiency on number and ratio of lymph nodal metastases in colorectal adenocarcinoma.

Approximately 15 % of colorectal adenocarcinomas (CRCs) are characterized by an altered expression of DNA mismatch repair (MMR) proteins (i.e. MMR deficiency [MMRd]). Lymph node ratio (LNR) represents one of the most important prognostic markers in non-advanced CRCs. No significant data are available regarding LNR distribution depending on MMR status. The aim of the present work was to compare pathological and clinical characteristics of MMRd tumors versus MMR proficient (MMRp) cases. Particular attention was paid to how these molecular sub-groups relate to the LNR. A mono-Institutional series of 1037 consecutive surgically treated stage I-IV CRCs were retrospectively selected and data were obtained from pathological reports. Cases were characterized for MMR/MSI status by means of immunohistochemistry or for microsatellite instability (MSI) analysis. MMRd/MSI tumors (n=194; 18.7 %) showed significant differences in comparison to MMRp lesions for sex (female prevalence 50.5 % vs 40.7 %; p=0.013), age (74.2 vs 69.2; p<0.001), location (right side; p<0.001), diameter (larger than MMRp; p<0.001), growth pattern (expansive pattern of growth; p<0.001), peri- (p=0.0002) and intra-neoplastic (p=0.0018) inflammatory infiltrate, presence of perineural invasion (p<0.001), stage (lower stage at presentation; p<0.001), grade (higher prevalence of high-grade tumors; p<0.001), and LNR (lower; p<0.001). MMRd/MSI tumors are a distinct molecular CRC subtype characterized by a significantly lower LNR in comparison to MMRp lesions. These data further support the prognostic impact of MMRd/MSI status in early-stage CRCs.

Utility of molecular subtypes and genetic alterations for evaluating clinical outcomes in 1029 patients with endometrial cancer

BackgroundWe investigated the utility of a molecular classifier tool and genetic alterations for predicting prognosis in Japanese patients with endometrial cancer.MethodsA total of 1029 patients with endometrial cancer from two independent cohorts were classified into four molecular subtype groups. The primary and secondary endpoints were relapse-free survival (RFS) and overall survival (OS), respectively.ResultsAmong the 265 patients who underwent initial surgery, classified according to immunohistochemistry, patients with DNA polymerase epsilon exonuclease domain mutation had an excellent prognosis (RFS and OS), patients with no specific molecular profile (NSMP) and mismatch repair protein deficiency had an intermediate prognosis, and those with protein 53 abnormal expression (p53abn) had the worst prognosis (P < 0.001). In the NSMP group, mutant KRAS and wild-type ARID1A were associated with significantly poorer 5-year RFS (41.2%) than other genomic characteristics (P < 0.001). The distribution of the subtypes differed significantly between patients with recurrence/progression and classified by sequencing (n = 764) and patients who underwent initial surgery (P < 0.001). Among patients with recurrence/progression, 51.4% had the opportunity to receive molecular targeted therapy.ConclusionsA molecular classifier is a useful tool for determining prognosis and eligibility for molecularly targeted therapy in patients with endometrial cancer.