Postmeiotic Segregation Increased 2 Research Articles

The Relationship of Microsatellite Instability with BRAF and p53 Mutations and Histopathological Parameters in Colorectal Adenocarcinoma.

This study aims to elucidate the associations between microsatellite instability (MSI) status, BRAF mutation, and p53 reactions with pathological parameters and survival outcomes in colorectal carcinoma. MutL homologous 1 (MLH1), Postmeiotic segregation increased 2 (PMS2), MutS homologous 2 (MSH2), MutS homologous 6 (MSH6), BRAF, and p53 antibodies were performed on 130 adenocarcinoma samples, including 65 from the right colon and 65 from the left colon. The relationships of MSI status with BRAF mutation, p53 reaction, clinical and pathological parameters, and survival times were statistically analyzed. A statistically significant relationship was found between MSI and right colon localization, tumor size, histological grade, intraepithelial tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, expansive growth pattern, and BRAF mutation (p < 0.05). No significant correlation was found between MSI status and the disease-free or overall survival times (p > 0.05). In colorectal adenocarcinoma, MSI and BRAF mutation are associated with parameters, indicating the host immune response and prognostic histopathological parameters, including tumor size and histological grade. The evaluation of MSI status and BRAF mutation can be particularly informative for predicting the prognosis and guiding the treatment management in poorly differentiated colorectal adenocarcinoma. Understanding the mechanisms of molecular carcinogenesis in colorectal carcinoma and organizing treatment algorithms based on molecular foundations will increase the success of the treatment.

Clinicopathological Implications of Mismatch Repair Status in Endometrioid Endometrial Cancer in Duhok City.

DNA mismatch repair (MMR) is a specialized system that corrects errors in DNA replication, namely, base substitution mismatches and minor insertion-deletion mismatches. The deficient mismatch repair (d-MMR) protein plays a vital role in predicting the prognosis of endometrioid carcinoma. The study aimed to determine the prevalence of MMR errors in endometrial cancer (EC) and their correlation with clinicopathological features. We examined the immunohistochemistry presence of four MMR proteins in 50 samples of EC tissues that were preserved in formalin and embedded in paraffin. The proteins identified were MutL homolog 1 (MLH1), post-meiotic segregation increased 2 (PMS2), MutS homolog 2 (MSH2), and MutS homolog 6 (MSH6). The study examined several clinicopathological characteristics and conducted MMR phenotyping. The findings revealed that among the 50 cases of EC, 40% of patients had grade I disease and 78% had stage I malignancy. Furthermore, among the 50 individuals evaluated, 56% exhibited competence in MMR, whereas 44% displayed loss in nuclear expression of MMR. The rate of MLH1 and PMS2 protein loss was recorded as the greatest, at 18%, while the loss of MSH2 and MSH6 was documented at 6%. Within the same range, the majority of patients with d-MMR were above the age of 50 years. The majority of the recruited EC patients in this study showed advanced age and a high percentage of d-MMR status.

Mismatch Repair Deficient (dMMR) Colorectal Carcinoma in a Pakistani Cohort: Association With Clinical and Pathological Parameters.

Introduction Microsatellite instability (MSI) is an important pathway in colorectal carcinoma (CRC) pathogenesis. MSI occurs due to mutations in mismatch repair (MMR) genes that include MutL protein homolog 1 (MLH1), postmeiotic segregation increased 2 (PMS2), MutS homolog 2 (MSH2), and MutS homolog 6 (MSH6). CRC with MSI is termed MMR deficient (dMMR) CRC. Conversely, CRC with intact MMR genes is called microsatellite stable (MSS) or MMR proficient (pMMR). In this study, we compared the clinicopathological features of dMMR CRC with pMMR CRC. Methods It was a retrospective study conducted in the Department of Histopathology, Liaquat National Hospital, Karachi, Pakistan, from March 2020 to February 2022, over a duration of twoyears. Biopsy-proven cases of CRC with upfront surgical resection were included in the study. Microscopic examination was performed to evaluate tumor type, grade, and extent of invasion, presence of necrosis, perineural invasion (PNI), lymphovascular invasion (LVI), peritumoral lymphocytes (PTL), intratumoral lymphocytes (ITL), and nodal metastasis. Immunohistochemical staining was performed using antibodies, namely, MLH1, PMS2, MSH2, and MSH6. Any loss of nuclear expression in tumor cells was termed dMMR or microsatellite instable, whereas the intact nuclear expression in tumor cells was labeled as MSS or pMMR. Results A total of 135 cases of CRC were included in the study. The mean age at diagnosis was 46.76 ± 17.74 years, with female predominance (60.7%). The loss of MLH1, PMS2, MSH2, and MSH6 expression was noted in 39.3%, 34.1%, 17.8%, and 16.3% cases, respectively. Overall, 59.3% of CRCs were pMMR, while 40.7% were dMMR. A significant association of MMR status was noted with respect to age, PNI, LVI, tumor grade, tumor (T) and nodal (N) stage, mucinous differentiation, and ITL. dMMR CRC was significantly above 50 years than pMMR CRC. The frequency of PNI and LVI was lower in dMMR CRC than in pMMR CRC. Conversely, the higher grade (grade 3) and higher T-stage (T4) were associated with dMMR CRC. Alternatively, the frequency of higher N stage (N2b) was more commonly seen in pMMR CRC. Moreover, mucinous differentiation and ITL were significantly associated with dMMR CRC. Conclusion A significant proportion of CRC patients in our population demonstrated dMMR status. dMMR CRC had a higher histological grade with a higher frequency of mucinous differentiation and higher T-stage. Conversely, the presence of LVI, PNI, and higher N stages were associated with pMMR CRC.

Early-Onset/Young-Onset Colorectal Carcinoma: A Comparative Analysis of Morphological Features and Biomarker Profile.

Introduction Colorectal carcinoma (CRC) is one of the most common cancers that involve the human body. Young-onset CRC (YO-CRC) or early-onset CRC (EO-CRC) is defined as CRC that develops before the age of 50 years, as opposed to CRC that is diagnosed after the age of 50, referred to as late-onset CRC (LO-CRC). EO-CRC is sparsely studied in our population. Therefore, in this study, we evaluated the clinicopathological parameters and biomarker profile of EO-CRC and compared them with those of LO-CRC. Methods This was a retrospective study conducted at the Department of Histopathology, Liaquat National Hospital, Karachi, Pakistan. A total of 254 biopsy-proven cases of CRC, reported over a period of nine years, were enrolled in the study. The specimens collected during surgery were sent to the laboratory for histopathological and immunohistochemical (IHC) status examinations. IHC staining of the specimens was performed using antibodies, namely, MutL protein homolog 1 (MLH1), postmeiotic segregation increased 2 (PMS2), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), and human epidermal growth factor receptor 2 (HER2/neu), on representative tissue blocks. A comparison of morphological and biomarker profiles between EO-CRC and LO-CRC was performed. Results The mean age at diagnosis was 46.27±17.75 years, with female predominance (59.8%). A significant difference between the two groups (EO-CRC and LO-CRC) was noted with respect to laterality, tumor site, tumor grade, tumor type, presence of pre-existing polyps, perineural invasion (PNI), lymphovascular invasion (LVI), and IHC markers. EO-CRC (as opposed to LO-CRC) significantly affected the left colon (92.6% vs. 72.9%, p<0.001), with the rectosigmoid being the most common site in the majority of cases (72.1% in EO-CRC vs. 61% in LO-CRC). EO-CRC showed a higher frequency of PNI and LVI than LO-CRC (42.6% vs. 23.7%, p=0.001; 29.4% vs. 18.6%, p=0.046, respectively). A significantly higher proportion of EO-CRCs were mucinous (42.6%) and medullary carcinoma (11.8%). Although the majority (54.4%) of cases of EO-CRC weregrade 2 tumors at the time of diagnosis, a significantly higher proportion of them were grade 3 (44.1%) compared with LO-CRC. IHC comparisons between the two age groups showed that a significantly higher proportion of cases of EO-CRC showed positive HER2/neu expression (27.1%) compared with LO-CRC (13.2%). Conversely, the loss of expression of microsatellite instability (MSI) markers was more commonly seen in LO-CRS compared with EO-CRC. Conclusions We found a relatively higher frequency of EO-CRC in our population. Moreover, compared with LO-CRCs, EO-CRCs were associated with prognostically poor histological parameters, such as mucinous and medullary carcinoma, high-grade, PNI, and LVI. Similarly, EO-CRC had a higher positive expression of HER2/neu with intact MSI markers compared with AO-CRC; all these characteristics indicate poor biological behavior in EO-CRC.

Spontaneous regression of advanced transverse colon cancer with deficient mismatch repair: a case report

BackgroundSpontaneous regression (SR) of cancer occurs in 1 in 60,000–100,000 patients. This phenomenon has been reported in almost all cancer types, most commonly neuroblastoma, renal cell carcinoma, malignant melanoma, and lymphoma/leukemia. However, SR in colorectal cancer (CRC) is extremely rare, particularly in advanced cases. Hence, this report describes a very rare case of spontaneous regression of advanced transverse colon cancer.Case presentationA 76-year-old female with anemia was diagnosed with a type II well-differentiated adenocarcinoma in the middle transverse colon. Two months later, a second colonoscopy examination was performed for preoperative marking, and it revealed tumor shrinkage and a shift to type 0–IIc morphology. Endoscopic tattooing was then performed, followed by a laparoscopic partial resection of the transverse colon with D3 lymph node dissection. However, the resected specimen contained no tumor, and colonoscopy showed no tumor remnants in the remaining colon. Histopathological examination revealed mucosal regeneration and a mucus nodule in between the submucosal and muscular layers, with no cancer cells detected. Immunohistochemical analysis revealed the loss of MutL homolog 1 (MLH1) and postmeiotic segregation increased 2 (PMS2) expression in the cancer cells of biopsied specimens, suggesting deficient mismatch repair (dMMR). The patient continues to be followed up until 6 years postoperatively, and no recurrence has been observed. In this study, we also reviewed similar reported cases of spontaneous regression of cancer involving dMMR.ConclusionThis study presents a rare case of spontaneous regression of advanced transverse colon cancer wherein dMMR is strongly involved. However, further accumulation of similar cases is needed to elucidate this phenomenon and to develop new treatment strategies for CRC.

MMR markers correlate with clinical outcome in patients with esophageal squamous cell carcinoma.

The DNA mismatch repair system is one of the defense mechanisms in the body, and the inactivation of mismatch repair plays a pivotal role in secondary carcinogenesis and progression. However, the significance of mismatch repair in esophageal squamous cell carcinoma (ESCC) has not been established. In this study, we explored the diagnostic and prognostic significance of mismatch repair markers, mutL homologue 1 (MLH1), post-meiotic segregation increased 2 (PMS2), mutS homologue 2 (MSH2), and mutS homologue 6 (MSH6), in patients with ESCC. We used a notation based on the proportion of immunoreactivity/expression for immunohistochemistry (PRIME notation), which allows the comparison of mismatch repair expression by assigning a score to PRIME notation. MLH1, PMS2, MSH2, and MSH6 were examined immunohistochemically in 189 surgically resected ESCC specimens. A total of 100/189 patients with ESCC (53%) received preoperative chemotherapy. The rates of ESCC cases with decreased mismatch repair status were 13.2%, 15.3%, 24.8%, and 12.6% for MLH1, PMS2, MSH2, and MSH6, respectively. The decreased status of individual mismatch repair markers was significantly correlated with worse prognosis in patients with ESCC. Additionally, MSH2, MSH6, and PMS2 were significantly associated with response to preoperative chemotherapy. Multivariate analysis revealed that MLH1, PMS2, and MSH2 are independent prognostic factors. Our results suggest that mismatch repair is a prognostic biomarker for ESCC and could contribute to the selection of appropriate adjuvant therapy for patients with ESCC.

PMS2 Pathogenic Variant in Lynch Syndrome-Associated Colorectal Cancer with Polyps.

Background Lynch syndrome (LS) is an autosomal dominant condition due to the germline mutation in the mismatch repair (MMR) genes including MLH1 , MSH2 , MSH6, and PMS2 (post-meiotic segregation increased 2). The MMR mutation carriers have high risk for cancers. Pathogenic PMS2 variants are rarely reported in LS-associated colorectal cancer (CRC) with colorectal polyps. The aim of the study was to investigate the genetic etiology of CRC in an individual with CRC with multiple colorectal polyps and a family history of cancers. Patients and Methods The index patient was an African male affected by CRC with multiple colorectal polyps. The clinical diagnostic for LS was based on the Amsterdam II criteria and pedigree. Next-generation sequencing with inherited cancer genes panel was used to detect the pathogenic variant. Results The patient fulfilled the Amsterdam II criteria and the pedigree revealed a family history of recurrent CRC. A deleterious PMS2 germline heterozygous mutation c.2192_2196delTAACT was detected. Conclusion Our study supports the notion that LS may be associated with polyps and shows the predisposition of PMS2 heterozygous mutation in LS-associated CRC at young age.

Expression of PD-L1 in Microsatellite Instability High Tumours: A Retrospective Study

Introduction: Microsatellite Instability (MSI) is the hallmark of Lynch syndrome/Constitutional Mismatch Repair Deficiency (CMMRD) and is also found in many sporadic cancers like colorectal cancer, endometrial, gastric, small intestine, urothelial, central nervous system and sebaceous gland neoplasms. MSI is a predictive biomarker for immunotherapy and Immunohistochemistry (IHC) antibodies against four Mismatch Repair (MMR) proteins: MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6) and Postmeiotic Segregation increased 2 (PMS2) can identify the MSI status of the tumour. In addition to MSI, immune checkpoint programmed cell death protein 1 (PD-1) expression and its ligand PD-L1 are biomarkers that can predict response to immunotherapy. Considering this increasing interest to identify deficient MMR (dMMR) status in different cancers, authors have assessed the expression of PDL1 and status of MSI in various cancer types. Aim: To evaluate the expression of PD-L1 in MSI-high status tumours. Materials and Methods: This retrospective cross-sectional study was done in the Department of Pathology, Panimalar Medical College Hospital and Research Institute for a period of six months from July 2022 to December 2022. A total of 151 cases were identified for the period of three years from January 2020 to December 2022. The slides and blocks were retrieved from the archives. Tumour sections from the paraffin embedded tissues were deparaffinised and antigen retrieval was done. IHC using four antibodies (MLH1, MH2, MSH6 and PMS2) was performed on these slides to assess the MSI status. The slides were reviewed and were further subjected to PD-L1 IHC. PD-L1 expression on tumour cells was compared with the MSI status of different cancer types. The p-value was calculated using t-test and p&lt;0.5 was considered statistically significant. Statistical analysis was done using International Business Machines (IBM) Statistical Package for the Social Sciences (SPSS) software version 21.0. Results: A total of 151 cases were included in the present study. A positive nuclear stain for the four MMR proteins denote expression of wild type MMR proteins, hence MSI low status. A loss of nuclear expression denotes mutation of MMR proteins and hence MSI high (MSI-H) status. The MSI was high in nine out of 48 cases (18.75%) of colon cancer, three out of 15 cases (20%) of endometrial cancers, three out of 20 cases (15%) of gastric cancers. Rest were one out of sixteen cases of ovarian cancer, one out of two malignant melanoma and one out of three glioblastoma. Out of these, PD-L1 was positive in seven of the 18 MSI-H cases (38.88% of MSI-H cases). The MSI was low/ stable in the remaining 133 cases. The p-value of significance was 0.03 (statistically significant). Conclusion: This study shows a significant association of MSI-H with PD-L1 expression in tumours. Further large scale studies can help in assessing the role of PD-L1 as an effective therapeutic biomarker in MSI-high status patients who can benefit from targeted therapy

Recurrent posterior fossa group A (PFA) ependymoma in a young child with constitutional mismatch repair deficiency (CMMRD).

Recurrent posterior fossa group A (PFA) ependymoma in a young child with constitutional mismatch repair deficiency (CMMRD).

A Review of MutSα and its Absence in Mismatch Repair Related Ovarian Carcinomas

This review investigates the roles of microsatellite instability (MSI) and the DNA mismatch repair (MMR) pathway in ovarian carcinomas. MMR promotes genome stability post‐replication by repairing DNA mismatches; defective MMR (dMMR) leaves genomic errors that can cause MSI. To repair these mismatches, the MMR system employs two sets of proteins that form heterodimers: MutL Homolog 1 (MLH1) in complex with post meiotic segregation increased 2 (PMS2) and MutS Homolog 2 (MSH2) in complex with MutS Homolog 6 (MSH6). The MSH2/MSH6 heterodimer (MutSα) recognizes the mismatch, while the MLH1/PMS2 heterodimer (MutLα) repairs the mismatch. The MSH2/MSH6 proteins are each composed of 5 asymmetrical structural domains, the first being responsible for mismatch binding, followed by the connector, lever, clamp, and ATPase domains, or domains I‐V, respectively. The MSH2 mismatch binding domain associates directly with DNA and extends a helix to block the polymerase, while MSH6 associates with DNA via its Phe‐X‐Glu motif. The MutSα complex has two states: an ADP‐bound state in which it searches for mismatches, and an ATP‐bound state in which it signals for repair. Lack of effective repair can contribute to carcinogenesis including ovarian carcinogenesis. Mismatches in microsatellites are phenotypic evidence that the MMR pathway is non‐functional in these tumors, and differences in MMR status are observed across ovarian carcinoma subtypes. For example MSH6 deficiency is associated with three subtypes of ovarian cancer: clear cell, mucinous, and endometrioid carcinomas, and there is a higher survival rate for patients with these MSH6 deficient tumors. Tumor MMR status also influences treatment efficacy and age of disease onset. Interestingly, only in familial carcinomas was MSI demonstrated as a supportive diagnostic tool. Tumors with high MSI can be treated with immunotherapy and immune checkpoint inhibitors; therefore investigating the MMR pathway functionality and MSI status of ovarian carcinomas can shape the course of treatment and patient outcomes.

Early Initiation of Temozolomide Therapy May Improve Response in Aggressive Pituitary Adenomas.

IntroductionAggressive pituitary adenomas (APAs) are, by definition, resistant to optimal multimodality therapy. The challenge lies in their early recognition and timely management. Temozolomide is increasingly being used in patients with APAs, but evidence supporting a favorable response with early initiation is lacking.MethodsThis was a single-center study of all patients with APAs who received at least 3 cycles of temozolomide (150–200 mg/m2). Their baseline clinico-biochemical and radiological profiles were recorded. Immunohistochemical evaluation for cell-cycle markers O6-methylguanine-DNA methyltransferase (MGMT), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), MutL homolog 1 (MLH1), and postmeiotic segregation increased 2 (PMS2) was performed, and h-scores (product of the number of positive cells and staining intensity) were calculated. Response was assessed in terms of radiological response using the RECIST criteria. Patients with controlled disease (≥30% reduction in tumor volume) were classified as responders.ResultsThe study comprised 35 patients (48.6% acromegaly, 37.1% prolactinomas, and 14.3% non-functioning pituitary adenomas). The median number of temozolomide (TMZ) cycles was 9 (IQR 6–14). Responders constituted 68.6% of the cohort and were more likely to have functional tumors, a lower percentage of MGMT-positive staining cells, and lower MGMT h-scores. There was a significantly longer lag period in the initiation of TMZ therapy in non-responders as compared with responders (median 36 vs. 15 months, p = 0.01). ROC-derived cutoffs of 31 months for the duration between diagnosis and TMZ initiation, low-to-intermediate MGMT positivity (40% tumor cells), and MGMT h-score of 80 all had a sensitivity exceeding 80% and a specificity exceeding 70% to predict response.ConclusionEarly initiation of TMZ therapy, functional tumors, and low MGMT h-score predict a favorable response to TMZ in APAs.

Assessment of mismatch repair deficiency, CDX2, beta-catenin and E-cadherin expression in colon cancer: molecular characteristics and impact on prognosis and survival - an immunohistochemical study.

Microsatellite instability (MSI) or the deficiency of mismatch repair (MMR) proteins is one of the molecular pathways of colorectal tumorigenesis and may have important clinical implications in predicting the treatment response. We evaluated the relationship between clinicopathological features and MMR proteins [mutL homologue 1 (MLH1), mutS homologue 2 (MSH2), mutS homologue 6 (MSH6), postmeiotic segregation increased 2 (PMS2)], adhesion molecules (E-cadherin, beta-catenin) and caudal-type homeobox 2 (CDX2) in 31 patients with colon adenocarcinoma, using immunohistochemistry. We also aimed to assess the prognostic value of the studied proteins. MLH1 loss was correlated to PMS2 loss (p=0.006) and MSH2 loss (p=0.023); MSH2 loss was significantly associated to MSH6 loss (p=0.011). Tumors with MSH6 loss, together with tumors with PMS2 loss, covered all the patients with MSI status. We found a significant correlation between MSI tumors and mucinous histological type (p=0.03), but no significant associations with other clinicopathological features or with survival rate. There was a significant correlation between E-cadherin expression and differentiation degree (p=0.018) and between beta-catenin expression and lymph node invasion (p=0.046). No significant association between CDX2 loss and any clinical or pathological features was found (p>0.05). No significant differences were identified in overall survival according to E-cadherin, beta-catenin or CDX2 expression (p>0.05). In our study, PMS2 loss was significantly correlated with CDX2 loss (p=0.03). In conclusion, the molecular analysis of biological markers for colon cancer may be important for patient stratification, in order to select the optimal treatment algorithm. Our results suggest that probably the double panel (MSH6 and PMS2) is enough to detect the MSI status, instead of using the quadruple panel.

A Lynch syndrome-associated mutation at a Bergerat ATP-binding fold destabilizes the structure of the DNA mismatch repair endonuclease MutL

In humans, mutations in genes encoding homologs of the DNA mismatch repair endonuclease MutL cause a hereditary cancer that is known as Lynch syndrome. Here, we determined the crystal structures of the N-terminal domain (NTD) of MutL from the thermophilic eubacterium Aquifex aeolicus (aqMutL) complexed with ATP analogs at 1.69-1.73 Å. The structures revealed significant structural similarities to those of a human MutL homolog, postmeiotic segregation increased 2 (PMS2). We introduced five Lynch syndrome-associated mutations clinically found in human PMS2 into the aqMutL NTD and investigated the protein stability, ATPase activity, and DNA-binding ability of these protein variants. Among the mutations studied, the most unexpected results were obtained for the residue Ser34. Ser34 (Ser46 in PMS2) is located at a previously identified Bergerat ATP-binding fold. We found that the S34I aqMutL NTD retains ATPase and DNA-binding activities. Interestingly, CD spectrometry and trypsin-limited proteolysis indicated the disruption of a secondary structure element of the S34I NTD, destabilizing the overall structure of the aqMutL NTD. In agreement with this, the recombinant human PMS2 S46I NTD was easily digested in the host Escherichia coli cells. Moreover, other mutations resulted in reduced DNA-binding or ATPase activity. In summary, using the thermostable aqMutL protein as a model molecule, we have experimentally determined the effects of the mutations on MutL endonuclease; we discuss the pathological effects of the corresponding mutations in human PMS2.

Evaluation of Concordance Between Deficient Mismatch Repair and Microsatellite Instability Testing and Their Association with Clinicopathological Features in Colorectal Cancer.

BackgroundMicrosatellite instability (MSI) is one of the most important molecular characteristics of colorectal cancer (CRC), which mainly results from defective DNA mismatch repair (MMR). This study was performed to investigate the concordance between deficient MMR and MSI testing, and to evaluate the association of these two results with clinicopathological characteristics in Chinese CRC patients.MethodsA total of 738 CRC patients were included. Tumor tissues and paired peripheral blood specimens were obtained. Screening for MMR was investigated using immunohistochemical (IHC) technique, and multiple polymerase chain reaction-capillary electrophoresis (PCR-CE) method was performed to detect the MSI status. All clinicopathological data, immunohistochemistry and microsatellite instability analyses were then statistically analyzed.ResultsOf the 738 (17.75%) CRC patients, 131 expressed as deficient mismatch repair (dMMR) status, and postmeiotic segregation increased 2 (PMS2) deficiency was the most frequent deficiency among these four MMR proteins. MSI-high (MSI-H) status occurred in 74 of the 738 (10.03%) CRC patients, 55 of whom showed instability at all six mononucleotides repeat markers. dMMR was significantly associated with MSI-H and moderate concordance was observed between IHC and PCR-CE in evaluating deficient MMR/MSI through Kappa test. Statistically, dMMR was significantly associated with younger age, right-sided colon and poor differentiation. MSI-H was associated with younger age, right-sided colon, poor differentiation, mucinous type and tumor, node, metastasis (TNM) stage II.ConclusionA moderate concordance between deficient MMR and MSI testing indicates that both IHC and PCR-CE methods should be routinely tested to provide reliable data for clinical treatment decisions.

Microsatellite instability in metaplasia-dysplasia-adenocarcinoma sequence of Barrett esophagus: a retrospective study.

AimTo analyze the loss of mismatch repair (MMR) system protein expression in metaplasia-dysplasia-adenocarcinoma sequence of Barrett esophagus (BE).MethodsThis study retrospectively analyzed the data from 70 patients with pathohistological diagnosis of BE or esophageal adenocarcinoma (EAC) treated at the Clinical Department of Pathology and Cytology, University Hospital Center Zagreb, from January 2009 to January 2011. Patients were divided into three groups: BE without dysplasia (22 patients), BE with dysplasia (37 patients), and EAC (11 patients). Immunohistochemical expression of MutL homologue 1 (MLH1), MutS homologue 2 (MSH2), postmeiotic segregation increased 2 (PMS2), and MutS homologue 6 (MSH6) of DNA MMR system was measured and compared with tumor protein p53 expression.ResultsA total of 81.8% and 81.8% patients with EAC, 32.4% and 35.1% patients with dysplasia, and 50% and 54.5% patients without dysplasia had loss of MLH1 and PMS2 expression, respectively. Patients with EAC and patients with dysplasia did not have loss of MSH2 and MSH6 expression, and 18.2% patients without dysplasia had loss of MSH2 and MSH6 expression. There was a strong positive correlation between MLH1 and PMS2 expression (Spearman ρ 0.97; P < 0.001) and between MSH2 and MSH6 expression (Spearman ρ 0.90, P < 0.001) in the entire sample and in all BE groups. No significant correlations of MLH1 and PMS2 with p53 expression were found, except in dysplasia group (φ 0.402, P = 0.030 for MSH1; φ 0.371, P = 0.042 for PMS2).ConclusionAlthough we demonstrated considerable loss of MLH1 and PMS2 expression in BE-associated carcinoma sequence, due to the retrospective study design and low number of patients we cannot conclude that MLH1 and PMS2 can be used as biomarkers for patient surveillance and therapy-making decisions.Oxford Centre for Evidence-based Medicine level of evidence: 3

Genetic testing for hereditary prostate cancer: Current status and limitations.

A significant proportion of prostate cancer diagnoses may be associated with a strong hereditary component. Men who have multiple single-gene polymorphisms and a family history of prostate cancer have a significantly greater risk of developing prostate cancer. Numerous single-gene alterations have been confirmed to increase the risk of prostate cancer. These include breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively), mutL homolog 1 (MLH1), mutS homologs 2 and 6 (MSH2 and MSH6, respectively), postmeiotic segregation increased 2 (PMS2), homeobox B13 (HOXB13), checkpoint kinase 2 (CHEK2), nibrin (NBN), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and ataxia telangiectasia mutated (ATM). Currently, there are no uniform guidelines on the definition of hereditary prostate cancer and genetic testing. With the advent of next-generation sequencing, which is capable of testing multiple genes simultaneously, and the approval of olaparib for BRCA1/BRCA2 or ATM-mutated, metastatic, castrate-resistant prostate cancer, it is being recognized that the results of genetic testing have an impact on therapeutic strategies. In this review, the authors examine the role of genetic counseling and testing, the challenges of insurance coverage for testing, the available germline and somatic testing panels, and the complexity of each testing method and its implications. Cancer 2018. © 2018 American Cancer Society.

Clinical Impact of Mismatch Repair Protein Testing on Outcome of Early Staged Colorectal Carcinomas.

Colorectal cancer is the third most common cancer in men and second most common in women globally. In the present study, we aimed to analyse the proportion of patients with loss of immunostaining for mismatch repair (MMR) proteins in all newly diagnosed stage II cases of colorectal cancer for the purpose of prognostication, for determination of further chemotherapeutic strategy and for familial screening. From January 2014 to December 2015, 62 consecutive newly diagnosed cases of stage II colorectal cancer were included in the study. Details of each patient related to their demographic profile and tumour profile were recorded. All the cases were grossed and staged according to College of American Pathologist (CAP) guidelines. The expression of MMR proteins (which was earlier validated on normal as well as tumour tissue) in FFPE tumour tissue using IHC for mut L homologue 1 (MLH1), mut S homologue 2 (MSH2), mut S homologue 6 (MSH6) and post-meiotic segregation increased 2 (PMS2) was studied. Information regarding stage, treatment, clinical outcome and overall survival was retrieved when available. Out of a total of 371 cases, 62 (16.7%) cases were of stage II CRC, out of which 43 (12%) were treatment naive. Among the selected 62 cases, 26 (41.9%) demonstrated loss of MMR proteins and 36 (58.0%) cases had intact nuclear expression. Out of the cases with MMR loss, 38.4% showed loss of MLH1 and PMS2, 30.7% showed loss of MSH2 and MSH6, 26.9% showed isolated loss of PMS2 and 3.8% showed isolated loss of MSH6. Right-sided location (57.6%) was more common than left-sided (19.2%) and transverse colon (23.0%). Majority of the cases were moderately differentiated (65.3%) in morphology. There was no intratumoural infiltrate in most of the cases (53.8%), and only 3.8% cases showed marked intratumoural infiltrate. Also, peritumoural lymphocytic infiltrate was mild to moderate in most of the cases (26.9%) and marked Crohn's-like infiltrate was seen in only 7.6% cases. Our study shows that the routine evaluation of MMR proteins is achievable and essential for the purpose of prognostication, planning of treatment strategies and ascertaining a hereditary basis of CRC. The incidence of MMR protein loss was quite high in our study compared to other studies probably due to a difference in ethnicity. Though a right-sided predominance was supported, none of the typical morphological features of microsatellite instability (MSI) tumours were substantiated by our study, highlighting the lack of importance of histology for predicting MSI, and emphasising the point that MSI testing should be done as a routine procedure in all stage II CRC. A short follow-up was done for all our cases and comparison between the survival of the chemotherapy treated MSI cases versus those which were treatment naïve was performed and revealed that chemotherapy (CT) did not provide additional benefit to survival; MSI tumours in general are a better prognostic category and do not require additional chemotherapy.

Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy

Despite a multiplicity of clinical trials testing immune checkpoint inhibitors, the frequency of expression of potential predictive biomarkers is unknown in glioma. In this study, we profiled the frequency of shared biomarker phenotypes. To clarify the relationships among tumor mutational load (TML), mismatch repair (MMR), and immune checkpoint expression, we profiled patients with glioma (n = 327), including glioblastoma (GBM) (n = 198), whose samples had been submitted for analysis from 2009 to 2016. The calculation algorithm for TML included nonsynonymous mutation counts per tumor, with germline mutations filtered out. Immunohistochemical analysis and next-generation sequencing were used to determine tumor-infiltrating lymphocyte expression positive for programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1) expression on tumor cells, MMR (MLH1, MSH2, MSH6, and PMS2) protein expression and mutations, and DNA polymerase epsilon (POLE) mutations. High TML was only found in 3.5% of GBM patients (7 of 198) and was associated with the absence of protein expression of mutL homolog 1 (MLH1) (P = .0345), mutS homolog 2 (MSH2) (P = .0099), MSH6 (P = .0022), and postmeiotic segregation increased 2 (PMS2) (P = .0345) and the presence of DNA MMR mutations. High and moderate TML GBMs did not have an enriched influx of CD8+ T cells, PD-1+ T cells, or tumor-expressed PD-L1. IDH1 mutant gliomas were not enriched for high TML, PD-1+ T cells, or PD-L1 expression. To clarify the relationships among TML, MMR, and immune checkpoint expression, we profiled the frequency of shared biomarker phenotypes. On the basis of a variety of potential biomarkers of response to immune checkpoints, only small subsets of glioma patients are likely to benefit from monotherapy immune checkpoint inhibition.

Mismatch Repair Protein Expression in Fordyce Granules.

Fordyce spots are a frequent condition under which sebaceous glands are found in the oral mucosa. There are 2 studies in the literature that have found an association between Fordyce spots and either Muir-Torre syndrome or Lynch syndrome. Despite this, no study on the expression of mismatch repair (MMR) proteins has been performed on biopsies of Fordyce granules. In this study, we intend to study the expression of MMR proteins under Fordyce condition. We investigated 9 cases of Fordyce spots of the oral mucosa from 6 men and 3 women, using immunohistochemistry with antibodies for the MutS protein homolog 6 (MSH6), MutS protein homolog 2 (MSH2), MutL protein homolog 1 (MLH1), and postmeiotic segregation increased 2 (PMS2). All cases showed the preservation of the expression of all markers. Even though a strong association has been demonstrated between Lynch syndrome and Fordyce spots, our study suggests that studying the biopsies of Fordyce condition by immunohistochemistry for MMR proteins might not be necessary.

PMS2 expression in epithelial ovarian cancer is posttranslationally regulated by Akt and essential for platinum-induced apoptosis.

Epithelial ovarian cancer (EOC) is the most lethal of the gynecologic malignancies, mainly due to the advanced stage at diagnosis and development of cisplatin resistance. The sensitivity of tumor cells to cisplatin is frequently affected by defect in DNA mismatch repair (MMR), which repairs mispaired DNA sequences and regulates DNA-damage-induced apoptosis. However, the role of postmeiotic segregation increased 2 (PMS2), a member of MMR protein family, in cisplatin resistance remains elusive. In the present study, we demonstrated the frequent deficiency of PMS2 and phosphorylation of Akt in EOC cell lines and tissues. Results of complex immunoprecipitation (co-IP) and protein stability assay indicated that activated Akt could directly bind to PMS2 and cause degradation of PMS2 in EOC cells. In addition, functional experiments revealed that PMS2 was required for cisplatin-induced apoptosis and cell cycle arrest in G2/M phase. These findings provide a novel insight into molecular mechanisms linking MMR with chemoresistance and suggest that stabilization of PMS2 expression may be useful in overcoming the cisplatin resistance in EOC.