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Aims: Loss of expression of tumour suppressor PAX2 and MMR deficiency (dMMR) has been frequently seen in endometrial endometrioid adenocarcinoma (EEC). However, the relationship between PAX2 expression and MMR status is unknown. Methods and Results: We studied the PAX2 expression and examined its association with MMR status at the protein and genetic levels in 180 cases of EEC. Overall, total loss of PAX2 expression was found in about 70%, while retained PAX2 expression was seen in 30% of EEC. Among 125 cases with loss of PAX2, 68.8% were found in EECs with pMMR, while 31.2% were seen in those with dMMR. Among 55 cases of EECs with retained PAX2 expression, 92.7% were EECs with dMMR and 7.3% were those with pMMR (P < 0.001). While dMMR cases with MLH1 hypermethylation show almost equal retained or loss of PAX2 expression (52% versus 48%), dMMR with genetic alterations had significantly more retained PAX2 expression than loss of PAX2 (92.3% versus 7.7%), regardless of somatic or germline mutations. Loss of PAX2 was observed in 97.3% of dMMR with MLH1 hypermethylation compared to 2.7% of dMMR with genetic alterations (P < 0.001). Aggressive features such as higher tumour grades (FIGO 2–3) and advanced clinical stage (T2–T4) were significantly more frequently seen in dMMR with retained PAX2 expression, compared those to pMMR with loss of PAX2 expression. Conclusion: Our study demonstrates a close correlation between retained PAX2 expression and dMMR in EEC. The molecular mechanism and clinical significance linking these two pathways in EEC remains to be unravelled. [ABSTRACT FROM AUTHOR]

Identifying individuals who have Lynch syndrome involves a complex diagnostic workup that includes taking a detailed family history and a combination of various tests such as immunohistochemistry and/or molecular which may be germline and/or somatic. The National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer have come together to publish this practice resource for the evaluation of Lynch syndrome. The purpose of this practice resource was to provide guidance and a testing algorithm for Lynch syndrome as well as recommendations on when to offer testing. This practice resource does not replace a consultation with a genetics professional. This practice resource includes explanations in support of this and a summary of background data. While this practice resource is not intended to serve as a review of Lynch syndrome, it includes a discussion of background information and cites a number of key publications which should be reviewed for a more in‐depth understanding. This practice resource is intended for genetic counselors, geneticists, gastroenterologists, surgeons, medical oncologists, obstetricians and gynecologists, nurses, and other healthcare providers who evaluate patients for Lynch syndrome. [ABSTRACT FROM AUTHOR]

Background: Mismatch repair (MMR) system has been implicated in the response of mammalian cells to ionizing radiation and DNA damaging agents. We investigated the value of the MMR system in predicting response to adjuvant therapy in endometrial cancer. Methods: This was a single institution retrospective study. MMR protein status of endometrial carcinomas was assessed by immunohistochemistry. MMR deficient (MMR‐D) tumors were identified as MLH1 methylated or nonmethylated by methylation‐specific multiplex ligation‐dependent probe amplification. Tumors with abnormal p53 staining or polymerase ϵ exonuclease domain mutation were excluded from the MMR proficient subgroup, which was termed as "no specific molecular profile" (NSMP). Disease‐specific survival analyses were adjusted for age, stage, histology and grade, depth of myometrial invasion, and lymphovascular space invasion. Results: A total of 505 patients were included in the study. Median follow‐up time was 81 months (range 1–136). Whole pelvic radiotherapy (adjusted hazard ratio [HR] 0.092 vs. no adjuvant therapy) and chemotherapy combined with radiotherapy (adjusted HR 0.18) were associated with improved disease‐specific survival in the NSMP subgroup (n = 218). In contrast, adjuvant therapies showed no effect on disease‐specific survival in the full MMR‐D cohort (n = 287) or in MLH1 methylated tumors (n = 154). Whole pelvic radiotherapy (adjusted HR 25 vs. no adjuvant therapy/vaginal brachytherapy) and chemotherapy combined with whole pelvic radiotherapy (adjusted HR 32) were associated with poor disease‐specific survival in MMR‐D nonmethylated tumors (n = 70). Conclusion: MMR protein and MLH1 methylation status predict the response to adjuvant therapy in endometrial cancer. The MMR system could be utilized for selection of patients who most likely benefit from adjuvant therapy. [ABSTRACT FROM AUTHOR]

Keywords: BRAF; colorectal carcinoma; Lynch syndrome; MLH1 methylation; NTRK EN BRAF colorectal carcinoma Lynch syndrome MLH1 methylation NTRK 335 336 2 07/11/23 20230801 NES 230801 Ethics statement For this study, approval and/or informed consent were not required. BRAF, colorectal carcinoma, Lynch syndrome, MLH1 methylation, NTRK Lynch syndrome-related colorectal carcinomas are NTRK-negative. [Extracted from the article]

Abstract: Background and Aim: Individuals with Lynch syndrome (LS) are at increased risk of LS‐related cancers including colorectal cancer (CRC). CRC tumor screening for mismatch repair (MMR) deficiency is recommended in Australia to identify LS, although its cost‐effectiveness has not been assessed. We aim to determine the cost‐effectiveness of screening individuals with CRC for LS at different age‐at‐diagnosis thresholds. Methods: We developed a decision analysis model to estimate yield and costs of LS screening. Age‐specific probabilities of LS diagnosis were based on Australian data. Two CRC tumor screening pathways were assessed (MMR immunohistochemistry followed by MLH1 methylation (MLH1‐Pathway) or BRAF V600E testing (BRAF‐Pathway) if MLH1 expression was lost) for four age‐at‐diagnosis thresholds—screening < 50, screening < 60, screening < 70, and universal screening. Results: Per 1000 CRC cases, screening < 50 identified 5.2 LS cases and cost $A7041 per case detected in the MLH1‐Pathway. Screening < 60 increased detection by 1.5 cases for an incremental cost of $A25 177 per additional case detected. Screening < 70 detected 1.6 additional cases at an incremental cost of $A40 278 per additional case detected. Compared with screening < 70, universal screening detected no additional LS cases but cost $A158 724 extra. The BRAF‐Pathway identified the same number of LS cases for higher costs. Conclusions: The MLH1‐Pathway is more cost‐effective than BRAF‐Pathway for all age‐at‐diagnosis thresholds. MMR immunohistochemistry tumor screening in individuals diagnosed with CRC aged < 70 years resulted in higher LS case detection at a reasonable cost. Further research into the yield of LS screening in CRC patients ≥ 70 years is needed to determine if universal screening is justified. [ABSTRACT FROM AUTHOR]

Background and Aim Tumor testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population-based CRC utilizing a combination of tumor and germline testing approaches. Methods Colorectal cancers from 813 patients diagnosed with CRC < 60 years of age from the Australasian Colorectal Cancer Family Registry (ACCFR) and from 826 patients from the Melbourne Collaborative Cohort Study (MCCS) were tested for MMR protein expression using immunohistochemistry, microsatellite instability (MSI), BRAFV600E somatic mutation, and for MLH1 methylation. MMR gene mutation testing (Sanger sequencing and Multiplex Ligation Dependent Probe Amplification) was performed on germline DNA of patients with MMR-deficient tumors and a subset of MMR-proficient CRCs. Results Of the 813 ACCFR probands, 90 probands demonstrated tumor MMR deficiency (11.1%), and 42 had a MMR gene germline mutation (5.2%). For the MCCS, MMR deficiency was identified in the tumors of 103 probands (12.5%) and seven had a germline mutation (0.8%). All the mutation carriers were diagnosed prior to 70 years of age. Probands with a MMR-deficient CRC without MLH1 methylation and a gene mutation were considered Lynch-like and comprised 41.1% and 25.2% of the MMR-deficient CRCs for the ACCFR and MCCS, respectively. Conclusions Identification of MMR gene mutation carriers in Australian CRC-affected patients is optimized by immunohistochemistry screening of CRC diagnosed before 70 years of age. A significant proportion of MMR-deficient CRCs will have unknown etiology (Lynch-like) proving problematic for clinical management. [ABSTRACT FROM AUTHOR]

Objective Deficiency of DNA mismatch repair (MMR) causes microsatellite instability (MSI) in a subset of colorectal cancers. Patients with these tumours have a better prognosis and may have an altered response to chemotherapy. Some of the tumours are caused by hereditary mutations (hereditary nonpolyposis colon cancer or Lynch syndrome), but most are epigenetic changes of sporadic origin. The aim of this study was to define a robust and inexpensive strategy for such classification in clinical practice. Method Tumours and blood samples from 262 successive patients with colorectal adenocarcinomas were collected. Expression of the MMR proteins MLH1, MSH2, and MSH6 by immunohistochemistry (IHC) was compared with MSI DNA analysis. Methylation analysis of MLH1 and mutation analysis for BRAF V600E were compared in samples with MSI and/or lack of MLH1 expression to determine if the tumour was likely to be sporadic. Results Thirty-nine (14.9%) of the tumours showed MMR deficiency by IHC or by microsatellite analysis. Sporadic inactivation by methylation of MLH1 promoter was found in 35 patients whereby the BRAF activating V600E mutation, indicating sporadic origin, was found in 32 tumours. On the basis of molecular characteristics we found 223 patients with intact MMR, 35 patients with sporadic MMR deficiency, and four patients who were likely to have hereditary MMR deficiency. Conclusion To obtain the maximal benefit for patients and clinicians, MMR testing should be supplemented with MLH1 methylation or BRAF mutation analysis to distinguish sporadic patients from likely hereditary ones. MMR deficient patients with sporadic disease can be reassured of the better prognosis and the likely hereditary cases should receive genetic counselling. [ABSTRACT FROM AUTHOR]