Mismatch repair deficiency screening in colorectal carcinoma by a four-antibody immunohistochemical panel in Pakistani population and its correlation with histopathological parameters

Hashmi, Atif Ali; Ali, Rabia; Hussain, Zubaida Fida; Faridi, Naveen; Khan, Erum Yousuf; Bakar, Syed Muhammad Abu; Edhi, Muhammad Muzzammil; Khan, Mehmood

doi:10.1186/s12957-017-1158-8

Cited by 30 publications

(35 citation statements)

References 26 publications

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“…Although the gold standard for detecting MSI is genetic testing by PCR, the College of American Pathologists (CAP) recommends an initial IHC workup to detect the presence or absence of MMR proteins (MLH1, MSH2, MSH6, and PMS2) 19. Loss of expression of the MMR proteins in IHC is generally associated with mutation (or methylation) of the corresponding genes, which cannot be determined with MSI testing.…”

Section: Discussionmentioning

confidence: 99%

<p>Mismatch repair status and high expression of PD-L1 in nasopharyngeal carcinoma</p>

Zhao¹,

Liao²,

Guan³

et al. 2019

CMAR

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Purpose To analyze the mismatch repair (MMR) status and PD-L1 expression in nasopharyngeal carcinoma (NPC), and investigate whether PD-L1 and MMR status could be used as a biomarker for predicting response of immune checkpoint blockades (ICBs) treatment. Patients and methods A total of 108 patients were initially histopathologically diagnosed with NPC between December 2017 and September 2018. All tissue specimens were collected before any treatment. Tumor tissue MMR status was determined by both immunohistochemistry and PCR. The expression of PD-L1 in NPC tissue was analyzed immunohistochemically. High PD-L1 expression in tumor cells (TC) or tumor-infiltrating immune cells (TIIC) was defined as ≥50% of corresponding cells with membranous staining. Results Tissue samples were obtained from 102 patients after written informed consent was obtained. Seventy-one (69.6%) patients were treated in our hospital after diagnosis. Disease in stages I–III accounted for 35 (49.3%) cases, while stage IVa–IVb was identified in 36 (50.7%) cases. Only two of 102 patients were identified as MMR-deficient (dMMR) by IHC and PCR. High PD-L1 expression in TC was confirmed in 77 of the 102 (75.5%) NPC cases, while only 13 of the 102 (12.7%) NPC cases were considered to exhibit high PD-L1 expression in TIIC. PD-L1 expression in TC was positively correlated with T stage ( P =0.033), while PD-L1 expression in TIIC was negatively associated with plasma Epstein–Barr virus DNA load ( P =0.021), N stage ( P =0.009), M stage ( P =0.014), and clinical stage ( P =0.001). Conclusion dMMR is a rare event in NPC and may not be a prospective biomarker to predict the effectiveness of treatment with ICBs in clinical practice. It was also determined that high PD-L1 expression in NPC is quite common and the importance of distinguishing PD-L1 expression in TC and TIIC was highlighted.

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Section: Discussionmentioning

confidence: 99%

<p>Mismatch repair status and high expression of PD-L1 in nasopharyngeal carcinoma</p>

Zhao¹,

Liao²,

Guan³

et al. 2019

CMAR

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“…Although a recent study from Pakistan identified 7 of 100 patients with CRC with a null phenotype, similar findings in a large series have not been reported in Western populations 5. To our knowledge, only two other single case reports have detailed loss of expression of all four MMR proteins; one in a sporadic CRC and the other in a LS-associated CRC 6 7…”

Section: Discussionmentioning

confidence: 76%

Additional loss of MSH2 and MSH6 expression in sporadic deficient mismatch repair colorectal cancer due to MLH1 promoter hypermethylation

et al. 2019

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Colorectal cancer (CRC) is common with 3% of cases associated with germline mutations in the mismatch repair pathway characteristic of Lynch syndrome (LS). The UK National Institute for Health and Care Excellence recommends screening for LS in all patients newly diagnosed with CRC, irrespective of age. The Yorkshire Cancer Research Bowel Cancer Improvement Programme includes a regional LS screening service for all new diagnoses of CRC. In the first 829 cases screened, 80 cases showed deficient mismatch repair (dMMR) including four cases showing areas with loss of expression of all four mismatch repair proteins by immunohistochemistry. The cases demonstrated diffuse MLH1 loss associated with BRAF mutations and MLH1 promoter hypermethylation in keeping with sporadic dMMR, with presumed additional double hit mutations in MSH2+/−MSH6 rather than underlying LS. Recognition and accurate interpretation of this unusual phenotype is important to prevent unnecessary referrals to clinical genetics and associated patient anxiety.

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“…An article by Hashmi et al has documented isolated MLH1 loss in a cohort of patients with colorectal carcinoma. 39 In their study, they noted that the cases demonstrating isolated MLH1 loss would undergo methylation analysis and BRAF mutational assessment. The identification of any degree of nuclear staining was interpreted as positive in the present study.…”

Section: Discussionmentioning

confidence: 99%

Identification of possible Lynch syndrome in endometrial carcinomas at a public hospital in South Africa

Wadee

Grayson

2020

Southern African Journal of Gynaecological Oncology

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Endometrial carcinomas are common malignancies worldwide. Microsatellite instability is often identified in endometrioid endometrial carcinomas (EECs) and in most Lynch syndrome (LS) associated tumours. The authors aimed to identify the number of EECs at a South African public hospital, using the four-mismatch repair immunohistochemical stains, which may suggest possible LS, for the period 2009-2015. Following ethical clearance, 145 cases of archived EEC underwent immunohistochemical testing for MLH1, MSH2, MSH6 and PMS2. Cases demonstrating loss of MLH1 staining were subjected to EpiTYPER for quantitative methylation of the MLH1 promoter region using the Agena MassARRAY® platform. Forty-one (28.28%) cases showed complete loss of tumour nuclei staining for ≥ 1 immunohistochemical stains. Twenty cases (13.79%) showed loss of MLH1/PMS2, 16 cases (11.03%) demonstrated isolated MLH1 loss and one case (0.69%) showed loss of MLH1, PMS2 and MSH6. Two cases showed isolated MSH6 loss and 2 cases showed loss of MSH2 and MSH6. Thirty-seven (90.24%) of 41 mismatch repair-deficient cases showed MLH1 loss. Most (83.78%) of these showed promoter hypermethylation, suggesting a sporadic occurrence of carcinogenesis. The patients from whom the two cases with isolated MSH6 loss, two cases with MSH2/MSH6 loss, and the six cases whereby MLH1 was not explained by methylation should be identified and offered genetic counselling with a view to possible germline mutation assessment as these patients are suspected of having Lynch syndrome. Thus, this study demonstrates a possible 10/145 (6.90%) patients who may have LS and require further testing and suggests a need to screen possible LS patients in the South African population.

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Mismatch repair deficiency screening in colorectal carcinoma by a four-antibody immunohistochemical panel in Pakistani population and its correlation with histopathological parameters

Cited by 30 publications

References 26 publications

<p>Mismatch repair status and high expression of PD-L1 in nasopharyngeal carcinoma</p>

<p>Mismatch repair status and high expression of PD-L1 in nasopharyngeal carcinoma</p>

Additional loss of MSH2 and MSH6 expression in sporadic deficient mismatch repair colorectal cancer due to MLH1 promoter hypermethylation

Identification of possible Lynch syndrome in endometrial carcinomas at a public hospital in South Africa

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