A potpourri of pathogenetic pathways in endometrial carcinoma with a focus on Lynch Syndrome

Wadee, Reubina; Grayson, Wayne

doi:10.1016/j.anndiagpath.2019.02.003

Cited by 9 publications

(16 citation statements)

References 79 publications

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“…49 In addition, with the option of targeted therapy being available, the presence of mismatch-repair mutations allows for consideration of use of an antibody directed against programmed cell death (PD-1), which has shown favourable results. 11,50…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10][11] Most cases of microsatellite instability are due to alterations in expression of proteins of the DNA mismatch-repair system; namely MLH1, MSH2, MSH6 and PMS2. 11,12 It may be common practice to screen endometrial cancers for loss of these proteins to detect mutations associated with Lynch syndrome, or to determine if a patient is eligible for targeted immunotherapy with pembrolizumab, an anti-PD-1 agent, in some countries. [13][14][15][16] This is not the case in South Africa.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…A case was identified as microsatellite unstable by PCR if one or more markers showed a difference in the size of the alleles [20]. A case was classified as MSI-H (microsatel-lite instability-high) if two or more markers showed dissimilarity in allele size, MSI-L (microsatellite instability-low) if one marker showed difference in allele size, and microsatellite stable (MSS) if none of the markers showed a difference in allele size [12]. The PCR markers used were NR-21, NR-24, NR-27, BAT-25 and BAT-26 [20].…”

Section: Methodsmentioning

confidence: 99%

“…A genomic analysis performed by The Cancer Genome Atlas Research Network (TCGA) classified endometrial cancers into four molecular groups: copy-number low, copynumber high, POLE ultramutated and microsatellite instability hypermutated [11]. Microsatellite instability (MSI) is one of the genetic abnormalities underlying endometrial carcinoma, especially endometrioid endometrial carcinoma and is associated with inherited and sporadic endometrial carcinomas [12,13]. It has been demonstrated that patients with POLE mutations have the best prognosis of the four categories, while those with MSI and copy-number low mutations have an intermediate prognosis and patients with p53 and copy-number high mutations have the poorest outcomes [11,14].…”

Section: Introductionmentioning

confidence: 99%

“…It has been demonstrated that patients with POLE mutations have the best prognosis of the four categories, while those with MSI and copy-number low mutations have an intermediate prognosis and patients with p53 and copy-number high mutations have the poorest outcomes [11,14]. MSI is present in up to 90% of endometrial carcinomas associated with the heritable Lynch syndrome and in approximately 30% of sporadic endometrial carcinomas [12]. Sporadic endometrial carcinomas are secondary to MLH1 promoter methylation via epigenetic silencing [13,15].…”

Section: Introductionmentioning

confidence: 99%

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An observational study of synchronous/metachronous tumours in microsatellite unstable/mismatch repair deficient endometrial carcinomas

Kotzé¹,

Wadee²

2021

EJGO

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Microsatellite instability (MSI) is one of the genetic abnormalities underlying endometrial carcinoma, especially endometrioid endometrial carcinoma (EEC). Microsatellite unstable endometrial carcinomas may be associated with multiple primary malignancies. We aimed to document the incidence and type of associated tumours in MSI/mismatch repair deficient (MMR-d) endometrial carcinomas at a single institution in South Africa. Methods: The study assessed EECs for the period 2009-2015 at a Johannesburg hospital and followed on previous research undertaken in our department in which 66/145 MSI/MMR-d EECs were identified using immunohistochemistry and polymerase chain reaction (PCR). After ethical clearance was granted, using the microsatellite unstable/MMR-d endometrial carcinoma case-specific laboratory reference numbers, a retrospective search and cross-reference for associated histologically proven tumours, was performed. Results: Three patients (4.5%) out of 66 confirmed MSI/MMR-d endometrial carcinoma cases had associated tumours, including an invasive squamous cell carcinoma of the cervix and mucinous breast carcinoma. One patient had two tumours, namely uterine leiomyosarcoma and rectal adenocarcinoma. The incidence of EEC patients with an associated tumour is significantly lower (p = 0.0045) than that documented in the United States of America (USA). Conclusion: Our study's incidence of associated tumours in MSI/MMR-d endometrial carcinoma patients was significantly lower than studies from the USA. The associated tumours in our study included traditional Lynch syndrome tumours such as colonic adenocarcinoma and demonstrated less commonly associated tumours, namely cervical carcinoma and uterine leiomyosarcoma. These findings highlight the need for further research in our population to assess risk factors and the true incidence of Lynch syndrome-associated tumours.

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Diffusion kurtosis imaging with multiple quantitative parameters for predicting microsatellite instability status of endometrial carcinoma

Song,

Dong,

Tian

et al. 2023

Abdom Radiol

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A potpourri of pathogenetic pathways in endometrial carcinoma with a focus on Lynch Syndrome

Cited by 9 publications

References 79 publications

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

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

An observational study of synchronous/metachronous tumours in microsatellite unstable/mismatch repair deficient endometrial carcinomas

Diffusion kurtosis imaging with multiple quantitative parameters for predicting microsatellite instability status of endometrial carcinoma

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