EP563 Mismatch repair deficiency glands in normal endometrial tissue as a predictor of endometrial carcinoma in patients with lynch syndrome

Lof, Pien; Lok, Car; Snæbjörnsson, Pétur; McCluggage, W. Glenn; Dorpe, Jo Van; Tummers, Philippe; Vijver, K. Van de

doi:10.1136/ijgc-2019-esgo.620

Cited by 2 publications

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“…The presence of a dMMR crypt or gland is a strong predictor for a variant being pathogenic given its specificity for Lynch syndrome [24][25][26][27][28][29]. In this study, a single endometrial gland showed loss of MSH2 expression in the patient harboring the MSH2 exon 1-6 duplication (ID_058), which would support this variant being pathogenic (Table 4).…”

Section: Discussionmentioning

confidence: 54%

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DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands

Walker,

Mahmood,

Como

et al. 2023

Cancers

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Section: Discussionmentioning

confidence: 54%

“…A novel finding in Lynch syndrome has been the identification of dMMR in morphologically normal colonic crypts [24][25][26][27] or endometrial glands [28,29]. dMMR crypts/glands are specific to people with Lynch syndrome, observed only in carriers and not in people with sporadic MSI-H/dMMR tumors [27].…”

Section: Introductionmentioning

confidence: 99%

DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands

Walker,

Mahmood,

Como

et al. 2023

Cancers

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“…The other two tumors (CRC_170 and CRC_111) were MSI-H/dMMR by NGS and showed a somatic second hit in the gene with the VUS (both LOH events), which may suggest false negative MMR IHC result. The presence of a dMMR crypt or gland is a strong predictor for a variant being pathogenic given its specificity for Lynch syndrome [24][25][26][27][28][29]. In this study, a single endometrial gland showed loss of MSH2 expression in the patient harboring the MSH2 exon 1-6 duplication (ID_058) which would support this variant being pathogenic (Table 4).…”

Section: Discussionmentioning

confidence: 57%

DNA mismatch repair gene variant classification: evaluating the utility of somatic mutations and mismatch repair deficient colonic crypts and endometrial glands

Walker,

Mahmood,

Como

et al. 2023

Preprint

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Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) in the MMR genes. Twenty-eight CRC or EC tumors from 25 VUS carriers (6xMLH1, 9xMSH2, 6xMSH6, 4xPMS2), underwent targeted tumor sequencing for the presence of microsatellite instability/MMR-deficiency (MSI-H/dMMR) status and identification of a somatic MMR mutation (second hit). Immunohistochemical testing for the presence of dMMR crypts/glands in normal tissue was also performed. The ACMG/InSiGHT framework reclassified 7/25 (28%) VUS to likely pathogenic (LP), three (12%) to benign/likely benign, and 15 (60%) VUS remained unchanged. For the seven re-classified LP variants comprising nine tumors, tumor sequencing confirmed MSI-H/dMMR (8/9, 88.9%) and a second hit (7/9, 77.8%). Of these LP reclassified variants where normal tissue was available, the presence of a dMMR crypt/gland was found in 2/4 (50%). Furthermore, a dMMR endometrial gland in a carrier of anMSH2exon 1-6 duplication provided further support for upgrade of this VUS to LP. Our study confirmed that identifying these Lynch syndrome features can improve MMR variant classification, enabling optimal clinical care.Simple SummaryLynch syndrome is caused by germline pathogenic variants in the DNA mismatch repair (MMR) genes predisposing carriers to colorectal and endometrial cancer. Genetic testing for Lynch syndrome, in the form of multigene panel testing, frequently identifies variants of uncertain clinical significance (VUS). These VUS have limited clinical actionability and create uncertainty for patients and clinicians regarding their risk of cancer. In this study, we tested carriers of germline VUS for features consistent with Lynch syndrome, namely 1) tumor microsatellite instability/MMR-deficiency, 2) the presence of a somatic second hit in the MMR gene harboring the VUS by tumor sequencing and 3) the presence of MMR-deficiency in normal colonic mucosa crypts or normal endometrial glands. Our findings showed that microsatellite instability/MMR-deficiency status and somatic second hits were consistent with MMR variant classifications as determined by the ACMG/InSiGHT framework. In addition to this, the presence of MMR-deficient crypts/glands were consistent with pathogenic variant classification.

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EP563 Mismatch repair deficiency glands in normal endometrial tissue as a predictor of endometrial carcinoma in patients with lynch syndrome

Cited by 2 publications

References 0 publications

DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands

DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands

DNA mismatch repair gene variant classification: evaluating the utility of somatic mutations and mismatch repair deficient colonic crypts and endometrial glands

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