scholarly journals Advances in genetic technologies result in improved diagnosis of mismatch repair deficiency in colorectal and endometrial cancers

2021 ◽  
pp. jmedgenet-2020-107542
Author(s):  
D Gareth Evans ◽  
Fiona Lalloo ◽  
Neil AJ Ryan ◽  
Naomi Bowers ◽  
Kate Green ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Genomic Medicine ◽  
Promoter Hypermethylation ◽  
Mismatch Repair Deficiency ◽  
Protein Loss ◽  
Pathogenic Variants ◽  
Repair Deficiency ◽  
Genetic Technologies ◽  
Endometrial Cancers

BackgroundTesting cancers for mismatch repair deficiency (dMMR) by immunohistochemistry (IHC) is a quick and inexpensive means of triaging individuals for germline Lynch syndrome testing. The aim of this study was to evaluate tumour dMMR and the prevalence of Lynch syndrome in patients referred to the Manchester Centre for Genomic Medicine, which serves a population of 5.6 million.MethodsTumour testing used IHC for MMR proteins with targeted BRAF and MLH1 promotor methylation testing followed by germline mutation and somatic testing as appropriate.ResultsIn total, 3694 index tumours were tested by IHC (2204 colorectal cancers (CRCs), 739 endometrial cancers (ECs) and 761 other), of which 672/3694 (18.2%) had protein loss, including 348 (9.4%) with MLH1 loss. MLH1 loss was significantly higher for 739 ECs (15%) vs 2204 CRCs (10%) (p=0.0003) and was explained entirely by higher rates of somatic MLH1 promoter hypermethylation (87% vs 41%, p<0.0001). Overall, 65/134 (48.5%) patients with MLH1 loss and no MLH1 hypermethylation or BRAF c.1799T>A had constitutional MLH1 pathogenic variants. Of 456 patients with tumours showing loss of MSH2/MSH6, 216 (47.3%) had germline pathogenic variants in either gene. Isolated PMS2 loss was most suggestive of a germline MMR variant in 19/26 (73%). Of those with no germline pathogenic variant, somatic testing identified likely causal variants in 34/48 (71%) with MLH1 loss and in MSH2/MSH6 in 40/47 (85%) with MSH2/MSH6 loss.ConclusionsReflex testing of EC/CRC leads to uncertain diagnoses in many individuals with dMMR following IHC but without germline pathogenic variants or MLH1 hypermethylation. Tumour mutation testing is effective at decreasing this by identifying somatic dMMR in >75% of cases.

scholarly journals Assessment of mismatch repair deficiency in ovarian cancer

2020 ◽  
pp. jmedgenet-2020-107270
Author(s):  
Emma J Crosbie ◽  
Neil A J Ryan ◽  
Rhona J McVey ◽  
Fiona Lalloo ◽  
Naomi Bowers ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Family History ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Genomic Medicine ◽  
Promoter Hypermethylation ◽  
Mismatch Repair Deficiency ◽  
Pathogenic Variants ◽  
Repair Deficiency ◽  
History Of

BackgroundHereditary causes of ovarian cancer include Lynch syndrome, which is due to inherited pathogenic variants affecting one of the four mismatch repair genes involved in DNA repair. The aim of this study was to evaluate tumour mismatch repair deficiency and prevalence of Lynch syndrome in high-risk women referred to the Manchester Centre for Genomic Medicine with ovarian cancer over the past 20 years.MethodsWomen with ovarian cancer diagnosed before the age of 35 years and/or with a suggestive personal or family history of Lynch syndrome cancers underwent tumour testing with immunohistochemistry for mismatch repair deficiency and, where indicated, MLH1 promoter methylation testing followed by constitutional testing for Lynch syndrome.ResultsIn total, 261 ovarian cancers were tested and 27 (10.3%; 95% CI 6.9% to 14.7%) showed mismatch repair deficiency by immunohistochemistry. Three of 7 with MLH1 loss showed MLH1 promoter hypermethylation, and 18 of the remaining 24 underwent constitutional testing for Lynch syndrome. A further 15 women with mismatch repair proficient tumours underwent constitutional testing because of a strong family history of Lynch syndrome cancers. Pathogenic variants were identified in 9/33 (27%) women who underwent constitutional testing, aged 33–59 years (median 48 years), including one whose tumour was mismatch repair proficient. Most Lynch syndrome tumours were of endometrioid histological subtype.ConclusionsTumour mismatch repair deficiency identified by immunohistochemistry is a useful prescreen for constitutional testing in women with ovarian cancer with personal or family histories suggestive of Lynch syndrome.

Tumor site discordance in mismatch repair deficiency in synchronous endometrial and ovarian cancers

2020 ◽  
Vol 30 (12) ◽  
pp. 1951-1958
Author(s):  
Soyoun Rachel Kim ◽  
Alicia Tone ◽  
Raymond Kim ◽  
Matthew Cesari ◽  
Blaise Clarke ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Ovarian Tumor ◽  
Tumor Site ◽  
Mismatch Repair Deficiency ◽  
Ovarian Cancers ◽  
Repair Deficiency ◽  
Endometrial Tumor ◽  
Germline Testing

ObjectivesFor synchronous endometrial and ovarian cancers, most centers rely on mismatch repair testing of the endometrial cancer to identify Lynch syndrome, and neglect the ovarian tumor site completely. We examined the mismatch repair immunohistochemistry and microsatellite instability results from the endometrium and ovary to assess discordance between the tumor sites and between tests.Methods30 women with newly diagnosed synchronous endometrial and ovarian cancer were prospectively recruited from three cancer centers in Ontario, Canada. Both tumor sites were assessed for mismatch repair deficiency by immunohistochemistry and microsatellite instability test; discordance in results between tumor sites and discordance between test results at each site was examined. Cases with discordant results had tumors sequenced with a targeted panel in order to reconcile the findings. All women underwent mismatch repair gene germline testing.ResultsOf 30 patients, 11 (37%) were mismatch repair deficient or microsatellite instable at either tumor site, with 5 (17%) testing positive for Lynch syndrome. Mismatch repair immunohistochemistry expression was discordant between endometrial and ovarian tumor sites in 2 of 27 patients (7%) while microsatellite instability results were discordant in 2 of 25 patients (8%). Relying on immunohistochemistry or microsatellite instability alone on the endometrial tumor would have missed one and three cases of Lynch syndrome, respectively. One patient with Lynch syndrome with a PMS2 pathogenic variant was not detected by either immunohistochemistry or microsatellite instability testing. The rate of discordance between immunohistochemistry and microsatellite instability test was 3.8% in the ovary and 12% in the endometrium.ConclusionsThere was discordance in immunohistochemistry and microsatellite instability results between tumor sites and between tests within each site. Endometrial tumor testing with mismatch repair immunohistochemistry performed well, but missed one case of Lynch syndrome. Given the high incidence of Lynch syndrome (17%), consideration may be given to germline testing in all patients with synchronous endometrial and ovarian cancers.

Constitutional mismatch repair deficiency and Lynch syndrome among consecutive Arab Bedouins with colorectal cancer in Israel

2017 ◽  
Vol 17 (1) ◽  
pp. 79-86 ◽  
Author(s):  
Naim Abu Freha ◽  
Yaara Leibovici Weissman ◽  
Alexander Fich ◽  
Inbal Barnes Kedar ◽  
Marisa Halpern ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency ◽  
Constitutional Mismatch Repair Deficiency
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