Lessons learnt from implementation of a Lynch syndrome screening program for patients with gynaecological malignancy

Najdawi, Fedaa; Crook, Ashley; Maidens, Jayne; McEvoy, Christopher R. E.; Fellowes, Andrew; Pickett, Justine; Ho, Musei; Nevell, David; McIlroy, Kirsten; Sheen, Amy; Sioson, Loretta; Ahadi, Mahsa; Turchini, John; Clarkson, Adele; Hogg, Russell; Valmadre, Sue; Gard, Greg; Dooley, S; Scott, Rodney J.; Fox, Stephen B.; Field, Michael J.; Gill, Anthony J.

doi:10.1016/j.pathol.2017.05.004

Cited by 34 publications

(32 citation statements)

References 28 publications

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“…79 In addition, MSH6 deficient EC can be microsatellite low or stable. 80 That said, IHC does enable a more targeted application of MLH1 promoter Heterogeneity: I 2 = 79%, τ 2 = 1.0813, p < 0.01 Egoavil et al 36 Frolova et al 15 Watkins et al 73 Najdawi et al 69 Backes et al 26 Buchanan et al 29 Kato et al 45 Chadwick et al 32 Goodfellow et al 40 Mills et al 53 Batte et al 14 Mas-Moya et al 17 Rubio et al 60 Hampel et al 41 Yoon et al 63 Hartnett et al 42 Dillon et al 13 Moline et al 54 Ferguson et al 37 Leenen et al 47 Lin et al 49 Rabban et al 18 Lu et al 50 hypermethylation testing, given that it need only be applied to MLH1 deficient tumors. In addition, germline analysis could be limited to the gene(s) that corresponds to the protein lost; this has potential cost saving implications.…”

Section: Discussionmentioning

confidence: 99%

“…In total, 14,770 tumors underwent tumor-based triage with IHC (n = 10,460) and/or MSI (n = 4310). Concurrent testing with both IHC and MSI was sufficiently reported in ten studies 16,27 Heterogeneity: I 2 = 85%, τ 2 = 0.2427, p < 0.01 González et al 39 Yoon et al 63 Riggi et al 58 Rubio et al 60 Ferguson et al 37 Najdawi et al 69 Long et al 67 Batte et al 14 Hartnett et al 42 Djordjevic et al 35 Backes et al 26 Watkins et al 73 Frolova et al 15 Egoavil et al 36 Mas-Moya et al 17 Bruegl et al 28 Resnick et al 57 Mills et al 53 Buchanan et al 29 Joehlin-Price et al 44 Goodfellow et al 40 Hampel et al 41 Dillon et al 13 Kato et al 45 Cossio et al 34 Woo et al 72 Lin et al 49 Pecorino et al 56 Kost et al 66 Matthews et al 51 Chu et al 68 Ring et al 71 Garg et al 38 Lu et al 50 Walsh et al 62 Rabban et al 18 Leenen et al 47 Sugawara et al 61 Tan et al 65 Moline et al 54 Lee et al 46 Berends et al 27 (n = 5594) all...…”

Section: Germline Analysismentioning

confidence: 99%

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The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis

Ryan

Glaire

Blake

et al. 2019

Genetics in Medicine

151

144

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Purpose: Endometrial cancer (EC) is often the sentinel cancer in women with Lynch syndrome (LS). However, efforts to implement universal LS screening in EC patients have been hampered by a lack of evidence detailing the proportion of EC patients that would be expected to screen positive for LS. Methods: Studies were identified by electronic searches of Medline, Embase, Cochrane CENTRAL and Web of Science. Proportions of test positivity were calculated by random and fixedeffects meta-analysis models. I 2 score was used to assess heterogeneity across studies. Results: Fifty-three studies, including 12,633 EC patients, met the inclusion criteria. The overall proportion of endometrial tumors with microsatellite instability or mismatch repair (MMR) deficiency by immunohistochemistry (IHC) was 0.27 (95% confidence interval [CI] 0.25-0.28, I 2 : 71%) and 0.26 (95% CI 0.25-0.27, I 2 : 88%), respectively. Of those women with abnormal tumor testing, 0.29 (95% CI 0.25-0.33, I 2 : 83%) had LS-associated pathogenic variants on germline testing; therefore around 3% of ECs can be attributed to LS. Preselection of EC cases did increase the proportion of germline LS diagnoses. Conclusion: The current study suggests that prevalence of LS in EC patients is approximately 3%, similar to that of colorectal cancer patients; therefore our data support the implementation of universal EC screening for LS.

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Section: Discussionmentioning

confidence: 99%

Section: Germline Analysismentioning

confidence: 99%

The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis

Ryan

Glaire

Blake

et al. 2019

Genetics in Medicine

151

144

View full text Add to dashboard Cite

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“…2,34,36 Later, universal screening using MMR IHC 7,45 and/or MSI analysis 36,46 (±age limitation) prevailed over these demographic selections. The earlier screening strategy desensitized the LS detection ratio when compared to universal screening (eg, the revised Bethesda guideline gave a rate of 0%-50% 5,7,47 and the Society of Gynecologic Oncology criteria gave a rate of 43% 15 in the setting of 100% sensitivity by universal screening). These data were compatible with the current result of no difference in the ratio of colorectal cancer cases meeting the revised Bethesda guideline among the three variant levels.…”

Section: Discussionmentioning

confidence: 99%

“…Lynch syndrome (LS; OMIM 120435) is an autosomal dominant cancer predisposition syndrome caused by germline variants in DNA mismatch repair ( MMR ) genes (eg, MLH1 , MSH2 , MSH6 , and PMS2 ). It accounts for 1%‐4% of colorectal cancer (CRC) and for 2%‐6% of endometrial cancers (EC) . Variant carriers are at risk of early onset CRC, EC, upper tract urothelial cancers, gastric cancer (particularly in Asian countries, such as Japan and Korea) and a spectrum of other tumors …”

Section: Introductionmentioning

confidence: 99%

“…It accounts for 1%-4% of colorectal cancer (CRC) [1][2][3][4] and for 2%-6% of endometrial cancers (EC). [5][6][7] Variant carriers are at risk of early onset CRC, 3,4 EC, 5,6 upper tract urothelial cancers, 8,9 gastric cancer (particularly in Asian countries, such as Japan and Korea 10 ) and a spectrum of other tumors. 11,12 The classical diagnosis of LS first lists high-risk individuals by their own cancer history and family cancer history, based on the Amsterdam II criteria 1 or revised Bethesda guidelines.…”

Section: Introductionmentioning

confidence: 99%

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Germline mismatch repair gene variants analyzed by universal sequencing in Japanese cancer patients

et al. 2019

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Background Lynch syndrome (LS) is the commonest inherited cancer syndrome caused by pathogenic variants of germline DNA mismatch repair (g.MMR) genes. Genome‐wide sequencing is now increasingly applied for tumor characterization, but not for g.MMR. The aim of this study was to evaluate the incidence and pathogenicity of g.MMR variants in Japanese cancer patients. Methods Four g.MMR genes (MLH1, MSH2, MSH6, and PMS2) were analyzed by next generation sequencing in 1058 cancer patients (614 male, 444 female; mean age 65.6 years) without past diagnosis of LS. The g.MMR variant pathogenicity was classified based on the ClinVar 2015 database. Tumor MMR immunohistochemistry, microsatellite instability (MSI), and BRAF sequencing were also investigated in specific cases. Results Overall, 46 g.MMR variants were detected in 167 (15.8%) patients, 17 likely benign variants in 119 patients, 24 variants of uncertain significance (VUSs) in 68 patients, two likely pathogenic variants in two patients, and three pathogenic variants in three (0.3%) patients. The three pathogenic variants included two colorectal cancers with MLH1 loss and high MSI and one endometrial cancer with MSH6 loss and microsatellite stability. Two likely pathogenic variants were shifted to VUSs by ClinVar (2018). One colon cancer with a likely benign variant demonstrated MLH1 loss and BRAF mutation, but other nonpathogenic variants showed sustained MMR and microsatellite stability. Conclusions Universal sequencing of g.MMR genes demonstrated sundry benign variants, but only a small proportion of cancer patients had pathogenic variants. Pathogenicity evaluation using the ClinVar database agreed with MSI, MMR immunohistochemistry, and BRAF sequencing.

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Evaluating the impact of universal Lynch syndrome screening in a publicly funded healthcare system

et al. 2020

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Purpose Referrals for Lynch syndrome (LS) assessment have traditionally been based on personal and family medical history. The introduction of universal screening practices has allowed for referrals based on immunohistochemistry tests for mismatch repair (MMR) protein expression. This study aims to characterize the effect of universal screening in a publicly funded healthcare system with comparison to patients referred by traditional criteria, from January 2012 to March 2017. Methods Patient files from the time of initiation of universal screening from 2012 to 2017 were reviewed. Patients were sorted into two groups: (a) universally screened and (b) referred by traditional methods. Mutation detection rates, analysis of traditional testing criteria met, and cascade carrier testing were evaluated. Results The mutation detection rate of the universal screening group was higher than the traditionally referred group (45/228 (19.7%) vs 50/390 (12.5%), P = .05), though each were able to identify unique patients. An analysis of testing criteria met by each patient showed that half of referred patients from the universal screening group could not meet any traditional testing criteria. Conclusion The implementation of universal screening in a publicly funded system will increase efficiency in detecting patients with LS. The resources available for genetic testing and counseling may be more limited in public systems, thus inclusion of secondary screening with BRAF and MLH1 promoter hypermethylation testing is key to further optimizing efficiency.

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Lessons learnt from implementation of a Lynch syndrome screening program for patients with gynaecological malignancy

Cited by 34 publications

References 28 publications

The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis

The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis

Germline mismatch repair gene variants analyzed by universal sequencing in Japanese cancer patients

Evaluating the impact of universal Lynch syndrome screening in a publicly funded healthcare system

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