Universal screening of both endometrial and colon cancers increases the detection of Lynch syndrome

Adar, Tomer; Rodgers, Linda; Shannon, Kristen M.; Yoshida, Makoto; Ma, Tao; Mattia, Anthony R.; Lauwers, Gregory Y.; Iafrate, A. John; Hartford, Nicole M.; Oliva, Esther; Chung, Daniel C.

doi:10.1002/cncr.31534

Cited by 79 publications

(65 citation statements)

References 31 publications

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“…Conversely, no PVs in any of the MMR genes were identified in patients with clinically suspected‐HNPCC and exhibiting MMR proficiency. Interestingly, the majority of the 50 MMR gene mutation carriers identified were MSH6 compared to MLH1 or MSH2 (23 vs .14 and 13, respectively), reflecting that the historical distribution of PVs has been probably driven by clinical criteria for testing . Special interest deserves the finding of four patients with young‐onset CRC and PVs in CHEK2 or ATM among the suspected‐HNPCC group with MMR proficiency.…”

Section: Discussionmentioning

confidence: 99%

Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels

Feliubadaló

López‐Fernández

Pineda

et al. 2019

Intl Journal of Cancer

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Multigene panels provide a powerful tool for analyzing several genes simultaneously. We evaluated the frequency of pathogenic variants (PV) in customized predefined panels according to clinical suspicion by phenotype and compared it to the yield obtained in the analysis of our clinical research gene panel. We also investigated mutational yield of opportunistic testing of BRCA1/2 and mismatch repair (MMR) genes in all patients. A total of 1,205 unrelated probands with clinical suspicion of hereditary cancer were screened for germline mutations using panel testing. Overall, 1,048 females and 157 males were analyzed, mean age at cancer diagnosis was 48; 883 had hereditary breast/ovarian cancer‐suspicion, 205 hereditary nonpolyposis colorectal cancer (HNPCC)‐suspicion, 73 adenomatous‐polyposis‐suspicion and 44 with other/multiple clinical criteria. At least one PV was found in 150 probands (12%) analyzed by our customized phenotype‐driven panel. Tumoral MMR deficiency predicted for the presence of germline MMR gene mutations in patients with HNPCC‐suspicion (46/136 vs. 0/56 in patients with and without MMR deficiency, respectively). Opportunistic testing additionally identified five MSH6, one BRCA1 and one BRCA2 carriers (0.6%). The analysis of the extended 24‐gene panel provided 25 additional PVs (2%), including in 4 out of 51 individuals harboring MMR‐proficient colorectal tumors (2 CHEK2 and 2 ATM). Phenotype‐based panels provide a notable rate of PVs with clinical actionability. Opportunistic testing of MMR and BRCA genes leads to a significant straightforward identification of MSH6, BRCA1 and BRCA2 mutation carriers, and endorses the model of opportunistic testing of genes with clinical utility within a standard genetic counseling framework.

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Section: Discussionmentioning

confidence: 99%

Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels

Feliubadaló

López‐Fernández

Pineda

et al. 2019

Intl Journal of Cancer

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“…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%

“…These patients are further evaluated by microsatellite instability (MSI) analysis and immunohistochemistry (IHC) of MMR proteins in their tumors, and a final diagnosis of the deleterious variant of the germline MMR (g. MMR ) genes is made by DNA sequencing . Currently, the strategy for LS detection has been shifted toward universal screening using MMR IHC and/or MSI analysis for all or for age‐limited conditions of LS‐related cancers, as this strategy is more sensitive than selection based only on demographic and clinical information . At present, genetic examination of g. MMR genes, which is essential for the diagnosis of LS, has been applied to highly suspect candidates with LS‐related cancers, but not to all cancer patients.…”

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%

“…1,2 Currently, the strategy for LS detection has been shifted toward universal screening using MMR IHC and/or MSI analysis for all or for age-limited conditions of LS-related cancers, as this strategy is more sensitive than selection based only on demographic and clinical information. 6,7,[13][14][15] At present, genetic examination of g.MMR genes, which is essential for the diagnosis of LS, has been applied to highly suspect candidates with LS-related cancers, but not to all cancer patients.…”

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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Universal screening of both endometrial and colon cancers increases the detection of Lynch syndrome

Cited by 79 publications

References 31 publications

Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels

Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels

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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