Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer

Hampel, Heather; Pearlman, Rachel; Beightol, Mallory; Zhao, Weiqiang; Jones, Daniel; Frankel, Wendy L.; Goodfellow, Paul J.; Yılmaz, Ahmet; Miller, Kristin S.; Bacher, Jason; Jacobson, Angela; Paskett, Electra D.; Shields, Peter G.; Goldberg, Richard M.; Chapelle, Albert de la; Shirts, Brian H.; Pritchard, Colin C.

doi:10.1001/jamaoncol.2018.0104

Cited by 144 publications

(123 citation statements)

References 36 publications

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“…These findings are in line with those reported by other studies, which found Germline testing with a multigene panel should be addressed for all early onset CRCs 46 49. Moreover, Hampel et al suggested tumour sequencing approach as a replacement for current multitest LS screening,50 but these new strategies are not widely available in Iran and are too expensive.…”

Section: Discussionsupporting

confidence: 83%

Prevalence and clinicopathological characteristics of mismatch repair-deficient colorectal carcinoma in early onset cases as compared with late-onset cases: a retrospective cross-sectional study in Northeastern Iran

et al. 2018

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ObjectivesLynch syndrome (LS), a genetically inherited autosomal disorder, increases the incidence of colorectal carcinoma (CRC). We aimed to perform a universal strategy to assess the prevalence and clinicopathological characteristics of early onset CRCs at high risk of LS versus late-onset ones in the Iranian population.SettingA local population-based study from Northeastern Iran.Participants321 consecutive CRCs and pathology specimen screened between 2013 and 2016.Primary and secondary outcome measuresRetrospectively, information regarding the clinical criteria was obtained by interviewing the patients with CRC or, their families. Pathologists tested tumours with immunohistochemistry (IHC) staining of four mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2). Tumours with absent IHC staining of MLH1 were tested for BRAF mutations to exclude sporadic CRCs. Prevalence of early onset CRCs at high risk of LS and familial CRC type X were assessed as primary and secondary outcome measures, respectively.ResultsOf 321 CRCs (13/123 (10.57%), early onset vs 21/198 (10.6%) late-onset) were detected to be MMR-deficient (dMMR). Nine early onset cases and 14 late-onset ones with a loss of MLH1 underwent testing for the BRAF mutation, none of the early onset and four (2.02%) late-onset were recognised as sporadic. The difference in the outcome of IHC-analysis between early and late-onset CRCs at high risk of LS was not statistically significant (p=0.34). Majority of the suspected LS tumours from early onset patients had arisen in distal part (8/11 (72.72%) vs 8/14 (57.14%)), all of which were occurred in the rectum or sigmoid.ConclusionClinically, these findings suggest that in case of limitation for BRAF testing, the practitioner in Iran may consider managing early onset dMMR cases like LS until access to BRAF testing becomes available to them, before germline testing to accurately diagnose LS.

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Section: Discussionsupporting

confidence: 83%

Prevalence and clinicopathological characteristics of mismatch repair-deficient colorectal carcinoma in early onset cases as compared with late-onset cases: a retrospective cross-sectional study in Northeastern Iran

et al. 2018

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“…Today, cancer genomic‐based precision medicine has led to the use of NGS for universal somatic and germline MMR sequencing for selected‐gene or genome‐wide analysis. This strategy saves the initial step of IHC screening and directly examines the genome; therefore, it may reduce costs if the charge for the genetic test decreases.…”

Section: Discussionmentioning

confidence: 99%

“…51 In tumors with repressed expression of MLH1 and PMS2, further analysis of BRAF mutation or MLH1 promoter methylation is needed to exclude somatic MLH1 alterations, 54 as in case 17 (Table 2). Today, cancer genomic-based precision medicine has led to the use of NGS for universal somatic 55 and germline 19,20 MMR sequencing for selected-gene or genome-wide analysis. This strategy saves the initial step of IHC screening and directly examines the genome; therefore, it may reduce costs if the charge for the genetic test decreases.…”

Section: Discussionmentioning

confidence: 99%

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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“…The inclusion of BRAF V600E in the smMIP-based MSI assay streamlines the LS screening pipeline, requiring only one tumour test prior to germline testing of MMR genes, equivalent to tumour-sequencing 22 . We were able to detect low variant allele frequencies in BRAF down to 1.7%, with improved sensitivity compared to HRM analysis, which has an estimated LLoD of 10% 33 .…”

Section: Discussionmentioning

confidence: 99%

“…Next generation sequencing (NGS) of tumours to diagnose MSI have been developed with sensitivities and specificities of >95% 21 . Tumour-sequencing could reduce the recommended LS screening pipeline to two steps (tumour-sequencing and germline confirmation) by simultaneous detection of MSI, BRAF V600E and MMR gene mutations 22 . Coupled tumour and germline-sequencing can also determine the somatic origin of MMR deficiency in 52% of Lynch-like tumours with double somatic MMR mutations, which may avoid unnecessary management of these CRCs as LS 23 .…”

Section: And the National Institute Of Healthmentioning

confidence: 99%

A molecular inversion probe and sequencing-based microsatellite instability assay for high throughput cancer diagnostics and Lynch syndrome screening

Gallon

Hayes

Redford

et al. 2018

Preprint

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Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer

Abstract: Up-front TS in CRC is simpler and has superior sensitivity to current multitest approaches to LS screening, while simultaneously providing critical information for treatment selection.

Cited by 144 publications

References 36 publications

Prevalence and clinicopathological characteristics of mismatch repair-deficient colorectal carcinoma in early onset cases as compared with late-onset cases: a retrospective cross-sectional study in Northeastern Iran

Prevalence and clinicopathological characteristics of mismatch repair-deficient colorectal carcinoma in early onset cases as compared with late-onset cases: a retrospective cross-sectional study in Northeastern Iran

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

A molecular inversion probe and sequencing-based microsatellite instability assay for high throughput cancer diagnostics and Lynch syndrome screening

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