Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer

Pérez–Carbonell, Lucía; Ruíz-Ponte, Clara; Guarinós, Carla; Alenda, Cristina; Payá, Artemio; Brea, Alejandro; Egoavil, Cecilia; Castillejo, Adela; Barberá, Víctor Manuel; Bessa, Xavier; Xicola, Rosa M.; Rodríguez–Soler, María; Sánchez–Fortún, Cristina; Acame, Nuria; Castellví–Bel, Sergi; Piñol, Virgı́nia; Balaguer, Francesc; Bujanda, Luís; De-Castro, María Luisa; Llor, Xavier; Andreu, Montserrat; Carracedo, Ángel; Soto, José Luís; Castells, Antoni; Jover, Rodrigo

doi:10.1136/gutjnl-2011-300041

Cited by 166 publications

(144 citation statements)

References 57 publications

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“…This accounted for 9.9% of all MSI-H cases, with the most common germline MMR mutation noted in MSH2 (5 cases; 62.5%), followed by MLH1 mutations (2 cases; 25%); MSH6 germline mutations were found to be the least common (1 case; 12.5%). These results are in agreement with earlier studies from the United States, Finland, and Spain, [34][35][36] with the most common MMR mutation observed in MSH2. Considering that the size of the average Saudi family tends to be approximately 6 individuals compared with a family size of 3 in the West, the detection rate among relatives of a Saudi LS proband would also be higher compared with the West.…”

Section: Discussionsupporting

confidence: 93%

Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer

Siraj

Prabhakaran

Bavi

et al. 2015

Cancer

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BACKGROUND: Lynch syndrome (LS; hereditary nonpolyposis colorectal cancer) is a common cause of hereditary colorectal cancer (CRC). CRC is the most common cancer diagnosed among males in Saudi Arabia but to the authors' knowledge there is a lack of data regarding the prevalence of LS in patients with CRC. There currently are no clear guidelines for the selection criteria for these patients to screen for LS. METHODS: A comprehensive molecular characterization was performed in a cohort of 807 CRC cases by immunohistochemical and microsatellite analysis using polymerase chain reaction. BRAF mutation screening, high CpG island methylator phenotype, and analysis for germline mutations were performed in 425 CRC samples. These were all high microsatellite instability (MSI-H) samples (91 cases), all low MSI samples (143 cases), and selected cases from the microsatellite stable group (191 cases) that met revised Bethesda guidelines. RESULTS: Polymerase chain reaction identified 91 MSI-H cases (11.3%) and sequencing revealed mismatch repair germline mutations in 8 CRC cases only. Of the total of 807 CRC cases, these 8 cases (0.99%) were MSI-H, met the revised Bethesda guidelines, and did not harbor BRAF mutations. CONCLUSIONS: The results of the current study confirmed cases of LS in approximately 1.0% of CRC samples and reflects the efficacy of screening among MSI-H cases that lack BRAF mutations. This comprehensive study from Saudi Arabia will help in implementing a universal screening/reflex testing strategy in a clinical setting in Saudi Arabia and in conducting a national screening program that benefits both patients and their relatives. Cancer 2015;121:1762-71.

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Section: Discussionsupporting

confidence: 93%

Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer

Siraj

Prabhakaran

Bavi

et al. 2015

Cancer

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“…13,14 These results strongly argue in favor of a molecular approach offering microsatellite instability testing and=or immunohistochemical MMR protein expression analysis for all colorectal cancers. Such an approach would also provide valuable information for patient management, because microsatellite instability status is a prognostic factor in colorectal cancer patients and seems to be predictive of chemotherapy responsiveness.…”

Section: Cancer Geneticsmentioning

confidence: 97%

“…11,12 One important shortcoming of current procedures is the fact that selection of tumors for microsatellite instability analysis by using clinical criteria bears a high risk of missing Lynch syndrome patients who do not fulfill the clinical criteria and who are therefore excluded from further germline mutation analysis. 13,14 To avoid underdiagnosis of Lynch syndrome among colorectal cancer patients, it has been proposed to perform microsatellite instability testing in all colorectal cancers; however, this approach will increase the number of sporadic MSI-H tumors that can only be differentiated from Lynch syndrome by laborious and cost-intensive germline mutation analysis.…”

mentioning

confidence: 99%

BRAF V600E‐specific immunohistochemistry for the exclusion of Lynch syndrome in MSI‐H colorectal cancer

Capper

Voigt

Bozukova

et al. 2013

Intl Journal of Cancer

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The differentiation between hereditary and sporadic microsatellite-unstable (MSI-H) colorectal cancer is a crucial step in Lynch syndrome diagnostics. Within MSI-H colorectal cancers, the BRAF V600E mutation is strongly associated with sporadic origin. Here, we asked whether BRAF V600E-specific immunohistochemistry (clone VE1) is helpful in separating sporadic from Lynch syndrome-associated MSI-H colorectal cancers. To that end, we performed VE1 immunohistochemistry and BRAF sequencing in a series of 91 MSI-H colorectal cancer specimens from patients tested for Lynch syndrome. Concordance of VE1 immunohistochemistry and molecular BRAF mutation status was observed in 90 of 91 (98.9%) MSI-H samples. All 11 tumors classified as BRAF V600E mutation-positive by Sanger sequencing were immunopositive, and 79 (98.8%) of 80 tumors classified as BRAF wild type showed negative staining. All VE1-positive tumors were MLH1-and PMS2-negative by immunohistochemistry. None of the tumors from mismatch repair (MMR) gene germline mutation carriers (n 5 28) displayed positive VE1 staining, indicating that BRAF V600E mutation-specific immunostaining has a low risk of excluding Lynch syndrome patients from germline mutation analysis. In conclusion, implementation of VE1 immunohistochemistry was able to detect BRAF-mutated MSI-H colorectal cancers with a sensitivity of 100% and a specificity of 98.8%. Among MLH1-negative colorectal cancers, the rate of VE1-positive lesions was 21%, offering the exclusion of these patients from MMR germline testing. Therefore, we suggest the integration of VE1 immunohistochemistry into the diagnostic panel of Lynch syndrome.Lynch syndrome, which represents one of the most frequent autosomal dominantly inherited cancer syndromes, is caused by germline mutations affecting DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2, followed by MSH6 and PMS2.

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“…IHC analysis of the four mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 in tumor tissue was performed in all patients using tissue microarrays (TMAs) as described previously. 10 In patients with a loss of MLH1, methylation of MLH1 and BRAF mutation status were analyzed. MLH1 methylation analysis was performed using methylation-specific multiplex ligationdependent probe amplification (MS-MLPA) according to the manufacturer´s protocol using the SALSA MS-MLPA kit ME011 Mismatch Repair Genes (MRC-Holland, Amsterdam, the Netherlands).…”

Section: Microsatellite Instability Immunohistochemical Staining Anmentioning

confidence: 99%

“…10 Patients with loss of MSH2 expression with no detected mutation were analyzed for EPCAM rearrangements using MLPA (MRCHolland, Amsterdam, the Netherlands) according to the manufacturer's recommended protocol. DNA sequencing was performed to characterize the deletion breakpoints.…”

mentioning

confidence: 99%

Risk of Cancer in Cases of Suspected Lynch Syndrome Without Germline Mutation

et al. 2013

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Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer

Abstract: Routine molecular screening of patients with CRC for Lynch syndrome using immunohistochemistry or MSI has better sensitivity for detecting mutation carriers than the Bethesda guidelines.

Cited by 166 publications

References 57 publications

Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer

Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer

BRAF V600E‐specific immunohistochemistry for the exclusion of Lynch syndrome in MSI‐H colorectal cancer

Risk of Cancer in Cases of Suspected Lynch Syndrome Without Germline Mutation

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