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Prevalence of somatic mutl homolog 1 promoter hypermethylation in Lynch syndrome colorectal cancer.
Cancer. 2015 May 01; 121(9):1395-404.C

Abstract

BACKGROUND

Colorectal cancers (CRCs) that have microsatellite instability (MSI) and mutL homolog 1 (MLH1) immunoloss are observed in 3 clinical scenarios: Lynch syndrome (LS), sporadic MSI CRC, and Lynch-like syndrome (LLS). v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational analysis is used to differentiate LS from sporadic MSI CRC. The role of MLH1 promoter methylation status for the differential diagnosis of these clinical forms is not well established. The objectives of this study were: 1) to analyze MLH1 promoter methylation in MLH1-deficient CRCs by pyrosequencing, and 2) to assess its role in the differential diagnosis of MLH1-deficient CRCs.

METHODS

In total, 165 CRCs were analyzed, including LS (n = 19), MSI BRAF-mutated CRC (n = 37), MSI BRAF wild-type CRC (n = 60), and a control group of CRCs without MSI (microsatellite stable [MSS] CRC; n = 49). MLH1 promoter methylation status was analyzed by pyrosequencing, and the ability of different strategies to identify LS was assessed.

RESULTS

The average ± standard deviation methylation in LS (9% ± 7%) was significantly lower than that in MSI BRAF-mutated CRC (42% ± 17%; P < .001) and in MSI BRAF wild-type CRC (25% ± 19%; P = .002). Somatic MLH1 hypermethylation was detected in 3 patients (15.8%) with LS, in 34 patients (91.9%) with MSI BRAF-mutated CRC, and in 37 patients (61.7%) with MSI BRAF wild-type tumors. Patients with MSI BRAF wild-type, unmethylated tumors (ie, LLS) had a stronger family history of CRC than those who had tumors with MLH1 methylation (P < .05). The sensitivity for ruling out LS was 100% for BRAF analysis, 84.2% for MLH1 methylation analysis, and 84.2% for the combination of both analyses.

CONCLUSIONS

Somatic MLH1 promoter methylation occurs in up to 15% of LS CRCs. Somatic BRAF analysis is the most sensitive strategy for ruling out LS. Patients who have CRCs with loss of MLH1 protein expression and neither BRAF mutation nor MLH1 methylation resemble patients with LS.

Authors+Show Affiliations

Department of Gastroenterology, Barcelona Hospital Clinic, Networked Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Catalonia, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25557234

Citation

Moreira, Leticia, et al. "Prevalence of Somatic Mutl Homolog 1 Promoter Hypermethylation in Lynch Syndrome Colorectal Cancer." Cancer, vol. 121, no. 9, 2015, pp. 1395-404.
Moreira L, Muñoz J, Cuatrecasas M, et al. Prevalence of somatic mutl homolog 1 promoter hypermethylation in Lynch syndrome colorectal cancer. Cancer. 2015;121(9):1395-404.
Moreira, L., Muñoz, J., Cuatrecasas, M., Quintanilla, I., Leoz, M. L., Carballal, S., Ocaña, T., López-Cerón, M., Pellise, M., Castellví-Bel, S., Jover, R., Andreu, M., Carracedo, A., Xicola, R. M., Llor, X., Boland, C. R., Goel, A., Castells, A., & Balaguer, F. (2015). Prevalence of somatic mutl homolog 1 promoter hypermethylation in Lynch syndrome colorectal cancer. Cancer, 121(9), 1395-404. https://doi.org/10.1002/cncr.29190
Moreira L, et al. Prevalence of Somatic Mutl Homolog 1 Promoter Hypermethylation in Lynch Syndrome Colorectal Cancer. Cancer. 2015 May 1;121(9):1395-404. PubMed PMID: 25557234.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prevalence of somatic mutl homolog 1 promoter hypermethylation in Lynch syndrome colorectal cancer. AU - Moreira,Leticia, AU - Muñoz,Jenifer, AU - Cuatrecasas,Míriam, AU - Quintanilla,Isabel, AU - Leoz,Maria Liz, AU - Carballal,Sabela, AU - Ocaña,Teresa, AU - López-Cerón,María, AU - Pellise,Maria, AU - Castellví-Bel,Sergi, AU - Jover,Rodrigo, AU - Andreu,Montserrat, AU - Carracedo,Angel, AU - Xicola,Rosa Maria, AU - Llor,Xavier, AU - Boland,Clement Richard, AU - Goel,Ajay, AU - Castells,Antoni, AU - Balaguer,Francesc, AU - ,, Y1 - 2014/12/29/ PY - 2014/07/17/received PY - 2014/10/17/revised PY - 2014/11/07/accepted PY - 2015/1/6/entrez PY - 2015/1/6/pubmed PY - 2015/6/27/medline KW - CpG island methylator phenotype KW - Lynch syndrome KW - colorectal cancer KW - methylation KW - microsatellite instability KW - mutL homolog 1 KW - v-Raf murine sarcoma viral oncogene homolog B1 SP - 1395 EP - 404 JF - Cancer JO - Cancer VL - 121 IS - 9 N2 - BACKGROUND: Colorectal cancers (CRCs) that have microsatellite instability (MSI) and mutL homolog 1 (MLH1) immunoloss are observed in 3 clinical scenarios: Lynch syndrome (LS), sporadic MSI CRC, and Lynch-like syndrome (LLS). v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational analysis is used to differentiate LS from sporadic MSI CRC. The role of MLH1 promoter methylation status for the differential diagnosis of these clinical forms is not well established. The objectives of this study were: 1) to analyze MLH1 promoter methylation in MLH1-deficient CRCs by pyrosequencing, and 2) to assess its role in the differential diagnosis of MLH1-deficient CRCs. METHODS: In total, 165 CRCs were analyzed, including LS (n = 19), MSI BRAF-mutated CRC (n = 37), MSI BRAF wild-type CRC (n = 60), and a control group of CRCs without MSI (microsatellite stable [MSS] CRC; n = 49). MLH1 promoter methylation status was analyzed by pyrosequencing, and the ability of different strategies to identify LS was assessed. RESULTS: The average ± standard deviation methylation in LS (9% ± 7%) was significantly lower than that in MSI BRAF-mutated CRC (42% ± 17%; P < .001) and in MSI BRAF wild-type CRC (25% ± 19%; P = .002). Somatic MLH1 hypermethylation was detected in 3 patients (15.8%) with LS, in 34 patients (91.9%) with MSI BRAF-mutated CRC, and in 37 patients (61.7%) with MSI BRAF wild-type tumors. Patients with MSI BRAF wild-type, unmethylated tumors (ie, LLS) had a stronger family history of CRC than those who had tumors with MLH1 methylation (P < .05). The sensitivity for ruling out LS was 100% for BRAF analysis, 84.2% for MLH1 methylation analysis, and 84.2% for the combination of both analyses. CONCLUSIONS: Somatic MLH1 promoter methylation occurs in up to 15% of LS CRCs. Somatic BRAF analysis is the most sensitive strategy for ruling out LS. Patients who have CRCs with loss of MLH1 protein expression and neither BRAF mutation nor MLH1 methylation resemble patients with LS. SN - 1097-0142 UR - https://www.unboundmedicine.com/medline/citation/25557234/Prevalence_of_somatic_mutl_homolog_1_promoter_hypermethylation_in_Lynch_syndrome_colorectal_cancer_ L2 - https://doi.org/10.1002/cncr.29190 DB - PRIME DP - Unbound Medicine ER -