Prevalence of somatic mutl homolog 1 promoter hypermethylation in Lynch syndrome colorectal cancer. Issue 9 (29th December 2014)

• Record Type: Journal Article
• Authors: Moreira, Leticia; Muñoz, Jenifer; Cuatrecasas, Míriam; Quintanilla, Isabel; Leoz, Maria Liz; Carballal, Sabela; Ocaña, Teresa; López‐Cerón, María; Pellise, Maria; Castellví‐Bel, Sergi; Jover, Rodrigo; Andreu, Montserrat; Carracedo, Angel; Xicola, Rosa Maria; Llor, Xavier; Boland, Clement Richard; Goel, Ajay; Castells, Antoni; Balaguer, Francesc
• Is Part Of: Cancer. Volume 121:Issue 9(2015)
• Page Start: 1395
• Page End: 1404
• Publication Date: 2014-12-29
• Subjects: Cancer -- Periodicals; Cancer -- Cytopathology -- Periodicals; 616.99405
• DOI: 10.1002/cncr.29190
• Languages: English
• ISSNs: 0008-543X

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="cncr29190-sec-0001" sec-type="section"> <title>BACKGROUND</title> <p>Colorectal cancers (CRCs) that have microsatellite instability (MSI) and mutL homolog 1 (<italic>MLH1</italic>) 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 (<italic>BRAF</italic>) mutational analysis is used to differentiate LS from sporadic MSI CRC. The role of <italic>MLH1</italic> promoter methylation status for the differential diagnosis of these clinical forms is not well established. The objectives of this study were: 1) to analyze <italic>MLH1</italic> promoter methylation in <italic>MLH1</italic>‐deficient CRCs by pyrosequencing, and 2) to assess its role in the differential diagnosis of <italic>MLH1</italic>‐deficient CRCs.</p> </sec> <sec id="cncr29190-sec-0002" sec-type="section"> <title>METHODS</title> <p>In total, 165 CRCs were analyzed, including LS (n = 19), MSI <italic>BRAF</italic>‐mutated CRC (n = 37), MSI <italic>BRAF</italic> wild‐type CRC (n = 60), and a control group of CRCs without MSI (microsatellite stable [MSS] CRC; n = 49). <italic>MLH1</italic> promoter methylation status was analyzed by pyrosequencing, and the ability of different strategies to identify LS was assessed.</p> </sec> <sec id="cncr29190-sec-0003" sec-type="section"> <title>RESULTS</title> <p>The average ± standard deviation methylation in LS (9% ± 7%) was significantly lower than that in MSI <italic>BRAF</italic>‐mutated CRC (42% ± 17%; <italic>P</italic> < .001) and in MSI <italic>BRAF</italic> wild‐type CRC (25% ± 19%; <italic>P</italic> = .002). Somatic <italic>MLH1</italic> hypermethylation was detected in 3 patients (15.8%) with LS, in 34 patients (91.9%) with MSI <italic>BRAF</italic>‐mutated CRC, and in 37 patients (61.7%) with MSI <italic>BRAF</italic> wild‐type tumors. Patients with MSI <italic>BRAF</italic> wild‐type, unmethylated tumors (ie, LLS) had a stronger family history of CRC than those who had tumors with <italic>MLH1</italic> methylation (<italic>P</italic> < .05). The sensitivity for ruling out LS was 100% for <italic>BRAF</italic> analysis, 84.2% for <italic>MLH1</italic> methylation analysis, and 84.2% for the combination of both analyses.</p> </sec> <sec id="cncr29190-sec-0004" sec-type="section"> <title>CONCLUSIONS</title> <p>Somatic <italic>MLH1</italic> promoter methylation occurs in up to 15% of LS CRCs. Somatic <italic>BRAF</italic> analysis is the most sensitive strategy for ruling out LS. Patients who have CRCs with loss of MLH1 protein expression and neither <italic>BRAF</italic> mutation nor <italic>MLH1</italic> methylation resemble patients with LS. <bold><italic>Cancer</italic> 2015;121:1395–1404.</bold> © <italic>2014 American Cancer Society</italic>.</p> </sec> </abstract>