Ann Surg Treat Res.  2014 Sep;87(3):123-130. 10.4174/astr.2014.87.3.123.

hMLH1 promoter methylation and BRAF mutations in high-frequency microsatellite instability colorectal cancers not fulfilling the revised Bethesda guidelines

• Kim SJ
• Kim HR
• Kim SH
• Han JH
• Cho YB
• Yun SH
• Lee WY
• Kim HC

• KMID: 1908482
• DOI: http://doi.org/10.4174/astr.2014.87.3.123

Abstract

PURPOSE
Sporadic colorectal cancers with high-frequency microsatellite instability (MSI-H) are related to hypermethylation of mismatch repair (MMR) genes and a higher frequency of BRAF mutations than Lynch syndrome. We estimated the feasibility of hereditary colorectal cancer based on hMLH1 methylation and BRAF mutations.
METHODS
Between May 2005 and June 2011, we enrolled all 33 analyzed patients with MSI-H cancer (male:female, 23:10; mean age, 65.5 +/- 9.4 years) from a prospectively maintained database that didn't match Bethesda guidelines and who had results of hMLH1 methylation and BRAF mutations.
RESULTS
Among the 33 patients, hMLH1 promoter methylation was observed in 36.4% (n = 12), and was not significantly related with clinicopathologic variables, including MLH1 expression. BRAF mutations were observed in 33.3% of the patients (n = 11). Four of 11 and five of 22 patients with MSI-H colon cancers were BRAF mutation (+)/hMLH1 promoter methylation (-) or BRAF mutation (-)/hMLH1 promoter methylation (+). Of the 33 patients, 21.2% were BRAF mutation (+)/hMLH1 promoter methylation (+), indicating sporadic cancers. Seventeen patients (51.5%) were BRAF mutation (-)/hMLH1 promoter methylation (-), and suggested Lynch syndrome.
CONCLUSION
Patients with MSI-H colorectal cancers not fulfilling the Bethesda guidelines possibly have hereditary colorectal cancers. Adding tests of hMLH1 promoter methylation and BRAF mutations can be useful to distinguish them from sporadic colorectal cancers.

Keyword

Colorectal neoplasms; hMLH1; BRAF; Hereditary colorectal cancer

MeSH Terms

Colonic Neoplasms
Colorectal Neoplasms*
Colorectal Neoplasms, Hereditary Nonpolyposis
DNA Mismatch Repair
Humans
Methylation*
Microsatellite Instability*
Prospective Studies

Figure

• 

  Fig. 1 Patient distribution according to hMLH1 promoter methylation and BRAF mutations. MSI-H, high frequency microsatellite instability; BGs, Bethesda guidelines.

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