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Review
. 2018 May 21;18(1):576.
doi: 10.1186/s12885-018-4489-0.

Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review

Takanori Yokoyama  1 , Kazuhiro Takehara  2 , Nao Sugimoto  3 , Keika Kaneko  3 , Etsuko Fujimoto  2 , Mika Okazawa-Sakai  2 , Shinichi Okame  2 , Yuko Shiroyama  2 , Takashi Yokoyama  2 , Norihiro Teramoto  4 , Shozo Ohsumi  3 , Shinya Saito  5 , Kazuho Imai  5 , Kokichi Sugano  5
Affiliations
Review

Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review

Takanori Yokoyama et al. BMC Cancer. .

Abstract

Background: Lynch syndrome is an autosomal dominant inherited disease caused by germline mutations in mismatch repair genes. Analysis for microsatellite instability (MSI) and immunohistochemistry (IHC) of protein expressions of disease-associated genes is used to screen for Lynch syndrome in endometrial cancer patients. When losses of both MLH1 and PMS2 proteins are observed by IHC, MLH1 promoter methylation analysis is conducted to distinguish Lynch syndrome-associated endometrial cancer from sporadic cancer.

Case presentation: Here we report a woman who developed endometrial cancer at the age of 49 years. She had a family history of colorectal cancer (first-degree relative aged 52 years) and stomach cancer (second-degree relative with the age of onset unknown). No other family history was present, and she failed to meet the Amsterdam II criteria for the diagnosis of Lynch syndrome. Losses of MLH1 and PMS2, but not MSH2 and MSH6, proteins were observed by IHC in endometrial cancer tissues. Because MLH1 promoter hypermethylation was detected in endometrial cancer tissue samples, the epigenetic silencing of MLH1 was suspected as the cause of the protein loss. However, because of the early onset of endometrial cancer and the positive family history, a diagnosis of Lynch syndrome was also suspected. Therefore, we provided her with genetic counseling. After obtaining her consent, MLH1 promoter methylation testing and genetic testing of peripheral blood were performed. MLH1 promoter methylation was not observed in peripheral blood. However, genetic testing revealed a large deletion of exon 5 in MLH1; thus, we diagnosed the presence of Lynch syndrome.

Conclusions: Both MLH1 germline mutation and MLH1 promoter hypermethylation may be observed in endometrial cancer. Therefore, even if MLH1 promoter hypermethylation is detected, a diagnosis of Lynch syndrome cannot be excluded.

Keywords: Endometrial cancer; Lynch syndrome; MLH1 germline mutation; MLH1 promoter hypermethylation; Screening.

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Conflict of interest statement

Ethics approval and consent to participate

This study has been approved by the ethical review board of Shikoku Cancer Center.

Consent for publication

Written informed consent to publish the data was obtained from the patients.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
Immunohistochemistry. Losses of MLH1 and PMS2 proteins were detected in the tumor cells. Expressions of MSH2 and MSH6 proteins were detected in the tumor cells. Expressions of MLH1, PMS2, MSH2, MSH6 proteins were detected in the lymphocytes
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