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

• Published in: BMC cancer Vol. 18; no. 1; p. 576
• Main Authors: Yokoyama, Takanori, Takehara, Kazuhiro, Sugimoto, Nao, Kaneko, Keika, Fujimoto, Etsuko, Okazawa-Sakai, Mika, Okame, Shinichi, Shiroyama, Yuko, Yokoyama, Takashi, Teramoto, Norihiro, Ohsumi, Shozo, Saito, Shinya, Imai, Kazuho, Sugano, Kokichi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 21-05-2018; BioMed Central; BMC
• Subjects: Age; Cancer patients; Cancer screening; Care and treatment; Case Report; Case reports; Colorectal cancer; Colorectal carcinoma; Diagnosis; DNA methylation; DNA Methylation - genetics; Endometrial cancer; Endometrial Neoplasms - diagnosis; Endometrial Neoplasms - genetics; Endometrial Neoplasms - pathology; Endometrial Neoplasms - surgery; Endometrium; Endometrium - pathology; Epigenetics; Family medical history; Female; Gastric cancer; Gene expression; Genes; Genetic aspects; Genetic Counseling; Genetic disorders; Genetic screening; Germ-Line Mutation; Health aspects; Health risk assessment; Humans; Hysterectomy; Immunohistochemistry; Literature reviews; Lynch syndrome; Lynch Syndrome II - diagnosis; Lynch Syndrome II - genetics; Microsatellite Instability; Middle Aged; Mismatch repair; MLH1 germline mutation; MLH1 promoter hypermethylation; MLH1 protein; MSH2 protein; MSH6 protein; Mutation; MutL Protein Homolog 1 - genetics; Oncology; Patients; Peripheral blood; Promoter Regions, Genetic - genetics; Proteins; Salpingo-oophorectomy; Screening; Stomach; Uterine cancer; Screening; Endometrial cancer; MLH1 germline mutation; MLH1 promoter hypermethylation; Lynch syndrome
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-018-4489-0

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.
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.
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.