Takeshi Makabe1, Wataru Yamagami2, Akira Hirasawa3, Izumi Miyabe4, Tomokazu Wakatsuki4, Mari Kikuchi4, Akemi Takahashi4, Junko Noda4, Go Yamamoto4, Daisuke Aoki1, Kiwamu Akagi4. 1. Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, 160-8582, Japan. 2. Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, 160-8582, Japan. gami@z8.keio.jp. 3. Department of Clinical Genomic Medicine, Okayama University, Okayama, 700-8530, Japan. 4. Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, 362-0806, Japan.
Abstract
[Objective] Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by a germline pathogenic variant in DNA mismatch repair (MMR) genes. Endometrial cancer frequently precedes another LS-associated tumor. This study aimed to clarify the incidence and features of LS in young Japanese endometrial cancer patients.[Methods] Sixty-five patients aged 40 years or younger, who were diagnosed with endometrial cancer, were enrolled in this study. Targeted sequencing of a hereditary colorectal cancer-related gene panel including the MMR genes MLH1, MSH2, MSH6, and PMS2 was conducted on DNA samples extracted from blood cells. [Results] Overall, 6 missense variants (2 in MSH2, 2 in MSH6, and 2 in PMS2), 1 inframe deletion variant in MSH2, 1 splice variant in MSH2, and 1 two-base substitution in the 3' untranslated region in MLH1 were detected in 9 (13.8%) patients. Among these, the splice variant c.1276G > T (p.Ile411_Gly426del16) in MSH2 was annotated as pathogenic, while other variants were of uncertain significance. The patient with the pathogenic variant had a family history of endometrial and colorectal cancer and was diagnosed with endometrial cancer at age 35. [Conclusion] The incidence of LS among Japanese endometrial cancer patients of reproductive age (≤ 40 years) in this study was at least 1.5%; however, 12.3% of patients had variants of uncertain significance in MMR genes.
[Objective] Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by a germline pathogenic variant in DNA mismatch repair (MMR) genes. Endometrial cancer frequently precedes another LS-associated tumor. This study aimed to clarify the incidence and features of LS in young Japanese endometrial cancer patients.[Methods] Sixty-five patients aged 40 years or younger, who were diagnosed with endometrial cancer, were enrolled in this study. Targeted sequencing of a hereditary colorectal cancer-related gene panel including the MMR genes MLH1, MSH2, MSH6, and PMS2 was conducted on DNA samples extracted from blood cells. [Results] Overall, 6 missense variants (2 in MSH2, 2 in MSH6, and 2 in PMS2), 1 inframe deletion variant in MSH2, 1 splice variant in MSH2, and 1 two-base substitution in the 3' untranslated region in MLH1 were detected in 9 (13.8%) patients. Among these, the splice variant c.1276G > T (p.Ile411_Gly426del16) in MSH2 was annotated as pathogenic, while other variants were of uncertain significance. The patient with the pathogenic variant had a family history of endometrial and colorectal cancer and was diagnosed with endometrial cancer at age 35. [Conclusion] The incidence of LS among Japanese endometrial cancer patients of reproductive age (≤ 40 years) in this study was at least 1.5%; however, 12.3% of patients had variants of uncertain significance in MMR genes.
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