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<p>Lynch syndrome is an autosomal dominant disorder caused by a heterozygous pathogenic germline variant in mismatch repair (MMR) genes including <i>MLH1</i>, <i>MSH2</i>, <i>MSH6</i>, <i>PMS2</i>, and <i>EPCAM</i>. This disease often causes a familial cluster of patients with malignant tumors. In this report, we describe a 37-year-old woman who presented with endometrioid carcinoma in the ovary and uterine corpus associated with Lynch syndrome. She carried two germline pathogenic variants, a recurrently reported <i>MLH1</i> c.2250C &gt; G (p.Tyr750*) and a previously unreported <i>MSH6</i> c.2385del (p.Ile795Metfs*15). The tumor cells showed microsatellite instability. Immunohistochemistry for the endometrial tumor showed decreased MLH1 expression, loss of PMS2 expression, retained MSH2 expression, and loss of MSH6 expression, which suggests that both variants impair each protein stability and thus cause MMR deficiency. Whether these variants were inherited from her parents or occurred de novo was unknown. The tumor cells had somatic variants <i>BRCA1</i> c.1016del and <i>BRCA2</i> c.36dupT that might be due to secondary mutation by MMR deficiency. The use of an immune checkpoint inhibitor pembrolizumab resulted in durable partial response of metastatic lung tumors. This case reminds clinicians of the rare possibility of multiple germline variants in MMR genes in individuals with Lynch syndrome.</p>

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Coexisting germline variants of MLH1 and MSH6 in a patient with Lynch syndrome who had uterine and ovarian cancer

  • 期刊论文

  • 发表日期：

    2025年3月3日

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  • Sho Umegaki,
  • Masanobu Takahashi,
  • Junko Hasegawa-Minato,
  • Maako Kawamura,
  • Sakura Taniguchi,
  • Keigo Komine,
  • Hideki Tokunaga,
  • Kota Ouchi,
  • Hiroo Imai,
  • Ken Saijo,
  • Hidekazu Shirota,
  • Fumiyoshi Fujishima,
  • Muneaki Shimada,
  • Yoko Aoki,
  • Chikashi Ishioka

摘要

Lynch syndrome is an autosomal dominant disorder caused by a heterozygous pathogenic germline variant in mismatch repair (MMR) genes including MLH1, MSH2, MSH6, PMS2, and EPCAM. This disease often causes a familial cluster of patients with malignant tumors. In this report, we describe a 37-year-old woman who presented with endometrioid carcinoma in the ovary and uterine corpus associated with Lynch syndrome. She carried two germline pathogenic variants, a recurrently reported MLH1 c.2250C > G (p.Tyr750*) and a previously unreported MSH6 c.2385del (p.Ile795Metfs*15). The tumor cells showed microsatellite instability. Immunohistochemistry for the endometrial tumor showed decreased MLH1 expression, loss of PMS2 expression, retained MSH2 expression, and loss of MSH6 expression, which suggests that both variants impair each protein stability and thus cause MMR deficiency. Whether these variants were inherited from her parents or occurred de novo was unknown. The tumor cells had somatic variants BRCA1 c.1016del and BRCA2 c.36dupT that might be due to secondary mutation by MMR deficiency. The use of an immune checkpoint inhibitor pembrolizumab resulted in durable partial response of metastatic lung tumors. This case reminds clinicians of the rare possibility of multiple germline variants in MMR genes in individuals with Lynch syndrome.