The Intersection of Lynch Syndrome and Hematological Malignancies: A Rare Short Report

Abstract

Lynch syndrome (LS), which is an autosomal dominant disorder caused primarily by germline pathogenic variants of mismatch repair (MMR) genes, cases a number of malignancies. Hematologic malignancies are not included as related tumors of LS because it has not yet been established whether the carcinogenesis of hematologic malignancies is associated with MMR genes. A 75-year-old woman was admitted to our hospital with acute myeloid leukemia (AML) that had progressed from myelodysplastic syndrome (MDS). She had a history of multiple myeloma (MM) and multiple tumors associated with LS. Genetic testing revealed extensive homozygous deletions ranging from Exon 9 of EPCAM to Exons 1-6 of MSH2. Finally, we diagnosed her with LS. It revealed that the MSH2 homo-deletion occurred in myeloid cells after the onset of MM. Immunohistochemistry for MMR proteins on bone marrow specimens at MDS showed the loss of staining for the MSH2 and MSH6 proteins in myeloid cells. However, microsatellite instability was negative in spite of the large homozygous deletion of MSH2. It remains unclear whether the homo-deletion of MSH2 is involved in the development of MDS/AML. Future studies are warranted to confirm the impact of MMR variants on the pathogenesis/chemoresistance of myeloid neoplasms. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

FIGURE 1

Pedigree chart. The case is indicated with II‐8. A large number of family members succumbed to young‐onset colorectal cancer or brain tumors. Her niece (III‐11) was diagnosed with LS.

FIGURE 2

(a) Genetic test results of the patient at MM and AML (MLPA). An extensive deletion ranging from exon 9 of EPCAM to exons 1–6 of MSH2 was heterozygous at MM (the top). The deletion then changed to homozygous at AML (the bottom). (b) Results of target sequencing at MM and MDS (CN analysis). No CN abnormality in chromosome 2 was observed at MM (top). However, a CN abnormality in the short arm region of chromosome 2 (including EPCAM and MSH2) was not noted at MDS, where an allele imbalance was detected, suggesting uniparental disomy (bottom). (c) Genetic test results of the niece (MLPA, middle). Heterozygous deletions were noted at exon 9 of EPCAM and exons 1–6 of MSH2, which confirmed the diagnosis of LS. The deletion range was exactly the same as that of the patient. AML, acute myeloid leukemia; CN, copy number; LS, Lynch syndrome; MLPA, multiplex‐ligation dependent probe amplification; MM, multiple myeloma.